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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 c: \2 o1 a" p1 @- ` K7 bGONADOTROPIN3 w# p4 d' ~! N; T- R9 `
RICHARD C. KLUGO* AND JOSEPH C. CERNY
4 h% P0 v* Y) V0 @7 B- G: V0 uFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan) |- f/ q* G4 ^' W; `4 L
ABSTRACT* P/ s0 `# f) D* n/ u/ x1 q0 N
Five patients were treated with gonadotropin and topical testosterone for micropenis associated. i1 k i/ h1 x
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ L; b q2 H; ~, Q. u
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
z# I$ ~8 v: ]$ ]( F# o5 wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' N' Y2 Y2 @: G) M9 @ Q" d: u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ I* N" V9 S! l7 E. Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 h: `2 u7 W% {$ V4 Fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 C1 R) I- V# G' eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( F3 G( i7 u$ H5 D7 ^* u- c
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* v( C; f# x* Z8 t$ w- e# o, Kgrowth. The response appears to be greater in younger children, which is consistent with previ-6 ?5 t7 \# z# Z# a2 W
ously published studies of age-related 5 reductase activity.
: {& l1 C7 ?' Q3 d$ @% eChildren with microphallus regardless of its etiology will
. S, B p5 [* q8 Y& wrequire augmentation or consideration for alteration of exter-3 a/ Y8 ?, c! k
nal genitalia. In many instances urethroplasty for hypo-7 G; h2 x( @# ~1 I; g
spadias is easier with previous stimulation of phallic growth.+ m" n4 c' J" e4 I* q, |& u. P
The use of testosterone administered parenterally or topically; G' u, g9 M; C3 M; y4 u5 m
has produced effective phallic growth. 1- 3 The mechanism of- G: m6 `' e& ~, p
response has been considered as local or systemic. With this
. K5 e) N D4 N3 A* {/ @: `in mind we studied 5 children with microphallus for response
9 i: l/ E2 n! R* ~4 {! t# R3 Ito gonadotropin and to topical testosterone independently.
' M( O2 q0 k a h `' m/ W. w" ZMATERIALS AND METHODS
# Z7 P* q6 U# SFive 46 XY male subjects between 3 and 17 years old were
& y; s n2 k% ^' xevaluated for serum testosterone levels and hypothalamic4 p6 M& J( J3 Y. a
function. Of these 5 boys 2 were considered to have Kallmann's
( z1 o' l$ N, u% S: P* A8 w+ S0 Dsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 _& J- e" A' V1 Dlamic deficiency. After evaluation of response to luteinizing2 w+ b& ~* y6 ?% [: o
hormone-releasing hormone these patients were treated with
! Z3 n& ?; S0 w9 \1 U+ V1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 V4 b$ {9 p: X0 J
after completion of gonadotropin therapy 10 per cent topical
6 j' k- U- c% o" {- c% Itestosterone was applied to the phallus twice daily for 3 weeks.9 H2 ^+ G& D* a2 x
Serum testosterone, luteinizing hormone and follicle-stimulat-7 f! ^3 Q& @. ?
ing hormone were monitored before, during and after comple-
$ \8 ?% K- K$ `& m5 I. H( Xtion of each phase of therapy. Penile stretch length was8 \4 @8 g+ O4 j( u8 r p
obtained by measuring from the symphysis pubis to the tip of
( a6 |. `/ i" C3 C8 b# fthe glans. Penile circumferential (girth) measurements were* T \6 y1 O6 h! \ `
obtained using an orthopedic digital measuring device (see9 E4 C. k( d$ x. |
figure).* X0 |3 t3 k: q
RESULTS
) S4 n" @: V4 ^/ v% LSerum testosterone increased moderately to levels between
/ F0 O4 H, S' H50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-* T! R2 D/ D4 Q" z5 X, \( P
terone levels with topical testosterone remained near pre-9 q" C# H4 _, u) l5 Q: g5 f
treatment levels (35 ng./dl.) or were elevated to similar levels5 }: k# e: \- P% e# k
developed after gonadotropin therapy (96 ng./dl.). Higher0 |" m5 `7 e3 Y- J6 l& {
serum levels were noted in older patients (12 and 17 years old),
" X$ }$ }5 u/ S5 c* ^while lower levels persisted in younger patients (4, 8, and 10( C2 S; D& N* L8 s
years old) (see table). Despite absence of profound alterations
6 c) U# ?& H8 f; Y' ]$ U# a E; Hof serum testosterone the topical therapy provided a greater
. T7 S9 f8 A; h" C6 m/ y' a2 [9 l- OAccepted for publication July 1, 1977. ·
2 R! h$ ?3 E$ m& t. Q; p: x' @Read at annual meeting of American Urological Association,+ N/ G/ i8 D3 W, J! K
Chicago, Illinois, April 24-28, 1977.
