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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND4 U6 f- l/ O" z8 R
GONADOTROPIN
5 b! ?! i6 q/ P1 X0 H( c3 _. {RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 C3 B [9 G- ~% zFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan8 s9 ^! L3 U( f3 Z; c6 [
ABSTRACT
: I$ W+ Z& i4 |4 P! WFive patients were treated with gonadotropin and topical testosterone for micropenis associated
8 Z: V' N9 p+ P6 F+ m+ Gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 y0 y1 Y6 ~" C' ^3 Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 V8 r+ E+ {; `' ]8 x( ~
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 J5 g" Z6 k5 ?" p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
! j8 O1 I9 e5 y& h9 u) yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
& ?0 R# _; n! y4 J9 a$ bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ A7 w6 ?7 H4 c& \
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& _( q" K0 |( ^
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ q d5 K4 o9 J" q" cgrowth. The response appears to be greater in younger children, which is consistent with previ-) `5 l9 V* j8 ^6 _* |
ously published studies of age-related 5 reductase activity.
- H( I: E1 H" o' Q& X" c! NChildren with microphallus regardless of its etiology will
3 {" M; S, }' W! ?require augmentation or consideration for alteration of exter-
2 X' t* k4 j6 Xnal genitalia. In many instances urethroplasty for hypo-/ H) [! G6 D+ O# l2 T! ]( R
spadias is easier with previous stimulation of phallic growth.
6 z% {3 i% r2 g' JThe use of testosterone administered parenterally or topically
+ i4 E8 p$ N! L' T0 A/ vhas produced effective phallic growth. 1- 3 The mechanism of
# x/ g/ t* c8 w" wresponse has been considered as local or systemic. With this
0 Q8 p2 Z2 B3 A- Uin mind we studied 5 children with microphallus for response& i9 j4 f2 a. E" S8 ^5 }
to gonadotropin and to topical testosterone independently.
, }! V! H% P+ Y( xMATERIALS AND METHODS ?7 [% K7 I( Q+ C( x) M
Five 46 XY male subjects between 3 and 17 years old were
2 C+ z' Y5 ]$ H3 g' s( K# Zevaluated for serum testosterone levels and hypothalamic# _6 g5 m, {6 D7 I3 M5 a
function. Of these 5 boys 2 were considered to have Kallmann's
5 H! X% q3 D7 [% u3 u) T% F d3 isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-4 D6 R1 D U5 F
lamic deficiency. After evaluation of response to luteinizing# \! a3 \" ?# W, d% Z) o
hormone-releasing hormone these patients were treated with5 Y+ K9 O1 a1 z, N. t' E
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 x- y, R, V8 @after completion of gonadotropin therapy 10 per cent topical
{2 {0 G1 } \( Ptestosterone was applied to the phallus twice daily for 3 weeks.$ V: s# c1 S+ V6 N8 E, U8 X( M2 X7 q
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 T* L z h5 S; D9 o0 \7 Zing hormone were monitored before, during and after comple-; _2 l: b, X* A9 u+ m9 p$ ?
tion of each phase of therapy. Penile stretch length was# Q% B( I3 c2 T- H5 K; M1 c5 p _
obtained by measuring from the symphysis pubis to the tip of, \, k* \, Y( p6 d( x- }1 p
the glans. Penile circumferential (girth) measurements were* N0 K, G" e' x# O3 @& C
obtained using an orthopedic digital measuring device (see" t/ X% z9 [0 ?+ ^& i8 A9 W
figure).
4 @5 f9 X2 f4 B0 V( @( j) XRESULTS
/ S8 K+ U [& t& \Serum testosterone increased moderately to levels between0 i& C$ n( _, A+ P! ?
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 {3 w8 J' A2 U; k% w( F. I) B
terone levels with topical testosterone remained near pre-0 R7 i: I' M6 Q0 E- o
treatment levels (35 ng./dl.) or were elevated to similar levels
2 W: Z- Q, ^2 N3 ydeveloped after gonadotropin therapy (96 ng./dl.). Higher
2 q& n* {, n P3 I$ oserum levels were noted in older patients (12 and 17 years old),& B2 l4 x. C- x8 V! J
while lower levels persisted in younger patients (4, 8, and 10% l* Q- d3 l& @- [
years old) (see table). Despite absence of profound alterations* b7 w& h7 c& z
of serum testosterone the topical therapy provided a greater
, B$ z# y) f* f8 `Accepted for publication July 1, 1977. ·
3 Y+ o; U3 i. @Read at annual meeting of American Urological Association,- K; X+ b3 e8 f
Chicago, Illinois, April 24-28, 1977.
