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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND; x# S& q3 C* D- N# ^
GONADOTROPIN
( d$ E( e1 n& t& l+ ]4 TRICHARD C. KLUGO* AND JOSEPH C. CERNY
3 y" ^# U. t7 _3 ]/ ~; m: _9 RFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 k& K( X" h: ^ABSTRACT* C! [# s( c- P4 ?# c' U+ u f- C3 K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
y) F+ `! V& [with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! E- I) B7 u3 h" p
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, w V2 H( s3 g& i6 `3 `4 T G/ j4 acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; O0 k* Q1 U1 Jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
, Y) S/ D) |' a2 F9 o& Xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 A1 c. S2 d) S; x2 tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 @6 v/ m' Y7 C8 W* l& z, hoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. X& u: L- h% p6 `, O8 Z' N. [study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ U- y8 N2 o% ]3 [
growth. The response appears to be greater in younger children, which is consistent with previ-6 C7 a T# v, C' m$ s
ously published studies of age-related 5 reductase activity.
9 z: x/ p( V! i% z% q, V2 hChildren with microphallus regardless of its etiology will
! o% r. e$ f+ _. y3 p) | lrequire augmentation or consideration for alteration of exter-* j7 j5 S/ M) j0 V/ q, v/ \
nal genitalia. In many instances urethroplasty for hypo-; T! M8 J) _+ T; P
spadias is easier with previous stimulation of phallic growth.
, n* Z" n0 f2 ?: K6 }7 LThe use of testosterone administered parenterally or topically
* p$ C, b; b" E4 l, Z* j* ihas produced effective phallic growth. 1- 3 The mechanism of3 P* L9 ~: \# I/ C4 `
response has been considered as local or systemic. With this; Z5 l3 }8 w: D E" I) G9 ^
in mind we studied 5 children with microphallus for response
4 y% L# A+ |- l: i Nto gonadotropin and to topical testosterone independently.
4 P6 b; p+ ?$ SMATERIALS AND METHODS, \# n! J% O6 |1 p' u! i4 f
Five 46 XY male subjects between 3 and 17 years old were
3 @* C6 D, b- M8 }- uevaluated for serum testosterone levels and hypothalamic' E7 [- t' o* a6 ~* M
function. Of these 5 boys 2 were considered to have Kallmann's
; |' r: {+ W R6 G. n" zsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 B# a5 b5 Q, f7 V: Alamic deficiency. After evaluation of response to luteinizing: l8 N4 W- Y% k
hormone-releasing hormone these patients were treated with
0 p+ h1 S5 I& i Q$ }4 o+ c1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! u1 Q9 q& {1 F. U) Xafter completion of gonadotropin therapy 10 per cent topical' \% S. k* l& u" S2 N9 C
testosterone was applied to the phallus twice daily for 3 weeks.
; K' u/ {' N" f+ B; Q: \8 d' LSerum testosterone, luteinizing hormone and follicle-stimulat-* Y6 q7 E* c7 Y/ m) j; u/ I& S
ing hormone were monitored before, during and after comple-7 O7 z6 m: I9 p
tion of each phase of therapy. Penile stretch length was
1 ~' ]; V5 } w# A$ E% ^obtained by measuring from the symphysis pubis to the tip of [, T' L f% Y3 ?# B5 r
the glans. Penile circumferential (girth) measurements were
, D/ g, }6 ?) o, pobtained using an orthopedic digital measuring device (see/ X# f7 `+ h8 Z$ S3 T/ ^# I
figure).$ L1 A3 ` {: E; F1 F
RESULTS
) P! V! ^: E2 k; X0 OSerum testosterone increased moderately to levels between
9 H' z0 W9 {( W2 r$ Q8 F4 ^; `50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 K$ }( R8 L* G( Iterone levels with topical testosterone remained near pre-% T/ y) \) ^4 b4 u) O
treatment levels (35 ng./dl.) or were elevated to similar levels
r4 Y l h# B7 Zdeveloped after gonadotropin therapy (96 ng./dl.). Higher5 a. a# ] z* x: U' h
serum levels were noted in older patients (12 and 17 years old),9 I2 _8 i# [$ P4 b, ^
while lower levels persisted in younger patients (4, 8, and 10# G y2 }( C. H( t5 V8 o) Z
years old) (see table). Despite absence of profound alterations
7 j! d8 s! t( z; ~+ V/ K4 w8 r+ Cof serum testosterone the topical therapy provided a greater
. V# q+ A. O0 K9 c& g0 H' c" m; ^% uAccepted for publication July 1, 1977. ·; A9 z! U. o5 R2 L' F
Read at annual meeting of American Urological Association,- ~& `6 r- X3 V' Q6 r% y
Chicago, Illinois, April 24-28, 1977.& r R8 Q3 M u( E
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 Q. C5 r) D) v* z. g9 x+ c2799 W. Grand Blvd., Detroit, Michigan 48202.
