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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* r1 J' {) ]. L7 c: fGONADOTROPIN
& H8 _6 e. L4 {7 i! x2 _RICHARD C. KLUGO* AND JOSEPH C. CERNY
$ _) {1 S3 C6 l: t3 L" Z5 n8 DFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan% z8 g& U/ Q3 M& G" X( {
ABSTRACT
/ T; n% M8 l7 H' w C$ P+ C K% dFive patients were treated with gonadotropin and topical testosterone for micropenis associated
, {0 `, J) Z/ a- [& v- Qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 O, W# W' h# [. t7 x6 t$ y, {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 K: b1 [ R( _; j; G& y8 Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! L" L: h$ u5 E; M6 Z+ g$ m$ \2 F4 Xfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent7 }7 Q1 Y8 m4 Y5 @% v# ?
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* `* {* e2 E% v
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 R8 Y3 C5 z# E& y6 B" O' koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 a. b2 A1 p8 M5 ~" m9 Tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
. q$ e7 v( t) z- Cgrowth. The response appears to be greater in younger children, which is consistent with previ-' U L. N8 ?& I( x* {
ously published studies of age-related 5 reductase activity.
( |3 S8 k. Q( U) g& U' rChildren with microphallus regardless of its etiology will
' b5 `8 \* S1 s0 z3 k$ {# j+ \require augmentation or consideration for alteration of exter-
& L( }+ V3 b- W( Ynal genitalia. In many instances urethroplasty for hypo-
+ r& E4 ^" D- p* ispadias is easier with previous stimulation of phallic growth.# r+ L% Y* H/ [% w w; ]" I# \
The use of testosterone administered parenterally or topically; V/ C& x; V0 v" n' X
has produced effective phallic growth. 1- 3 The mechanism of
, u! ~5 F4 K ?! |response has been considered as local or systemic. With this
( B9 o) @( T2 K0 Fin mind we studied 5 children with microphallus for response
+ g0 U8 w7 G! Q# A$ _- v1 V) r, @$ ito gonadotropin and to topical testosterone independently./ x; j( I7 W7 d* \2 r- ]- z9 N. R. k0 T
MATERIALS AND METHODS
2 N/ D% ~6 W4 Q9 {Five 46 XY male subjects between 3 and 17 years old were( h4 r/ Q0 v5 f8 o' _/ S- V
evaluated for serum testosterone levels and hypothalamic/ {; n1 k! O2 c3 `- v% X
function. Of these 5 boys 2 were considered to have Kallmann's; o/ e$ u& @' e5 }. x' N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 d7 x, G! z9 x; z8 W% S Ylamic deficiency. After evaluation of response to luteinizing1 c# }% ]' P1 v. t6 v
hormone-releasing hormone these patients were treated with
1 [& k3 q: f' |% i4 W3 s# I1,000 units of gonadotropin weekly for 3 weeks. Six weeks
+ o$ b( U8 C/ z2 c8 `, u& f* Yafter completion of gonadotropin therapy 10 per cent topical( w# `1 ?6 Z. M6 d
testosterone was applied to the phallus twice daily for 3 weeks.
- j5 w0 Z5 r# O7 h4 p1 f7 DSerum testosterone, luteinizing hormone and follicle-stimulat-
0 c( Y! u+ U/ \1 O X9 k6 ging hormone were monitored before, during and after comple-
1 b; Z4 s ]' o6 Ktion of each phase of therapy. Penile stretch length was
& b0 j, v& Y. j7 p+ [8 A5 Dobtained by measuring from the symphysis pubis to the tip of& s7 ~5 c) P. Z: F& L2 h
the glans. Penile circumferential (girth) measurements were- x! J" {$ F1 }3 U
obtained using an orthopedic digital measuring device (see$ \/ v4 r7 b, W" V" E( s' H1 F
figure)./ l I+ D% H2 N1 w! P
RESULTS
& d! x) q- u/ K# ]- KSerum testosterone increased moderately to levels between
\9 _/ b# K0 s, ]9 l( H50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# y6 ~! _+ R* h {terone levels with topical testosterone remained near pre-
2 I. Y+ ~$ J7 W }treatment levels (35 ng./dl.) or were elevated to similar levels
$ s' E# p7 {, R9 l2 Ideveloped after gonadotropin therapy (96 ng./dl.). Higher& H# P7 e7 M( z. g7 t& f
serum levels were noted in older patients (12 and 17 years old),9 ^- n J! Z3 \( }" M- b) z; ?
while lower levels persisted in younger patients (4, 8, and 10) f' }5 `" S8 J$ I# `! b% ~
years old) (see table). Despite absence of profound alterations' s( Y" F* c$ X1 W4 o& m
of serum testosterone the topical therapy provided a greater
! r4 f, K: @6 Y/ y3 O! v; TAccepted for publication July 1, 1977. ·# ~! v9 A" D& l5 D* D) G
Read at annual meeting of American Urological Association,; y: p' u8 V. f6 J! O3 x' e( u
Chicago, Illinois, April 24-28, 1977.
