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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 w k( f9 P8 `+ O( Z+ f5 e1 K
GONADOTROPIN$ J9 c8 z3 W' G- y j$ S
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 u# g' v; o" u2 g! u4 {* P$ s" VFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 l6 r' x; ^$ O% e; H6 fABSTRACT
% v4 O. R5 F0 LFive patients were treated with gonadotropin and topical testosterone for micropenis associated
: |$ S* n) i2 j% s1 H( Vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, U' m/ m9 d- P1 z" P, o" q+ Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) `9 }3 E# `4 g0 g0 L9 kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* I$ g% w# y1 p1 L4 h: ?6 j
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 S) S; a( b; U! ~
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. o% z, c/ @! J% Z4 s* fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: a* x' |) `; c* z. Uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& `$ W( B0 ?- I( {8 w( d: l A9 @
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 c W" K! l# Q% I
growth. The response appears to be greater in younger children, which is consistent with previ-" I6 _' {( f6 o, ~: r+ u# u: T, X
ously published studies of age-related 5 reductase activity.
4 ?; O% x% c, C' Q& S/ |5 qChildren with microphallus regardless of its etiology will
& g3 j8 k" M$ o! v. drequire augmentation or consideration for alteration of exter-
- K4 q; x( V, \0 ]* e3 u5 \nal genitalia. In many instances urethroplasty for hypo-
$ E( P, M. s1 | [spadias is easier with previous stimulation of phallic growth.4 g- r5 n/ K9 t g# l
The use of testosterone administered parenterally or topically6 @5 @2 t# ?* p- N) M! m: b
has produced effective phallic growth. 1- 3 The mechanism of! P" I' ~4 h7 D F+ y: v
response has been considered as local or systemic. With this2 Y! G' l# k3 j2 P9 L4 ]
in mind we studied 5 children with microphallus for response
' I7 l+ n, ~( P1 z* Mto gonadotropin and to topical testosterone independently.
' ]% X( \3 w+ W/ B# P, T1 {MATERIALS AND METHODS
* r0 f) K) s- ~- @7 I% `Five 46 XY male subjects between 3 and 17 years old were
' V8 l2 Y! o" y9 D* W( D& Wevaluated for serum testosterone levels and hypothalamic
9 T q, m( P( C M$ Z3 U% c" t, p0 ofunction. Of these 5 boys 2 were considered to have Kallmann's. g* I- D" Z+ o& f: \0 [8 ?- h
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 d, R0 ~. u! n# }/ Vlamic deficiency. After evaluation of response to luteinizing
& }. k1 a* O" @7 mhormone-releasing hormone these patients were treated with. _" b! A' I5 C9 Q0 D# T
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 j$ @' J" e% l$ }) Fafter completion of gonadotropin therapy 10 per cent topical5 ~! q% \+ A! }* X" N2 a: H9 W
testosterone was applied to the phallus twice daily for 3 weeks. A0 E0 u3 e2 i3 I$ }8 [% M# E
Serum testosterone, luteinizing hormone and follicle-stimulat-' t% w* K3 t6 N& l
ing hormone were monitored before, during and after comple-
: d! E; p6 e: I, \9 Y9 Ution of each phase of therapy. Penile stretch length was
! V# \! j6 Z. |! X4 iobtained by measuring from the symphysis pubis to the tip of; ?6 Z6 E2 B+ {0 n! T6 u1 L) q
the glans. Penile circumferential (girth) measurements were) e% ~, M, i8 `
obtained using an orthopedic digital measuring device (see
5 g: G- e8 W! g. |* f: e! Wfigure).+ R& b1 i0 n6 C& q
RESULTS9 I8 N# z( J) z7 f8 h" a% x5 C
Serum testosterone increased moderately to levels between
/ o4 u3 O+ X3 {# X' |50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ Q/ E" ^: F& O
terone levels with topical testosterone remained near pre-6 E& f$ a* |* y0 r& G- M
treatment levels (35 ng./dl.) or were elevated to similar levels2 e5 I$ r) T4 S. n- q
developed after gonadotropin therapy (96 ng./dl.). Higher$ v: z+ l+ Q0 o( V8 u! U u
serum levels were noted in older patients (12 and 17 years old),
: }4 ?2 v2 D! `3 M D+ y9 s& T4 @while lower levels persisted in younger patients (4, 8, and 10( F1 v) W0 j; \' b5 s. J. w
years old) (see table). Despite absence of profound alterations
7 z' N0 V# i( e6 L z6 oof serum testosterone the topical therapy provided a greater
( s, m; I* A6 }Accepted for publication July 1, 1977. ·4 O$ {- g1 U$ _3 K' L0 k
Read at annual meeting of American Urological Association,/ o4 R- p) T! W6 m. Y
Chicago, Illinois, April 24-28, 1977.* C3 [: J9 S& i. n
* Requests for reprints: Division of Urology, Henry Ford Hospital,
( b) l, q9 P& O) x9 W2799 W. Grand Blvd., Detroit, Michigan 48202.