[1 v `, S/ @' g3 q/ c8 Dimprovement in phallic growth compared to gonadotropin.: e: G& l8 D8 M' ` L5 F" P
Average phallic growth with gonadotropin was 14.3 per cent
1 ]/ i5 m) F1 w- W1 g" Sincrease in length and 5.0 per cent increase of girth. Topical
1 Z) ]# C! R4 M4 q) S# ~! Vtestosterone produced a 60.0 per cent increase of phallic length
1 Y# Q7 }2 D0 yand 52.9 per cent increase of girth (circumference). The
& z& ~( s9 L! L) Oresponse to topical testosterone was greatest in children be-
! `* {: c& ], p' r& E: t, D* `" qtween 4 and 8 years old, with a gradual decrease to age 17
8 U/ |9 ^) I( Zyears (see table).
. Z$ P$ t' y2 {" ^DISCUSSION, g# H. Z+ q9 C4 n, D; w: N, e. U
Topical testosterone has been used effectively by other0 ]# x& p5 ], f' z5 X
clinicians but its mode of action remains controversial. Im-
/ _$ f" ?7 _0 R$ i0 ymergut and associates reported an excellent growth response/ c. v: J7 {' {, P2 G+ W
to topical testosterone with low levels of serum testosterone,! t0 K U% x6 E: i* j
suggesting a local effect.1 Others have obtained growth re-
5 }/ U+ [+ f9 P/ \+ R: o; l% Xsponse with high. levels of serum testosterone after topical) `9 m8 D: j* P0 X
administration, suggesting a systemic response. 3 The use of7 M) h+ |% N; k; i! ~& r" \/ _
gonadotropin to obtain levels of serum testosterone compara-
- D# a# k3 x9 mble to levels obtained with topical testosterone would seem to
8 y/ H5 c4 ^% ^1 ~0 o9 @provide a means to compare the relative effectiveness of$ z9 i2 k) |9 e% ^ ^- ?
topical testosterone to systemic testosterone effect. It cer-
; x, y: H4 T; P5 F7 G: f) [1 Ltainly has been established that gonadotropin as well as par-1 m, `8 e8 G! |$ a# u6 ~$ L1 c
enteral testosterone administration will produce genital' y6 g' O, R) k+ F" l4 h
growth. Our report shows that the growth of the phallus was
$ e9 Q- Y' x" W9 gsignificantly greater with topical applications than with go-
4 _4 H u# T) X8 fnadotropin, particularly in children less than 10 years old.* H2 }# }& F: J4 r& N
The levels of serum testosterone remained similar or lower
y% w* C' J) O; s8 n$ }2 Pthan with gonadotropin during therapy, suggesting that topi-
1 k! @7 D9 S/ V3 t- scal application produces genital growth by its local effect as
* P# K6 E M) Y9 \* N. ?" S. [well as its systemic effect.