R# b( d# C% S7 q* Requests for reprints: Division of Urology, Henry Ford Hospital,1 \. ?* z, Z9 c& ]8 p4 |+ I
2799 W. Grand Blvd., Detroit, Michigan 48202.8 z3 h1 i2 T; ]1 ]/ B1 Z
improvement in phallic growth compared to gonadotropin.- p+ t+ s7 `# ?0 B
Average phallic growth with gonadotropin was 14.3 per cent
! ~9 J9 ^2 i* Z" Mincrease in length and 5.0 per cent increase of girth. Topical
& d, i+ `/ g5 d! I8 ]testosterone produced a 60.0 per cent increase of phallic length
& N4 l' D, l% D+ U9 g3 H. }and 52.9 per cent increase of girth (circumference). The* s( w. r9 b. E6 S2 q
response to topical testosterone was greatest in children be-8 {4 Q8 W8 x3 Y
tween 4 and 8 years old, with a gradual decrease to age 173 |; W2 R c! z" P; f1 {
years (see table).5 V; h! p7 R, l5 {
DISCUSSION
: F, [: T9 C+ h' r" p- VTopical testosterone has been used effectively by other
2 H3 i: r2 E+ ~& X5 Sclinicians but its mode of action remains controversial. Im-
3 H& G2 f2 }, q0 U, t; f1 }; lmergut and associates reported an excellent growth response2 j# m- S$ s" u( R
to topical testosterone with low levels of serum testosterone,
$ s! W2 H* G7 P usuggesting a local effect.1 Others have obtained growth re-4 S9 Q( O/ v4 r5 D* k
sponse with high. levels of serum testosterone after topical6 Y8 d! y2 j% x) w
administration, suggesting a systemic response. 3 The use of
: M. ]8 W' w% r2 n3 B0 [6 K' z2 K) qgonadotropin to obtain levels of serum testosterone compara-
2 T5 y% ]2 @3 }5 u" Z4 H8 rble to levels obtained with topical testosterone would seem to
- U4 M. F+ J. Y2 bprovide a means to compare the relative effectiveness of
. r; }/ v' x- vtopical testosterone to systemic testosterone effect. It cer-
. @7 ` B9 O0 t+ }) o. Ttainly has been established that gonadotropin as well as par-" l% d9 q4 ]% }- T! \4 v
enteral testosterone administration will produce genital' K" p4 v$ Y/ S4 K
growth. Our report shows that the growth of the phallus was
+ J' h+ l" A5 h, x$ A$ `5 j; Dsignificantly greater with topical applications than with go-, }0 o& P- G0 P0 ]1 y2 `) D- j
nadotropin, particularly in children less than 10 years old.1 k' B8 u9 c4 \. w$ v- q
The levels of serum testosterone remained similar or lower
- F' K6 V; r! R5 \7 [than with gonadotropin during therapy, suggesting that topi-
" c" R- _) S: T3 ~ ]8 h- |cal application produces genital growth by its local effect as+ F# {& _+ B5 a4 v* E
well as its systemic effect.9 z! s+ q# h1 Q! h/ s% f4 h3 x
Review of our patients and their growth response related to5 a3 I& _$ S8 _% H2 g! Y$ T9 a5 O
age shows a greater growth response at an earlier age. This is
6 |0 Z5 G# e( c$ Hconsistent with the findings of Wilson and Walker, who
+ R7 W! o4 F* k! T/ ~# U6 qreported an increased conversion of testosterone to dihydrotes-( Z4 W; B3 H7 q% g
tosterone in the foreskin of neonates and infants.4 This activ-( f- @5 u! T i! B" R
ity gradually decreases with age until puberty when it ap-
0 N3 i: R! | X0 e0 J1 M' uproaches the same level of activity as peripheral skin. It may9 I" S- S+ K0 G/ z# `1 W
well be that absorption of testosterone is less when applied at
9 ]+ D; a3 g, ]: b& Ran earlier age as suggested by lower serum levels in children
+ y2 K( L' D2 {$ L. z' r% d ~less than 10 years old. This fact may be explained by the- ^) w$ X9 x; [9 M9 C
greater ability of phallic skin to convert testosterone to dihy-
+ r. X/ b8 Q: Qdrotestosterone at this age. Conversely, serum levels in older
/ A8 w( O- T2 z+ A+ gpatients were higher, possibly because of decreased local( m% @, s2 {+ G4 V- t* U3 G9 E
667- u, a2 B1 N/ f: J6 h$ \/ Z
668 KLUGO AND CERNY
" x% v I* @( v1 |Pt. Age
}2 l1 ~- f: S1 B4 h& g9 A2 }(yrs.)