. j6 T* V7 }) Qimprovement in phallic growth compared to gonadotropin.
T( S R1 ~7 D, F( z! mAverage phallic growth with gonadotropin was 14.3 per cent
/ a! C% ?* p6 L9 H9 U4 Eincrease in length and 5.0 per cent increase of girth. Topical. D5 f$ O7 h# ^) @) n$ B: Z: J4 }
testosterone produced a 60.0 per cent increase of phallic length
: V% ^/ k2 Z0 A0 {7 m) W# z, i- sand 52.9 per cent increase of girth (circumference). The1 G0 j& G3 V) O$ F$ [) l
response to topical testosterone was greatest in children be-
6 x$ v% b" b' Rtween 4 and 8 years old, with a gradual decrease to age 170 n7 l, y2 y3 T8 u# F
years (see table).+ Q4 k- T2 v3 e. m# E: F2 `6 o7 l- Q- p
DISCUSSION1 G9 W$ v+ s. ^) }( ]9 S' o
Topical testosterone has been used effectively by other
) G& h2 F" r! _/ D; C5 jclinicians but its mode of action remains controversial. Im-3 W# N. k5 e7 o, {
mergut and associates reported an excellent growth response5 o2 ]' r" x- p1 R
to topical testosterone with low levels of serum testosterone,6 ]' |2 q6 m8 L! Y( t8 X g2 q
suggesting a local effect.1 Others have obtained growth re-
{/ ~' u( k. o# Usponse with high. levels of serum testosterone after topical
9 E' v( \- C8 L7 b2 r; ]+ a eadministration, suggesting a systemic response. 3 The use of( _5 {" v4 r" d
gonadotropin to obtain levels of serum testosterone compara-" ~* j) A* x C1 u5 X
ble to levels obtained with topical testosterone would seem to' ~+ X* V' R7 [/ C8 |* L* ?7 R
provide a means to compare the relative effectiveness of% h* y! M/ _& S% N. w+ R( A( @# l
topical testosterone to systemic testosterone effect. It cer-
. B4 V. q# L7 c- i1 q* X7 gtainly has been established that gonadotropin as well as par-- D. N1 f( \$ B2 O5 Y( N
enteral testosterone administration will produce genital
3 Y' H5 w$ C% E; h& pgrowth. Our report shows that the growth of the phallus was* W0 l7 F8 ~; v+ \9 f
significantly greater with topical applications than with go-
- m/ b6 g% g5 z' `- m& nnadotropin, particularly in children less than 10 years old.