1 Y6 K1 ^' R" X9 ~9 o2 DReview of our patients and their growth response related to a# Z2 t& U* D! H! Y) W
age shows a greater growth response at an earlier age. This is
0 ?4 P: |, s; ^& `consistent with the findings of Wilson and Walker, who
4 R. Y: h9 n V5 |* v% y2 l2 Dreported an increased conversion of testosterone to dihydrotes-
# S5 E& J1 n8 j$ L% htosterone in the foreskin of neonates and infants.4 This activ-9 m8 Q# ?: G; H1 C* N B& m" z1 I
ity gradually decreases with age until puberty when it ap-3 H$ _$ G9 }( e" K1 r3 y' p5 Z: M
proaches the same level of activity as peripheral skin. It may
' U& w" h2 A( v3 u3 R7 w9 A7 Xwell be that absorption of testosterone is less when applied at' K. Z; `- f* z1 y Z
an earlier age as suggested by lower serum levels in children) q! k, T$ W. E# |$ F% l- I
less than 10 years old. This fact may be explained by the3 W1 G; A8 [6 I7 |0 n1 H* E/ J
greater ability of phallic skin to convert testosterone to dihy-
) Z6 J0 x/ {1 f) M& @drotestosterone at this age. Conversely, serum levels in older! j" V6 b0 Y5 t) j& j! |1 }
patients were higher, possibly because of decreased local0 j7 d& D" T3 S8 t! v
667
/ n, o2 N2 N; ?& E668 KLUGO AND CERNY
) F3 {: F4 D7 L* zPt. Age$ \- b7 m2 ?2 }/ ]/ y& K3 p
(yrs.) Q' z) V) \0 m+ X& d! P9 ]: S
Serum Testosterone Phallus (cm.) Change Length- b0 O4 Z/ B2 R# z
(ng./dl.) Girth x Length (%)0 ^) N- a+ i/ T4 ~) x
4
) G1 Z1 P2 `, j) c3 c; ~# `% C8" \/ `2 @- i% \0 H V. |. H
10
( f3 Z, M* W7 C% P! U r7 K12
( E( j0 p- A) b" ~17! O# k7 n3 }- e3 k Y6 }1 W( P
Gonadotropin' J6 f( M# r% q, V
71.6 2.0 X 3 16.6; B: S" c1 C) W: R' Z. s' n
50.4 4.0 X 5.0 20.08 y2 h L* V! r! u
22.0 4.5 X 4.0 25.0& ~9 T5 t; l# c" L
84.6 4.0 X 4.5 11.1
) Q. @! n# Q* L# B* a85.9 4.5 X 5.5 9.0
4 r1 g. o4 Z0 Y9 O# bAv. 14.3
' H ^2 Y% y5 v- ]4
, m& i, B$ u: s) J1 {85 E$ e ^- b4 C, _& E) @
10. m5 u H& \; X* S; j/ p: T
120 i' a) m+ p1 Y$ z( q
17
) S: G4 r4 [ ^6 g0 {* A/ D& v( oTopical testosterone1 x4 Y3 R# B' x+ B, R* P" M
34.6 4.5 X 6.5 852 y/ S( |5 B) K! j$ L( j# _+ Q
38.8 6.0 X 8.5 70
( Q. M1 |8 }2 ~; R" Z$ ?$ i40.0 6.0 X 6.5 62.5
5 N' L5 X; _: g7 Z8 o93.6 6.0 X 7.0 55.5
8 p) T- ~/ x J+ ~95.0 6.5 X 7.0 27.25 K; D% m7 G( Z+ {2 j
Av. 60.0
1 |3 A9 w9 T: b# [# L! iavailable testosterone. Again, emphasis should be placed on
# l5 L5 M2 Q6 R; f" C; Q A) mearly therapy when lower levels of testosterone appear to" h* E4 E4 R6 q# E' B% U: m
provide the best responses. The earlier therapy is instituted
% Y5 J$ c+ o$ X4 ^1 ?the more likely there will be an excellent response with low
2 J& s1 G+ x* Y1 Oserum levels. Response occurs throughout adolescence as7 w/ {3 Y+ E6 l0 q- U9 O
noted in nomograms of phallic growth. 7 The actual response; o d$ P; l1 ^) C/ ?6 t y
to a given serum level of testosterone is much greater at birth- z; ^& ?; Z2 z! w8 t0 M
and gradually decreases as boys reach puberty. This is most; Q; \) S- X* k5 y* g9 f' |& K
likely related to the conversion of testosterone to dihydrotes-6 W+ e% [ n. w9 ?* n* t0 C; B
tosterone and correlates well with the studies of testosterone
' R* W& O# ^7 \; S- R# {conversion in foreskin at various ages.6 { l/ }- v9 t
The question arises regarding early treatment as to whether* `3 [/ r5 e1 }, f' K+ v/ ]: a" l
one might sacrifice ultimate potential growth as with acceler-
) g, z0 h" z( L. Xated bone growth. The situation appears quite the reverse
" q+ _3 Z/ j2 m& rwith phallic response. If the early growth period is not used o6 X2 h. S W# o5 H4 G1 t/ |
when 5a reductase activity is greatest then potential growth
* i) q. G ^' p% |: m( t9 [may be lost. We have not observed any regression of growth3 g1 s! K) m$ x Q/ z2 k' h/ j
attained with topical or gonadotropin therapy. It may well% \0 L3 V! ]5 q0 g4 E
be that some patients will show little or no response to any1 g$ Q/ i6 `8 B. K) ?$ n
form of therapy. This would suggest a defect in the ability to! v& k: E( g# C' O, o
convert testosterone to dihydrotestosterone and indicate that; F. Z$ ]: g t, [, V+ m