p' i {6 N5 W+ r5 h* Requests for reprints: Division of Urology, Henry Ford Hospital,3 T7 D2 N2 m. A
2799 W. Grand Blvd., Detroit, Michigan 48202.
. x$ G/ L& D* cimprovement in phallic growth compared to gonadotropin.5 c8 y* F& l! B* E( Y$ R' q
Average phallic growth with gonadotropin was 14.3 per cent# `1 L: I8 @! i' W- _% u7 {4 Z: ~
increase in length and 5.0 per cent increase of girth. Topical5 `# i, ^4 N+ x% U7 T2 x
testosterone produced a 60.0 per cent increase of phallic length$ W" D+ R. X0 y+ `
and 52.9 per cent increase of girth (circumference). The5 i8 R0 |, _! I$ Y4 L6 p
response to topical testosterone was greatest in children be-' V6 v: O4 q$ G. t r# N/ U7 c) G6 s
tween 4 and 8 years old, with a gradual decrease to age 17
* {) Z3 t L7 e7 [* myears (see table).% a( B* X8 E0 S4 \
DISCUSSION' e& K! s2 Z$ q2 |/ Z9 Q
Topical testosterone has been used effectively by other
" c, R5 w) O& i6 M) C7 j1 G7 sclinicians but its mode of action remains controversial. Im- N3 w; m7 C, D- H. _1 x7 j; q2 C
mergut and associates reported an excellent growth response
5 V* e! I* {6 c8 ~to topical testosterone with low levels of serum testosterone,4 n: T9 \0 `7 z) f
suggesting a local effect.1 Others have obtained growth re-
" c) ?* o5 s) [' y; Y9 ~' hsponse with high. levels of serum testosterone after topical4 {9 Q- g% ]( W+ L$ O& k. a
administration, suggesting a systemic response. 3 The use of
% w, {; o5 n' a% B& kgonadotropin to obtain levels of serum testosterone compara-8 b) s8 _7 {: E, w! G
ble to levels obtained with topical testosterone would seem to% p8 ~/ ~3 h) m' U* \/ `6 r& E
provide a means to compare the relative effectiveness of
% y* G" z5 H/ ^topical testosterone to systemic testosterone effect. It cer-/ k3 ]. Y+ ]3 B* Z- H. f/ i: y
tainly has been established that gonadotropin as well as par-# [. B- f0 O) P7 p. }+ y
enteral testosterone administration will produce genital9 [7 T" y, z# E( |' \
growth. Our report shows that the growth of the phallus was
/ M0 ~! `" t2 g2 I; I: Csignificantly greater with topical applications than with go-6 K: D$ [: f7 w1 s' \7 G+ Z4 }5 y
nadotropin, particularly in children less than 10 years old.7 I- V7 a3 e1 B. J
The levels of serum testosterone remained similar or lower5 y5 K7 r1 g, R5 U7 m
than with gonadotropin during therapy, suggesting that topi-6 m+ A# q) \* K2 t- }
cal application produces genital growth by its local effect as9 K, X) J& {! y- Z, T( ~
well as its systemic effect.3 v/ l( l. e/ B: R# D
Review of our patients and their growth response related to
, d5 M0 l9 k2 c8 A8 Y2 a+ t" {age shows a greater growth response at an earlier age. This is/ B' h2 X& G* @+ M5 Y6 |. m
consistent with the findings of Wilson and Walker, who
. B3 w0 r3 z! B4 Xreported an increased conversion of testosterone to dihydrotes-
( R8 q8 c0 i1 M. r1 |tosterone in the foreskin of neonates and infants.4 This activ-# X1 L) h j4 R
ity gradually decreases with age until puberty when it ap-
7 R( @# V4 v; k2 w' I; L" Z2 tproaches the same level of activity as peripheral skin. It may, }, o$ I1 G% X$ X1 {! Z3 b( T: J- N
well be that absorption of testosterone is less when applied at
$ {5 j9 b7 i" L) }, b1 H& k; {an earlier age as suggested by lower serum levels in children
3 E4 ~5 J2 v8 B; N0 A0 nless than 10 years old. This fact may be explained by the: W% V9 }. f7 w* q
greater ability of phallic skin to convert testosterone to dihy-2 y* P# R \6 ~* ^* A
drotestosterone at this age. Conversely, serum levels in older! M. X2 H, r* z) o# h3 |
patients were higher, possibly because of decreased local% Z) p5 u6 Q1 P6 p4 R0 N/ P/ \
667+ E; z$ S* _# C( H1 T# l+ s7 I
668 KLUGO AND CERNY
+ H! t$ O3 l4 H GPt. Age( \0 S7 [: A8 y6 g1 d
(yrs.)
