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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 k# C; P, K$ z n
GONADOTROPIN
& m$ J0 P( ^& s7 R* H/ ]2 @( Q' j9 J% @RICHARD C. KLUGO* AND JOSEPH C. CERNY1 X3 m# x. T0 v) P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 U: h; ?- @8 A/ I( B9 oABSTRACT* C/ I3 d) w. k5 T
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 { T, c9 v5 M7 Q
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% S7 F3 q5 A/ l& q6 \! B7 `
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 t! |6 ]7 y0 c! X/ X8 e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 d3 K) }" B" Q$ S1 V3 k
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 J7 |( P' n# G A+ A9 d; k( U5 bincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
( j" K9 B/ W- D8 X Q& ~# [' ? Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ a& |: n4 s: G( V& Doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 t( k1 u( @ {% I6 [% k9 ostudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 E3 \/ ~; S( R0 {8 C' K0 J4 jgrowth. The response appears to be greater in younger children, which is consistent with previ-
/ K5 H% P' W/ r, v8 ^1 L& }8 }ously published studies of age-related 5 reductase activity.
" @( h& H% y- i2 @5 Z" ^+ _1 LChildren with microphallus regardless of its etiology will
/ a% ]1 g4 J o. `require augmentation or consideration for alteration of exter-
9 c% \$ {' @2 bnal genitalia. In many instances urethroplasty for hypo-: {5 \1 O/ V# x5 ~
spadias is easier with previous stimulation of phallic growth.: n4 f$ n4 H" ~1 b r
The use of testosterone administered parenterally or topically
2 i! f2 N8 M5 @+ Y2 Q9 [has produced effective phallic growth. 1- 3 The mechanism of: Y# f. w" F- [9 a
response has been considered as local or systemic. With this) V0 ?, w, O* R5 X3 o# b
in mind we studied 5 children with microphallus for response8 a5 M: Z7 E& ] b' x7 K
to gonadotropin and to topical testosterone independently.
( s0 H3 g3 O7 {MATERIALS AND METHODS2 C& ]6 r a% C6 L& k
Five 46 XY male subjects between 3 and 17 years old were
( i7 s$ |9 n, X/ V) Q/ Hevaluated for serum testosterone levels and hypothalamic5 w: J1 O" g+ p& x( N8 {+ y
function. Of these 5 boys 2 were considered to have Kallmann's
4 y7 K7 a j, J G1 Vsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! K+ g, y6 I( F1 r+ ulamic deficiency. After evaluation of response to luteinizing6 K7 y7 r. u6 d- C8 A
hormone-releasing hormone these patients were treated with* i: @; `9 S$ u2 N
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
" {) s3 ?3 E" C: j7 Iafter completion of gonadotropin therapy 10 per cent topical; @0 L; N. G5 V8 j! O# X* z% c8 Y1 x
testosterone was applied to the phallus twice daily for 3 weeks.0 P3 r- G% r5 S* ^) F; I
Serum testosterone, luteinizing hormone and follicle-stimulat-
- K0 j2 K- R- W* { C# v- eing hormone were monitored before, during and after comple-
7 @& l4 B z {4 K+ Dtion of each phase of therapy. Penile stretch length was$ B# k8 p- @& N [* J
obtained by measuring from the symphysis pubis to the tip of
6 G2 A- R: p6 n: j9 Z5 j9 l6 H7 tthe glans. Penile circumferential (girth) measurements were7 O/ B& X S' u$ L
obtained using an orthopedic digital measuring device (see
- O& v$ }1 t8 @8 P* |figure).
$ g$ c1 ?, M& nRESULTS& H' `9 E- L+ _
Serum testosterone increased moderately to levels between
4 ?- ~' B: {' J, b) _50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ z1 t8 {) q" c4 y2 |( L/ x. x
terone levels with topical testosterone remained near pre-( J' }! d; }; V; l1 L
treatment levels (35 ng./dl.) or were elevated to similar levels/ h: x! \5 ? T
developed after gonadotropin therapy (96 ng./dl.). Higher$ A4 w/ }+ O2 J- m3 t: E# K# Y7 v
serum levels were noted in older patients (12 and 17 years old),! e0 y4 H) E. A% z% n
while lower levels persisted in younger patients (4, 8, and 10+ y1 N, e7 Q+ s
years old) (see table). Despite absence of profound alterations% m; }8 M1 K, p1 p. m+ G; L
of serum testosterone the topical therapy provided a greater
+ N' _# Z- } _Accepted for publication July 1, 1977. ·- d6 q+ I8 h7 N2 e& x
Read at annual meeting of American Urological Association,
' _5 l$ ~ Q! l# V5 \4 hChicago, Illinois, April 24-28, 1977.