7 T2 P- \8 O/ R8 T! ~The levels of serum testosterone remained similar or lower; s. G" ^1 C, |: c) [' |+ h
than with gonadotropin during therapy, suggesting that topi-( a2 v5 i9 {. X
cal application produces genital growth by its local effect as5 i6 z" A- ]# y* I* u
well as its systemic effect.! r- r" g, v+ T# g7 Q
Review of our patients and their growth response related to$ N; L! r4 W% a' |# F& k
age shows a greater growth response at an earlier age. This is$ @: I" z9 \* m. J* _, v
consistent with the findings of Wilson and Walker, who5 D. h- @3 I2 _( g( l0 f
reported an increased conversion of testosterone to dihydrotes-/ C( v# y0 C0 g3 A+ F# Q8 N
tosterone in the foreskin of neonates and infants.4 This activ-
" a$ ]0 `) l0 m# p5 T7 Q4 mity gradually decreases with age until puberty when it ap-
2 [. u: Q) \6 g* c1 Oproaches the same level of activity as peripheral skin. It may' T5 _4 c2 C) K# z5 u! v0 X' b
well be that absorption of testosterone is less when applied at$ ?: d4 V k, S+ o }
an earlier age as suggested by lower serum levels in children7 R4 B a' S( z) r" U
less than 10 years old. This fact may be explained by the
" I( ^ F* W" o/ w% T$ F, kgreater ability of phallic skin to convert testosterone to dihy-
1 ^# S7 g8 e1 j: P5 Idrotestosterone at this age. Conversely, serum levels in older% Q" H: @' m* t6 m* _
patients were higher, possibly because of decreased local
8 b- S2 r7 D& a3 ^1 ~3 m667( @3 R8 B) m% f
668 KLUGO AND CERNY
5 _8 u: q/ `/ K! w$ {Pt. Age
, R; i _/ @2 L3 n! i2 t h, A(yrs.)
) f* W# P o5 y5 e. h b7 q5 j; k; {Serum Testosterone Phallus (cm.) Change Length
% L0 [1 j& L5 S(ng./dl.) Girth x Length (%)7 T. e# q8 P3 b
4: d. @. @1 P' x& T% Z b
8
& P# y: u: E( \+ }* {& u10
: V7 t X- l2 I! U1 e12; V/ {& B+ u1 V
17
6 l! X/ o X7 w9 iGonadotropin/ J; k; U# Q8 e# T7 T
71.6 2.0 X 3 16.6. @! h. @2 ~' W- f
50.4 4.0 X 5.0 20.0
) n5 G" t1 |& j' T, C% j22.0 4.5 X 4.0 25.0
2 L( q2 v1 B8 Z2 h, M4 b' _84.6 4.0 X 4.5 11.1: d9 a7 C1 [' Q$ `. V. c% {/ E
85.9 4.5 X 5.5 9.0
0 V" I: D' l8 {9 H7 rAv. 14.3, N0 A' U& A( {5 c* r' ?
4
, M9 {9 Y8 O) W V) r% N4 \8
. q4 H" J) U$ |# k# i3 ]+ ~10& R# D- v2 s/ ^/ Y# @
12; S* k1 i0 ^% u* R3 g- m$ p
17# Q4 o2 _3 f. y6 a; U
Topical testosterone: J" R) i: Y8 z$ n J
34.6 4.5 X 6.5 85/ w" ~5 E. f) R4 r' M7 c" L
38.8 6.0 X 8.5 70
) b9 R8 ~& D! Z40.0 6.0 X 6.5 62.5
8 k* y+ b! j c& y3 |/ |& {! Z4 u93.6 6.0 X 7.0 55.51 q# G$ n% j; _5 A" s, {+ x
95.0 6.5 X 7.0 27.2" y* |: P2 H! L$ |# i* v' N7 J( p( l
Av. 60.0
' k+ b% T& \) _! j" F: kavailable testosterone. Again, emphasis should be placed on2 J6 Y( u; a8 R' N
early therapy when lower levels of testosterone appear to
7 e; T1 L4 f$ x2 a% C: aprovide the best responses. The earlier therapy is instituted7 z- \, z& c: O# X
the more likely there will be an excellent response with low
: j, n3 v" ]/ G; O( I, V- lserum levels. Response occurs throughout adolescence as
( l, c* j. n# Y0 ~noted in nomograms of phallic growth. 7 The actual response0 H9 g4 h0 T9 |# l
to a given serum level of testosterone is much greater at birth
( @% A/ r; y* qand gradually decreases as boys reach puberty. This is most/ I. _2 ]# s% x2 |% a# Y$ v$ Z
likely related to the conversion of testosterone to dihydrotes-
; o; H# K5 s9 J6 w/ {/ j3 W+ W2 x7 ztosterone and correlates well with the studies of testosterone
/ l: J: Q0 ?0 k7 _. vconversion in foreskin at various ages.