/ S6 e% L' U+ Q" a# gSerum Testosterone Phallus (cm.) Change Length
1 Y* b+ t# g3 h! K(ng./dl.) Girth x Length (%)2 z2 A ]% F7 N# i8 [ ~+ ~1 B' B" d# B
4
5 j: E# G) C, E( c8
7 U- w7 y+ r- Z/ Z& H% }103 \% D ^$ _& n2 J! ^8 @2 Z( @
12
" ]3 p3 }5 \3 e* J* P17! ]* ?6 w# C. |9 s6 M) v y/ s) ~4 W
Gonadotropin
( z+ P9 i7 M$ N71.6 2.0 X 3 16.6
" r, j. ]+ Q! I1 m7 f% W% X( E50.4 4.0 X 5.0 20.0& A- R5 _) n, H& y
22.0 4.5 X 4.0 25.0
8 f2 J1 G6 l/ S! r- @3 g9 a84.6 4.0 X 4.5 11.1
: d5 f. P2 C, H2 {( S85.9 4.5 X 5.5 9.0
* S3 e! \) |5 A% U9 t+ x0 ~Av. 14.3. N( y! _( j# T
44 Q9 A" G6 @. P* Z
8
3 }! v9 I. m% e2 L4 R/ y10
8 h- A$ R- Z0 L& k* r ^12
. a0 l9 ]" X# x! S: T' i17
& ?) Q8 a% Q5 {! _Topical testosterone
3 m% E( n) `% j, X7 W34.6 4.5 X 6.5 85) Y& i$ ? M* Q4 m) R
38.8 6.0 X 8.5 707 w: q% z$ m% a
40.0 6.0 X 6.5 62.59 C. m3 }6 T% H9 W# y( s: o
93.6 6.0 X 7.0 55.5
6 z1 e* [2 y5 M/ j, H. s5 W& t95.0 6.5 X 7.0 27.2/ b: J0 \* Y( Q+ R0 @& t
Av. 60.0
2 G' i: y/ S6 y$ p7 e" d. Navailable testosterone. Again, emphasis should be placed on
+ W- [5 X4 l2 Bearly therapy when lower levels of testosterone appear to8 b2 b+ d7 z. A" q% S
provide the best responses. The earlier therapy is instituted$ v T5 n6 F: S0 D9 ]: w, w
the more likely there will be an excellent response with low4 @; ^: G. g; z. r
serum levels. Response occurs throughout adolescence as7 D: B5 M9 e; y0 n# J, _
noted in nomograms of phallic growth. 7 The actual response' [5 e- L: l: L+ S [
to a given serum level of testosterone is much greater at birth
$ a, o7 |- Y& q. K1 f& gand gradually decreases as boys reach puberty. This is most
4 Z. P; y4 R* e# Q. M- Qlikely related to the conversion of testosterone to dihydrotes-# C6 _2 @( \/ \2 f/ w
tosterone and correlates well with the studies of testosterone
- Q& ?( Q. H( s: e' J3 \# U, ?2 fconversion in foreskin at various ages.
) _! M$ X8 `7 `. mThe question arises regarding early treatment as to whether
3 H1 }+ B0 |0 d7 j: h2 E7 J; Mone might sacrifice ultimate potential growth as with acceler-) A& Y3 T# ^; h0 t) F; S7 F9 n; H
ated bone growth. The situation appears quite the reverse
# n# Y( h: o$ M( y5 a6 R% @- e. {' Xwith phallic response. If the early growth period is not used
3 n& O6 v, g$ j: G( Swhen 5a reductase activity is greatest then potential growth
3 {/ l" E4 R3 U1 q6 Wmay be lost. We have not observed any regression of growth
" U. P5 V% }/ ^" wattained with topical or gonadotropin therapy. It may well' Y* b6 z1 _$ H" H' I0 z$ u" S5 w
be that some patients will show little or no response to any/ l" Q7 Q/ h" i( g/ E6 ~
form of therapy. This would suggest a defect in the ability to, I* f+ }9 l' L M9 c& H1 R" X
convert testosterone to dihydrotestosterone and indicate that b n* _, j1 x. ]. l
phallic and peripheral skin, and subcutaneous tissue should
& ~0 g( ?% n2 F; zbe compared for 5a reductase activity.' i7 ]' t7 P( ]( O0 `4 @+ v2 O
A, loop enlarges to measure penile girth in millimeters. B,
. y5 P/ Y- O) ?9 A: mexample of penile girth computed easily and accurately.