! ^9 l( A6 n, e; k" l9 G* Requests for reprints: Division of Urology, Henry Ford Hospital,
$ g6 \9 d7 P' c2799 W. Grand Blvd., Detroit, Michigan 48202.
5 a) m* p8 o2 M# i$ w( X. ]+ }improvement in phallic growth compared to gonadotropin.7 Y! o( ?- q1 j) X; s I8 O* U
Average phallic growth with gonadotropin was 14.3 per cent- R3 [* P) y5 v' i" d8 b/ x
increase in length and 5.0 per cent increase of girth. Topical7 @$ p( z d, G" w1 ] `0 E& \
testosterone produced a 60.0 per cent increase of phallic length
& @# E1 Y$ q7 s1 fand 52.9 per cent increase of girth (circumference). The7 P' G+ \* ?) g! ?7 u+ j' H
response to topical testosterone was greatest in children be-; R% q1 h6 R r2 S9 e5 j1 P+ w
tween 4 and 8 years old, with a gradual decrease to age 17' M$ x% ]- O3 K* V- A
years (see table).
5 f/ [1 I. K; v; |; o$ m+ o1 ~( lDISCUSSION
: \/ U: |' g, F5 ]( Z2 I$ s$ NTopical testosterone has been used effectively by other4 L' q, C$ i0 b O6 B+ a: e+ Y
clinicians but its mode of action remains controversial. Im-1 Z0 G, n# n* S: B" X4 Q# F5 \
mergut and associates reported an excellent growth response7 ]: d& a) m$ e: D$ n2 B# X
to topical testosterone with low levels of serum testosterone,- W+ ^# r) M" {$ j* t9 k' N
suggesting a local effect.1 Others have obtained growth re-
/ t1 U) t! e7 D8 Isponse with high. levels of serum testosterone after topical
6 T5 `, B) c9 g% w2 V% ladministration, suggesting a systemic response. 3 The use of) k- V7 U$ K& H3 A
gonadotropin to obtain levels of serum testosterone compara-* y, H" D2 q( v$ Z1 \/ [
ble to levels obtained with topical testosterone would seem to
* b0 p! B9 w- {: U& Xprovide a means to compare the relative effectiveness of) f' a$ P/ I1 p6 k( z& i
topical testosterone to systemic testosterone effect. It cer-
4 [9 v+ Y4 l6 w8 d2 E* Utainly has been established that gonadotropin as well as par-4 H! ~6 O8 v# A
enteral testosterone administration will produce genital
! w" _- Z) K$ D3 Ogrowth. Our report shows that the growth of the phallus was: Z, K: k8 Y1 N( E
significantly greater with topical applications than with go-
5 \- m; `& R6 lnadotropin, particularly in children less than 10 years old.
7 W1 y& ?1 V: ~$ V" \0 EThe levels of serum testosterone remained similar or lower9 l o5 z h0 q
than with gonadotropin during therapy, suggesting that topi-
0 R$ E8 c5 N) i9 j% u8 ^- Jcal application produces genital growth by its local effect as
. g% \3 t7 Q" I4 n) ^) Bwell as its systemic effect.( }' P& ]1 a7 T# V8 T. ?