phallic and peripheral skin, and subcutaneous tissue should
3 s8 J L+ o9 z8 H+ c& T( gbe compared for 5a reductase activity.6 W: }. R a0 b# G" [5 F3 x; t+ o
A, loop enlarges to measure penile girth in millimeters. B, {- L9 D0 ^) }$ c" D' f V
example of penile girth computed easily and accurately.0 c* E3 B. P: Z. H5 l) I1 ^1 @
conversion of testosterone to dihydrotestosterone. It is in this3 y! t% }* a' U+ ~
older group that others have noted high levels of serum) ]' o; F6 r$ e9 K
testosterone with topical application. It would also appear
7 Y1 n9 S4 Y/ l Rthat phallic response during puberty is related directly to the
R9 ~! B( N! d) Pserum testosterone level. There also is other evidence of local
5 L% e( T* w4 g2 lresponse to testosterone with hair growth and with spermato-& V+ ]1 h7 _6 v5 ` @& f8 q4 P/ K
genesis. 5• 6 `( @7 S* A) e8 O" r
Administration of larger doses of gonadotropin or systemic
0 ]* v0 E7 F/ D+ Q8 U" dtestosterone, as well as topical applications that produce
1 U6 x) F6 \% x+ Rhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 L2 C3 m4 E0 d* F1 L3 Q% [also produce phallic growth but risks accelerated skeletal5 A4 K+ ~0 }$ F, K; F
maturation even after stopping treatment. It would appear
% z$ z. [: m3 m. k, T6 ^that this may be avoided by topical applications of testosterone
2 D) c$ Q5 f! Yand monitoring of serum testosterone. Even with this control
) {3 t& E0 z6 o& H$ ]2 Qthe duration of our therapy did not exceed 3 weeks at any
- {' w) D. b9 L( I& v L+ t# `2 Jtime. It is apparent that the prepuberal male subject may& l) a/ p6 i4 s( t. I% j" w
suffer accelerated bone growth with testosterone levels near& A2 x6 w# i# }) l" P
200 ng./dl. When skeletal maturation is complete the level of; s" m* h! }) @- [; S) l
serum testosterone can be maintained in the 700 to 1,300 ng./
1 a( F& ]# K( F' _- adl. range to stimulate phallic growth and secondary sexual# e e. \- g1 a- E; U9 e
changes. Therefore, after skeletal maturation parenteral tes-
: ?4 ^$ J) X J& A* L, D6 G$ Otosterone may be used to advantage. Before skeletal matura-' y; \5 H% f6 H6 k1 |( L: j7 o: X( y
tion care must be taken to avoid maintaining levels of serum; B7 {3 K- S" a
testosterone more than 100 ng./dl. Low-dose gonadotropin- ^( Y1 C" f- {7 J& H$ `6 d4 `
depends upon intrinsic testicular activity and may require
, L7 x3 _7 T, W+ a- E5 vprolonged administration for any response.% V$ e1 ~" y$ }" T, v4 h
Alternately, topical testosterone does not depend upon tes-
1 I9 A( F8 i- W5 G# lticular function and may provide a more constant level of
- J3 J# H9 {9 xREFERENCES) H! M& n: p: T$ ]8 X/ A/ j
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 g3 u& i& C" O% U& G ~R.: The local application of testosterone cream to the prepub-2 d3 t% n# U3 Y- a. `8 l
ertal phallus. J. Urol., 105: 905, 1971.9 {" W4 x% N) h7 r. n$ \1 ^1 e1 w
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 ^% S& X: D+ J: _( @$ v% V0 Ctreatment for micropenis during early childhood. J. Pediat.,
8 X, f; r) X4 `8 H% x& r# `. |8 a; W83: 247, 1973.
( P8 ^6 c7 v" C# g3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; T- R" p. q- H
one therapy for penile growth. Urology, 6: 708, 1975.) B" w& ]+ f2 C, X
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
# E' f* z8 L. B6 L9 uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: U$ T- f/ r) e' ~
skin slices of man. J. Clin. Invest., 48: 371, 1969.- X* }" J2 [; L7 e5 K$ j2 Q7 V
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth1 i3 y+ ~& i: o, D* W
by topical application of androgens. J.A.M.A., 191: 521, 1965.
0 ]# }( u0 Y; ~, G6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 N: f/ \! d/ c2 a8 Bandrogenic effect of interstitial cell tumor of the testis. J.
( Y* L7 ^. n& `0 Y8 u( KUrol., 104: 774, 1970.
/ B& ^. a7 _ b6 N7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* v F9 E& |( L$ etion in the male genitalia from birth to maturity. J. Urol., 48: |
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