6 F# P$ W& g. F: |/ \conversion of testosterone to dihydrotestosterone. It is in this% J6 s4 e3 G. f f# \+ f
older group that others have noted high levels of serum
6 N3 t% i, {: `3 x3 qtestosterone with topical application. It would also appear, r! K* \- f; U
that phallic response during puberty is related directly to the W7 a+ Y) `) R* `: H+ V! p6 j9 t
serum testosterone level. There also is other evidence of local$ _# w8 q5 ~2 o _/ x q
response to testosterone with hair growth and with spermato-' f/ c; [* f+ w V2 P7 }
genesis. 5• 6
* o' k- J$ m% b# YAdministration of larger doses of gonadotropin or systemic9 Y9 {+ a0 B8 y% Q. Y
testosterone, as well as topical applications that produce
i# `. z4 }; ^7 Vhigher levels of serum testosterone (150 to 900 ng./dl.), will1 w0 m `- F9 k" S# U `: g1 @# k* [- j& B
also produce phallic growth but risks accelerated skeletal$ n; n( z- r1 C5 g
maturation even after stopping treatment. It would appear
: ~! g* y& _' z. A* y8 jthat this may be avoided by topical applications of testosterone: Y8 p4 g7 V2 I/ x; j3 G; n
and monitoring of serum testosterone. Even with this control
! T5 q2 e3 E: p4 z5 u4 M2 |the duration of our therapy did not exceed 3 weeks at any! Y& M7 Z0 }" a! q( s5 Z& H
time. It is apparent that the prepuberal male subject may: g$ m' x# o, r/ q- j2 g* n4 z8 K
suffer accelerated bone growth with testosterone levels near) `- G2 X9 E! }- o2 t M
200 ng./dl. When skeletal maturation is complete the level of
8 _ p0 v$ O7 m: [1 g; dserum testosterone can be maintained in the 700 to 1,300 ng./% l0 y" U+ o: f: q% q, v
dl. range to stimulate phallic growth and secondary sexual7 S! ]: j. h( e# H. [3 ~
changes. Therefore, after skeletal maturation parenteral tes-
$ r9 F- o3 g9 r* x4 I1 x2 otosterone may be used to advantage. Before skeletal matura-
& ~0 F6 N2 J* g9 k1 xtion care must be taken to avoid maintaining levels of serum
* S( Z3 F# f4 n8 }, j; gtestosterone more than 100 ng./dl. Low-dose gonadotropin% A/ O0 U: L. T& `- g
depends upon intrinsic testicular activity and may require' l5 x: _3 b. N# C$ k+ U
prolonged administration for any response.1 S% l! Q# q5 K) Y& k3 z
Alternately, topical testosterone does not depend upon tes-2 ^% I( r, G5 R! Z! a/ R
ticular function and may provide a more constant level of8 I" W. I% J8 r$ U9 D
REFERENCES" s3 m( ~9 g3 Y) X# P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
' c% j1 r; h( PR.: The local application of testosterone cream to the prepub-( t1 b' z& H0 `/ D
ertal phallus. J. Urol., 105: 905, 1971.; [) P* S! C8 P! [
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone; K( Y9 J6 x% i2 G% }6 l- o
treatment for micropenis during early childhood. J. Pediat.,* p$ r* z0 _. j. y* d( j8 ^6 w
83: 247, 1973." @! t- U* p* l+ G7 H0 o& v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" i) w- |+ g* ]% A3 q5 eone therapy for penile growth. Urology, 6: 708, 1975.& D$ U6 P% d' I% I% t# ~5 w7 ^
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
8 n: r2 d5 t( P* w$ Z3 W' |4 pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% ]* b5 k7 a1 ^skin slices of man. J. Clin. Invest., 48: 371, 1969.
! e* }% \3 H" S" q! C! r5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! R' c+ x. u+ \2 U: nby topical application of androgens. J.A.M.A., 191: 521, 1965.
" f1 A3 m( l3 u) k3 R/ G6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. H3 Y( V+ s: U7 T2 p/ g+ nandrogenic effect of interstitial cell tumor of the testis. J.
, w. ~) A8 P% ]Urol., 104: 774, 1970.- j( |3 p7 y8 U; N
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 R" P+ P/ T8 |2 d2 M q" F$ `# vtion in the male genitalia from birth to maturity. J. Urol., 48: |
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