Review of our patients and their growth response related to
" ]( Q& f# K0 u/ e7 p* `age shows a greater growth response at an earlier age. This is
$ l+ y% |3 c8 | Pconsistent with the findings of Wilson and Walker, who
: @2 w6 t7 _9 A. l! l9 Wreported an increased conversion of testosterone to dihydrotes-8 B5 B- a' d* \
tosterone in the foreskin of neonates and infants.4 This activ- ~0 G; H& ?6 D' ~& k) w' x
ity gradually decreases with age until puberty when it ap-
! j6 m0 \( p0 k8 d$ A: G+ [proaches the same level of activity as peripheral skin. It may$ e0 x% |2 j! @) ~! T+ _
well be that absorption of testosterone is less when applied at3 {; b- Z6 ]" \
an earlier age as suggested by lower serum levels in children
) z$ U( u8 j2 k, Aless than 10 years old. This fact may be explained by the
7 n7 L' ^7 s& F# m$ Fgreater ability of phallic skin to convert testosterone to dihy-% i: X: l" I |
drotestosterone at this age. Conversely, serum levels in older! }0 u" z9 z5 }! e! Q4 T
patients were higher, possibly because of decreased local' B# l) V% r+ Z
6679 z0 Y/ E& T) \+ k8 c
668 KLUGO AND CERNY
7 j e% C$ P& B" E3 s" _Pt. Age
2 C& F# T6 ~4 S8 s(yrs.)8 T3 G) q) |4 J! f& Y/ @8 E* a
Serum Testosterone Phallus (cm.) Change Length1 x# i# M- T; e& X1 Z2 _
(ng./dl.) Girth x Length (%)
) p0 h: b, J4 x6 q" s0 V; d( `: i47 _9 d2 J- c& r6 }2 b$ ^
8' _! U- Z; j# F, [
10
3 w" p" n& J) q& C- R9 `) S12: B4 ^: W2 c, @
17
- k' z6 e; F4 ^Gonadotropin
, M1 g# F5 j5 j T6 I71.6 2.0 X 3 16.6
, t R' O& E$ r50.4 4.0 X 5.0 20.0
( N4 L. ~+ G; D! O9 C. a22.0 4.5 X 4.0 25.0
/ P7 G! ?: o% A4 L84.6 4.0 X 4.5 11.1
: m0 e( F* z1 R& O' p/ I85.9 4.5 X 5.5 9.0
! c- R! F( W5 @8 `Av. 14.3
# K8 s' q) V# p! S+ o. ~2 r9 P4
+ y& r2 [- I; G82 j. U% n w* g8 c
10, b) D L4 u+ _7 u' I5 P
12
, W& G7 O0 I* _( d( y17
" h8 G0 _5 N# ]4 e" C$ qTopical testosterone
1 n) ?1 N+ {+ a. }6 Q34.6 4.5 X 6.5 85
, u, e; a( [5 Q* G38.8 6.0 X 8.5 70
! D6 q- ~+ f! w7 K40.0 6.0 X 6.5 62.5
9 p! C* ~5 z; ~0 @' I93.6 6.0 X 7.0 55.5
' D/ c; s% R8 p& Y0 S, w( s95.0 6.5 X 7.0 27.23 N6 C8 q, h& B0 {
Av. 60.09 m+ T" ?! r$ u; N' l8 N/ L1 q- N; i& K
available testosterone. Again, emphasis should be placed on
& m& V: s1 z( N% Bearly therapy when lower levels of testosterone appear to
* {$ j# ^! a4 W% k$ vprovide the best responses. The earlier therapy is instituted
6 H/ y) x Q1 C/ sthe more likely there will be an excellent response with low3 T' [+ ]& A) w# X0 R* L1 }/ h
serum levels. Response occurs throughout adolescence as, i8 S$ r. _; d
noted in nomograms of phallic growth. 7 The actual response( q7 M. b; H+ o% ~2 ?" L% \
to a given serum level of testosterone is much greater at birth
7 N- U; g" n5 K, i0 [# C% Q7 Aand gradually decreases as boys reach puberty. This is most
& U4 m0 c3 s0 {2 S1 D5 Glikely related to the conversion of testosterone to dihydrotes-
9 u D" \7 F! Q# H# Mtosterone and correlates well with the studies of testosterone
: ~5 m! w% v) P" pconversion in foreskin at various ages.
, i# p2 t# D8 D$ N( e5 C, s& C1 g) ]The question arises regarding early treatment as to whether3 K- W( j& v- ]& `8 J
one might sacrifice ultimate potential growth as with acceler-& l9 p) \# r3 z( i( y5 W; f
ated bone growth. The situation appears quite the reverse- ?6 ~4 l5 V- X
with phallic response. If the early growth period is not used
/ I% r2 a% ~; E& N2 ]% y9 ^) n5 {when 5a reductase activity is greatest then potential growth
3 m" V; t/ K' z/ D+ c( G5 kmay be lost. We have not observed any regression of growth
: a J7 S0 p, E/ rattained with topical or gonadotropin therapy. It may well p: e' r! _$ @5 G) z
be that some patients will show little or no response to any2 U; X" M* U6 D* r. B% E, M
form of therapy. This would suggest a defect in the ability to0 s4 }8 }7 ?3 X# @) q7 D% t* H
convert testosterone to dihydrotestosterone and indicate that0 l0 ?6 S6 r! g; V3 z
phallic and peripheral skin, and subcutaneous tissue should
7 ~7 ]( z [8 X+ L6 `) Tbe compared for 5a reductase activity./ K$ u w- d& j; k+ ^+ d c/ ?