; k/ A$ J0 E; H. i$ y* Requests for reprints: Division of Urology, Henry Ford Hospital,( E# e2 u# s: {/ M4 b* i4 \
2799 W. Grand Blvd., Detroit, Michigan 48202.
! s. E4 ]& x2 X: Nimprovement in phallic growth compared to gonadotropin.- H3 _8 k V6 w/ Q8 s2 C
Average phallic growth with gonadotropin was 14.3 per cent! N; G" n7 c' x y x. f
increase in length and 5.0 per cent increase of girth. Topical" c5 v& ^% x6 ^, u' x& @8 ]; g- j
testosterone produced a 60.0 per cent increase of phallic length6 o) Y5 P+ O" j& @" N/ C" B
and 52.9 per cent increase of girth (circumference). The
0 M/ a1 H6 B, I* |response to topical testosterone was greatest in children be-: S4 D( ]" c/ K, a/ c
tween 4 and 8 years old, with a gradual decrease to age 17
4 |9 G8 y! ~9 jyears (see table).
) _; G, Y; z* XDISCUSSION
2 k# D( h3 \6 b- h8 RTopical testosterone has been used effectively by other% W7 t; Z& |! ^3 N
clinicians but its mode of action remains controversial. Im-
9 O* K! H1 E3 }! c' s9 J* g" {4 v6 ]0 ymergut and associates reported an excellent growth response) G, v; Q8 u9 K3 h; @: J0 {
to topical testosterone with low levels of serum testosterone,% G" o* e3 A4 K. ?% g3 v, L; z
suggesting a local effect.1 Others have obtained growth re-
- P; p) j1 C0 T9 t, Z8 Y6 Bsponse with high. levels of serum testosterone after topical
0 T5 l: B& r0 Qadministration, suggesting a systemic response. 3 The use of
4 _- J0 O# |6 C* Q0 m8 |gonadotropin to obtain levels of serum testosterone compara-/ f9 ^$ `, L2 n; @% a0 j
ble to levels obtained with topical testosterone would seem to5 d6 I u- y" @" w5 W
provide a means to compare the relative effectiveness of
5 S8 N) h o& ?. r: ntopical testosterone to systemic testosterone effect. It cer-
5 @( b' t) p8 L5 [tainly has been established that gonadotropin as well as par-6 J" Q7 Q- Z/ A
enteral testosterone administration will produce genital
/ [; W) n1 F2 _7 kgrowth. Our report shows that the growth of the phallus was8 m; i2 G! m: K9 \* r
significantly greater with topical applications than with go-5 Q! g4 I N8 }6 n5 _+ Q
nadotropin, particularly in children less than 10 years old.
+ n/ o! o, s: A' s& ?3 v5 i& I' VThe levels of serum testosterone remained similar or lower/ B' B8 E- S2 M4 Z) C0 i
than with gonadotropin during therapy, suggesting that topi-8 h+ A( t, ~% x! H9 w9 A( U% j4 X
cal application produces genital growth by its local effect as9 L6 M' n7 ^* B: E. t
well as its systemic effect.+ U% b; F% T+ }/ f( o
Review of our patients and their growth response related to
: p& v$ {# s7 M7 ^ ~3 W7 ~# l% {age shows a greater growth response at an earlier age. This is
: q2 l5 s3 W3 E% u! Iconsistent with the findings of Wilson and Walker, who
( s6 B3 I! n y Ureported an increased conversion of testosterone to dihydrotes-6 e+ u" O* S' f! G, G2 t
tosterone in the foreskin of neonates and infants.4 This activ-" T) D# { {! [, l0 ^
ity gradually decreases with age until puberty when it ap-; r" z. f5 f0 ]0 }
proaches the same level of activity as peripheral skin. It may) h* M r! c) l4 U8 ~9 D
well be that absorption of testosterone is less when applied at
6 J9 C: Q. w( ~3 _8 d4 can earlier age as suggested by lower serum levels in children: f y' x1 l+ ? ?+ k