) i, W* z. u) S ^) ASerum Testosterone Phallus (cm.) Change Length
6 Q8 V) E5 @' q3 Y. U7 p(ng./dl.) Girth x Length (%)
+ O6 j$ N* p3 W6 x& A4/ x$ o8 w {2 w
85 Q/ L- @$ G# ~
10
0 Q0 E1 `$ f6 z12
% j: j' m/ b8 i; P/ O! w9 r5 w0 c5 A17* b# Z) O% b% M8 d7 k$ j, a
Gonadotropin0 Q7 l1 A# K# A- u* a s
71.6 2.0 X 3 16.68 N8 a( T; m+ v/ D( ?+ r' t3 R
50.4 4.0 X 5.0 20.0
1 h4 D4 \$ p/ k/ g6 |" T22.0 4.5 X 4.0 25.0
1 P4 E8 Z6 T+ z' K84.6 4.0 X 4.5 11.16 a% |, j4 x% O$ d# o3 Y7 f
85.9 4.5 X 5.5 9.0
6 K8 ], C, E O4 f; SAv. 14.3
6 O2 W5 A$ _- H" g0 e2 \( V% A4
9 g; M4 |8 {9 w# ?# T8* a+ c, ^# ]3 p7 u% g; t6 `4 j% x
10 |; w: k' s# Q
12* z8 s" G2 i T( L
17! G. f9 G/ y4 D1 P0 q3 Q
Topical testosterone
6 O* n3 o9 J6 U& ^ y6 B; b3 ^. U34.6 4.5 X 6.5 85
3 z0 ^5 R1 A+ h3 M! ^7 e% M, g38.8 6.0 X 8.5 70
2 O! {* f& \. `: o* X2 M* g40.0 6.0 X 6.5 62.5
: g0 a) `7 a, |6 z8 u& y) a93.6 6.0 X 7.0 55.5
) m3 p1 e8 Q" a( v" S! t# Q" W4 z. [95.0 6.5 X 7.0 27.2
) Y6 J# J+ w# u& k! QAv. 60.0
' h9 x+ y) {" R9 havailable testosterone. Again, emphasis should be placed on# R& Y6 T" O" q7 s: k& p
early therapy when lower levels of testosterone appear to
0 [& H( a4 \- y" U0 cprovide the best responses. The earlier therapy is instituted
! k3 X/ w6 O0 v- I# Mthe more likely there will be an excellent response with low4 x+ ?' c) T% k& {8 N$ S& Q8 ~
serum levels. Response occurs throughout adolescence as, G+ T: e7 ^/ W" `4 d
noted in nomograms of phallic growth. 7 The actual response
/ t$ D& H, F! ~# M# _to a given serum level of testosterone is much greater at birth
6 I: W% O! o# g1 w, Y: c& Q. Qand gradually decreases as boys reach puberty. This is most
3 j' f7 Q2 D+ ]5 i# m) E; L/ {likely related to the conversion of testosterone to dihydrotes-
8 m7 t3 |! n; gtosterone and correlates well with the studies of testosterone
" c" [* c" Z( O/ R9 Z/ m4 ?" b/ Xconversion in foreskin at various ages./ s5 n& c k: x' e; L
The question arises regarding early treatment as to whether
( e% ^) T+ j0 ?8 Q" D& A$ Z/ yone might sacrifice ultimate potential growth as with acceler-" N: \ ~. d s6 z1 t% \
ated bone growth. The situation appears quite the reverse
2 d+ Y+ p+ k: }with phallic response. If the early growth period is not used
: I' V! O! V; `5 gwhen 5a reductase activity is greatest then potential growth
! h) n4 G0 [3 R1 x) U' y9 y+ }% qmay be lost. We have not observed any regression of growth% K5 p. V+ g' t! `
attained with topical or gonadotropin therapy. It may well
: P( m, j' \ m" h! W kbe that some patients will show little or no response to any
! I Q& d* Q4 @2 T' Gform of therapy. This would suggest a defect in the ability to C! P' s/ u1 e- E1 z1 D1 N
convert testosterone to dihydrotestosterone and indicate that6 s2 Z: O5 s* G. J
phallic and peripheral skin, and subcutaneous tissue should
/ h" g3 h% _/ D8 D; f2 S! Y& @be compared for 5a reductase activity.3 S8 J$ r# p' Y. \& D/ V' f; Y
A, loop enlarges to measure penile girth in millimeters. B,
0 ]' o8 d6 N B" |+ qexample of penile girth computed easily and accurately.