A, loop enlarges to measure penile girth in millimeters. B,+ Q: `* h: r0 B! f$ {
example of penile girth computed easily and accurately.; O1 O5 w) R, J6 N, n( H. a( A
conversion of testosterone to dihydrotestosterone. It is in this
$ {: ]/ h2 C0 bolder group that others have noted high levels of serum
X: U9 f: {3 Ltestosterone with topical application. It would also appear2 R5 v% e/ Q9 w6 w: {+ A
that phallic response during puberty is related directly to the7 J( A' w6 q: o0 I& c
serum testosterone level. There also is other evidence of local
. X8 S: M0 Q, V5 @response to testosterone with hair growth and with spermato-7 }3 k6 g: M' x i' D
genesis. 5• 6, l/ q6 }( ?( M2 \5 d
Administration of larger doses of gonadotropin or systemic Y3 O! {& _* v
testosterone, as well as topical applications that produce* b& Z8 m9 F& `: \
higher levels of serum testosterone (150 to 900 ng./dl.), will
' }9 g, l* g+ [also produce phallic growth but risks accelerated skeletal/ A* c* i, N" ?1 a. Z, X; ^9 ^9 h, E6 e
maturation even after stopping treatment. It would appear
/ f0 E" o# `' H' U- [that this may be avoided by topical applications of testosterone
* _% y# h+ s. }+ a% c7 n9 @and monitoring of serum testosterone. Even with this control! I1 t; a6 x6 M# h) m z8 F) C+ P
the duration of our therapy did not exceed 3 weeks at any
4 K. }0 P3 `" v! b- | Q htime. It is apparent that the prepuberal male subject may. [0 ]/ y& j/ m5 Y! o) n8 G4 l
suffer accelerated bone growth with testosterone levels near) S% v* C' _: ?9 u5 e
200 ng./dl. When skeletal maturation is complete the level of
- j, m' c+ M2 |$ D5 @0 Vserum testosterone can be maintained in the 700 to 1,300 ng./1 l- P2 i; _1 P2 `
dl. range to stimulate phallic growth and secondary sexual
; M* n R7 `7 G; O7 B Fchanges. Therefore, after skeletal maturation parenteral tes-0 h0 n) |+ N% M- g- @7 j$ q, y& S
tosterone may be used to advantage. Before skeletal matura-: J; F5 G1 V. J& ]; l7 V
tion care must be taken to avoid maintaining levels of serum
! W# S3 O' s X6 U- a) g4 d8 atestosterone more than 100 ng./dl. Low-dose gonadotropin
# r I6 q) b" \1 s2 X, Hdepends upon intrinsic testicular activity and may require3 f- y6 j+ {& i0 U4 t
prolonged administration for any response.# z# w( ?1 z; T2 `' i" {& C: ?
Alternately, topical testosterone does not depend upon tes-/ Y- x$ ^! H. [
ticular function and may provide a more constant level of
S; @5 f: g; E' ~3 A& m; @& K3 wREFERENCES
! p! i9 S; j2 i' u8 N* c8 e; z( `1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: q; @; Z2 `8 t1 y, ]R.: The local application of testosterone cream to the prepub-
' U( w; c' r8 `' }! v, N4 S" Sertal phallus. J. Urol., 105: 905, 1971.) r) E1 ]+ |# o$ T
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 e6 v6 p# N* T W+ M) o# t6 \treatment for micropenis during early childhood. J. Pediat.,
0 B3 x. | h. w; C83: 247, 1973.
( J8 X }' `8 ~0 P4 v3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 C" m. c$ H3 ]3 Z3 [2 m' O# [
one therapy for penile growth. Urology, 6: 708, 1975.; ^' E7 s- \0 q7 z3 D$ @) b: U, i6 M
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( \+ R: O* h8 M6 D# {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ J. |+ H3 W8 r* o; g( ~8 ]
skin slices of man. J. Clin. Invest., 48: 371, 1969.# @ |6 Y. G4 ?; F' v$ r
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. f9 ?( p3 r! w/ E0 V( W1 qby topical application of androgens. J.A.M.A., 191: 521, 1965.
+ O3 u2 Q; b+ a( y8 r. q/ D$ u: s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 y% n1 v5 P& F8 M5 h, w8 U, D! Pandrogenic effect of interstitial cell tumor of the testis. J.! B0 T' V, X2 p- U' c& Q" w( I
Urol., 104: 774, 1970.
/ S6 o: I- J N7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 \5 h: }6 h, I+ k) ?tion in the male genitalia from birth to maturity. J. Urol., 48: |
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