less than 10 years old. This fact may be explained by the( Y$ d) m# T+ r) @% d1 j0 i4 I
greater ability of phallic skin to convert testosterone to dihy-8 q' {( Q6 R4 n& v5 e" D
drotestosterone at this age. Conversely, serum levels in older( g1 m. M0 F' S% ?& [8 K' A) E# `* m5 w
patients were higher, possibly because of decreased local
1 g& D$ u+ u' Y- \* r% J1 y/ ^667+ o; R0 D, d) M: |- Q& h1 H2 f
668 KLUGO AND CERNY
4 D$ u' Q+ q/ Y% XPt. Age
; I6 r1 q- ~2 P; _(yrs.); U. Y; F+ b C* Q) k$ s% u8 A" E
Serum Testosterone Phallus (cm.) Change Length3 M4 z$ x# R! n- `+ w+ k1 D
(ng./dl.) Girth x Length (%)
! x# f+ K' x' H& V% r0 k. l* P1 t4
- m4 j- ^* q+ s/ S- i5 d* C8& u9 c! w e; a r. y
10: |) p% s0 V# i9 _5 } X0 Z1 P
12! s7 V6 S) d. I) Q/ n- ]
17
1 I. q0 W7 W: A( _Gonadotropin
, ?7 Y. }/ q* X7 _! r2 I71.6 2.0 X 3 16.63 H- L1 Y+ e+ V' `
50.4 4.0 X 5.0 20.0
3 {" t( E3 u3 `* d0 {4 l7 V g. U! F22.0 4.5 X 4.0 25.0
. A& [" W: F/ d- |) n84.6 4.0 X 4.5 11.1
8 Q: \. k1 ?. J, g85.9 4.5 X 5.5 9.0
5 t% X" Q! o Q1 G& H6 K) K% oAv. 14.3
: T7 Y/ ? w& T! |7 Y7 a44 n! G' B( ~# y+ l1 z/ H2 f
8
2 h% ~, n( R. @4 Q0 C10& C; J3 h) E) m* _
12
) n- [* z2 ~2 k& q$ I6 b, z17) M6 d, m/ A" m1 G
Topical testosterone, \7 h [% M5 c4 E+ ^
34.6 4.5 X 6.5 85
" C) [% B; t- K& b8 A38.8 6.0 X 8.5 70
0 c% H. Q l! {$ |40.0 6.0 X 6.5 62.54 ?$ E b/ d0 c- d* e l
93.6 6.0 X 7.0 55.5
6 g5 o$ _- L4 C8 o0 i& [95.0 6.5 X 7.0 27.2: W. L; Z5 c; Q. ^" {
Av. 60.0/ M6 M3 S! _# G4 J
available testosterone. Again, emphasis should be placed on
5 |, B9 T0 b8 t. Jearly therapy when lower levels of testosterone appear to
8 W! M/ s4 X8 n8 T9 F/ yprovide the best responses. The earlier therapy is instituted
$ t% B3 n. E# r9 F5 O* y/ lthe more likely there will be an excellent response with low# R; C" _; w, u! [( v
serum levels. Response occurs throughout adolescence as; p5 t" @6 G7 n" K; e! u
noted in nomograms of phallic growth. 7 The actual response
" t. |: i- A4 U. m0 W4 V Kto a given serum level of testosterone is much greater at birth
7 ?. ?: d' W; N6 V6 k6 D; w8 Cand gradually decreases as boys reach puberty. This is most
1 b4 v. u3 O8 L" s8 u8 Elikely related to the conversion of testosterone to dihydrotes- l4 R* q7 S1 [2 {
tosterone and correlates well with the studies of testosterone3 i) ] ~, h, o1 R
conversion in foreskin at various ages.
5 v# z; `8 \% a5 HThe question arises regarding early treatment as to whether- g& z* f4 C) _
one might sacrifice ultimate potential growth as with acceler-1 H5 I2 R3 ~7 w' D g2 D
ated bone growth. The situation appears quite the reverse% B$ i6 {; q* \& W
with phallic response. If the early growth period is not used) K7 v+ Z" x+ j$ ^ ^3 K
when 5a reductase activity is greatest then potential growth& \# H( @1 }& q& P. u1 }' g
may be lost. We have not observed any regression of growth
1 ~) O/ J8 I, kattained with topical or gonadotropin therapy. It may well
. A w. X0 V* G1 @+ z1 A; D/ ~be that some patients will show little or no response to any
: y8 m* M+ F3 C7 j$ j- eform of therapy. This would suggest a defect in the ability to
3 c5 O/ v$ F. Oconvert testosterone to dihydrotestosterone and indicate that
& x# x9 a) l: h1 \! }phallic and peripheral skin, and subcutaneous tissue should
1 l9 r: F$ R" C, ube compared for 5a reductase activity.