# {- u' b" r& b3 {conversion of testosterone to dihydrotestosterone. It is in this2 R0 m& A O/ U' Z6 C5 b I9 v
older group that others have noted high levels of serum
3 r9 L9 ]% M* S# b7 J' I9 ]9 itestosterone with topical application. It would also appear# ]* N/ U( x! W# L( q
that phallic response during puberty is related directly to the
( D8 c! M$ k* ^0 b5 i; h" H/ zserum testosterone level. There also is other evidence of local
1 v% f. C! m8 X1 J& Dresponse to testosterone with hair growth and with spermato-
9 C- {; `. ~$ g$ Y3 kgenesis. 5• 6& D# n1 R0 ^3 w0 c4 m, C, w
Administration of larger doses of gonadotropin or systemic
, W+ u, Q; Y" e4 u4 B# Xtestosterone, as well as topical applications that produce6 r) n0 A; W3 H7 v K3 l3 Z
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 g1 q' j- o3 m6 }2 L' Z- palso produce phallic growth but risks accelerated skeletal
) l! [1 ~* C; t/ `" omaturation even after stopping treatment. It would appear
@$ i, F M, Z0 e8 s+ a& p3 Ythat this may be avoided by topical applications of testosterone8 k b6 H9 p6 k
and monitoring of serum testosterone. Even with this control
% V* q) ?5 i$ [2 d: [9 N1 ~* p9 Fthe duration of our therapy did not exceed 3 weeks at any
% I! Y$ J0 P# k3 wtime. It is apparent that the prepuberal male subject may7 o$ @" a. H0 x* q' N2 O
suffer accelerated bone growth with testosterone levels near9 x8 g1 G! Z9 i5 O
200 ng./dl. When skeletal maturation is complete the level of: L% ~1 |* L. A- T% V
serum testosterone can be maintained in the 700 to 1,300 ng./
: P, [. t3 U- X( Idl. range to stimulate phallic growth and secondary sexual9 k9 ^6 P1 w( w' m: W, \3 O
changes. Therefore, after skeletal maturation parenteral tes-
+ N' e7 |, P& W# H' u# A! Ttosterone may be used to advantage. Before skeletal matura-( n) V9 ]4 f& x, G+ h! ~7 \3 ]2 l# z
tion care must be taken to avoid maintaining levels of serum
6 M/ V+ N5 }% H/ [testosterone more than 100 ng./dl. Low-dose gonadotropin+ g) \0 ~9 ]! c3 d% x) R0 f* N/ d
depends upon intrinsic testicular activity and may require
6 s- p. ~: Q1 m) ~% }; bprolonged administration for any response.9 z. J. X3 e8 h0 E, l6 |2 Z M
Alternately, topical testosterone does not depend upon tes-/ @. x6 \7 @# l- v' Y( e" i
ticular function and may provide a more constant level of7 ]% I1 L: C" H$ O
REFERENCES
8 E3 g5 g: O7 v# _ x1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 n% c( [# G7 `4 K1 j+ OR.: The local application of testosterone cream to the prepub-
7 M4 d0 {0 F" K6 y! U4 ~ertal phallus. J. Urol., 105: 905, 1971.
9 l9 M* y# Z) z5 ~) n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# n. ]$ Q. u3 ]. Ttreatment for micropenis during early childhood. J. Pediat.,8 j4 |* f: j7 D, K# C' c; r3 s/ N
83: 247, 1973.
# V" j/ ?* j' K# F( Y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
4 ^. p- ?5 H" c" r% S( Lone therapy for penile growth. Urology, 6: 708, 1975.1 B' o7 A) Q! ^& Q
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 C: r2 c+ @! j
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" u' W3 [% J, `' D+ S, v0 \
skin slices of man. J. Clin. Invest., 48: 371, 1969.$ d" p# f: r0 x1 v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% f- n C2 _6 x
by topical application of androgens. J.A.M.A., 191: 521, 1965.
" D! V# x( G$ Z1 f' x3 \6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' w( ]5 J$ U; ]3 O1 p( l7 }% Aandrogenic effect of interstitial cell tumor of the testis. J.
) |& @! S& Y2 }! vUrol., 104: 774, 1970.
8 K5 G+ i, L/ ]9 X" @7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ F7 f- J0 _ A) A: f; g) n/ Ftion in the male genitalia from birth to maturity. J. Urol., 48: |
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