9 }9 a! G+ B. \6 C2 {$ T1 ?A, loop enlarges to measure penile girth in millimeters. B,
: v- [5 I, z% h+ Mexample of penile girth computed easily and accurately. i+ r1 ^1 ?& @ a4 [5 O1 m' b; g
conversion of testosterone to dihydrotestosterone. It is in this
* [: H5 Y; P; k! n5 polder group that others have noted high levels of serum. J- A j( d3 A
testosterone with topical application. It would also appear% ]6 ^& ?, ^1 v
that phallic response during puberty is related directly to the
/ x2 o; J* X/ n1 }: W5 m9 Nserum testosterone level. There also is other evidence of local# j* y1 l/ z9 M# g) W& ?# r! h
response to testosterone with hair growth and with spermato-7 s1 p# K2 N3 P5 i; D* L. K" U
genesis. 5• 6# _+ _2 [% t8 n8 z- X2 _; X
Administration of larger doses of gonadotropin or systemic
# v, g1 D( n' A) s8 N! h6 utestosterone, as well as topical applications that produce& t9 |. T5 j8 n3 b7 t3 Z
higher levels of serum testosterone (150 to 900 ng./dl.), will
- u# a {6 Z9 L) n. P* Q, H# m% h! N1 Oalso produce phallic growth but risks accelerated skeletal: W- `9 _8 x: N; a) K0 k9 a
maturation even after stopping treatment. It would appear
5 b; w, n; ~* }4 vthat this may be avoided by topical applications of testosterone5 S7 k: L0 I* d* Y7 i6 B
and monitoring of serum testosterone. Even with this control$ W) m/ |6 _. w2 u8 m
the duration of our therapy did not exceed 3 weeks at any
3 o* b" ?6 i9 b# b2 utime. It is apparent that the prepuberal male subject may
/ T+ E, Y6 S/ i; ?suffer accelerated bone growth with testosterone levels near' H8 y. N% V6 k( P) B; O8 H7 t
200 ng./dl. When skeletal maturation is complete the level of$ N* @$ a6 [9 X& q
serum testosterone can be maintained in the 700 to 1,300 ng./' }; G1 u! x G0 W, o; m+ b+ u
dl. range to stimulate phallic growth and secondary sexual6 I3 q9 D4 C3 E/ G
changes. Therefore, after skeletal maturation parenteral tes-& P& P Q, e7 u' l# f
tosterone may be used to advantage. Before skeletal matura-) J! i0 x- b! U& n: N
tion care must be taken to avoid maintaining levels of serum
% F N3 h, |2 P" rtestosterone more than 100 ng./dl. Low-dose gonadotropin
' b* m' W+ w- ]7 f7 |" P% Qdepends upon intrinsic testicular activity and may require, P I: @2 x# M# Z @5 h5 H: J
prolonged administration for any response.$ R {2 v- Y- L, O, P0 z
Alternately, topical testosterone does not depend upon tes-
7 U2 n0 P) c- W* g$ D' G+ H. Q; Iticular function and may provide a more constant level of
+ X& j/ Z6 S, V" Y4 g Q1 \' F! QREFERENCES$ v) t D& b7 J- }: S9 n! X t2 Z, [: F
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,( i# ] {- f; q
R.: The local application of testosterone cream to the prepub-
# b$ Q- U( L( Z% lertal phallus. J. Urol., 105: 905, 1971.5 ]* Q, N/ _; [% C
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
: q" ~( V: v V u/ R7 [4 Xtreatment for micropenis during early childhood. J. Pediat.,
8 `+ v. r2 U4 k83: 247, 1973." M8 `) n( m2 i+ S
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. K& }( g$ a1 {; ?: U3 Y
one therapy for penile growth. Urology, 6: 708, 1975.
+ L3 ?/ @1 u% }8 _% ]! A4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, _7 `' G. X8 {; Z3 e+ I5 T3 Hto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: v! u& Q& B/ `: J& k1 w: [skin slices of man. J. Clin. Invest., 48: 371, 1969.
1 P5 \( K& `/ ?/ z% W5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 D9 T- }& [1 I# H3 \5 o1 Lby topical application of androgens. J.A.M.A., 191: 521, 1965.
; u2 x9 U4 V9 C0 H( M; M+ \) N6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. u( B+ }) y8 m+ Z. Y7 s
androgenic effect of interstitial cell tumor of the testis. J.
1 B% A( F- J# Q8 V% KUrol., 104: 774, 1970.( X1 l* e' D. @6 J6 Y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 n1 C3 v8 ]2 V7 \+ T! o. m
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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