; p& ?% `) z0 B ZThe question arises regarding early treatment as to whether
' ^" X9 Z* t8 h5 U9 eone might sacrifice ultimate potential growth as with acceler-
2 e9 R) Y: H. R: f, v( Aated bone growth. The situation appears quite the reverse! {% u; t/ a8 S2 p
with phallic response. If the early growth period is not used. I5 p9 } m* a5 ^& G
when 5a reductase activity is greatest then potential growth
* X( R: G; q l$ r6 Q8 \* W* [8 s L- pmay be lost. We have not observed any regression of growth. y- `9 y3 ]3 I( ?2 c% |9 q6 [
attained with topical or gonadotropin therapy. It may well) e V2 {* b/ ^0 i9 O8 X. F' I
be that some patients will show little or no response to any/ ]4 n; N+ Q" w* U) \, y5 a, O5 e
form of therapy. This would suggest a defect in the ability to
+ G8 f! x! F+ w0 j' c: B1 d3 \4 c Xconvert testosterone to dihydrotestosterone and indicate that
& ]) H1 {( s" ]9 T' qphallic and peripheral skin, and subcutaneous tissue should X* y4 M; \ V" e; X6 k3 r/ k
be compared for 5a reductase activity.
; W3 w" X3 `4 W1 ?: n; dA, loop enlarges to measure penile girth in millimeters. B,
- n1 ^4 d. u! J9 M: dexample of penile girth computed easily and accurately.) N& p8 f+ h/ G, X
conversion of testosterone to dihydrotestosterone. It is in this7 U# i6 \9 P B& x/ H; @ K
older group that others have noted high levels of serum
9 f% y2 g! `4 _1 Z! ptestosterone with topical application. It would also appear
. m H% y, d2 j/ y* {9 Q: D6 M8 zthat phallic response during puberty is related directly to the
K% d* T3 J+ z1 Gserum testosterone level. There also is other evidence of local# F/ v* e4 c9 v- ]- @5 Y, X
response to testosterone with hair growth and with spermato-$ e+ r3 j9 G L) K$ W$ U* F8 J
genesis. 5• 6
% n! s6 ~. \) M6 ?0 qAdministration of larger doses of gonadotropin or systemic$ ~; C3 T: S l; y
testosterone, as well as topical applications that produce, }' r7 j+ Z. d9 u& B% T
higher levels of serum testosterone (150 to 900 ng./dl.), will
' s9 q2 f/ V3 s& s" Walso produce phallic growth but risks accelerated skeletal( o3 a- g5 g" \8 V2 u6 |* ?7 H
maturation even after stopping treatment. It would appear
4 R2 S1 Y4 B- {" Bthat this may be avoided by topical applications of testosterone" B& L% W- k9 Z: V; m
and monitoring of serum testosterone. Even with this control
# G) K2 {* C& O) m+ o2 Athe duration of our therapy did not exceed 3 weeks at any p. r" Y+ I# a( m
time. It is apparent that the prepuberal male subject may
! w) p, P" f( |/ t5 d, p; ^suffer accelerated bone growth with testosterone levels near4 t' m+ [6 f/ |' q
200 ng./dl. When skeletal maturation is complete the level of0 t& C. j7 k' ^6 [) x
serum testosterone can be maintained in the 700 to 1,300 ng./. L# @- Y/ H( i. C2 U# P. E) B
dl. range to stimulate phallic growth and secondary sexual( H, X$ h9 ]; C5 ?3 S
changes. Therefore, after skeletal maturation parenteral tes-1 T' M% l, U" w+ I- @7 W5 k L
tosterone may be used to advantage. Before skeletal matura-
- {* h6 F$ n" Z$ L5 V) ation care must be taken to avoid maintaining levels of serum- m5 j0 ~0 l$ N; _5 n- L- m9 d
testosterone more than 100 ng./dl. Low-dose gonadotropin u- S) H. ~4 i0 q- ?1 m
depends upon intrinsic testicular activity and may require
' e2 i/ ^+ ~' \( ]prolonged administration for any response.$ V% F9 W1 E3 e( {
Alternately, topical testosterone does not depend upon tes-, E3 G# i0 r# D8 ~8 ?2 C4 N
ticular function and may provide a more constant level of
0 m. u% @1 a$ f& z4 i$ s% RREFERENCES+ F" x* X, n4 T; o/ B* C
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 f2 O6 {1 ~$ S# Q& dR.: The local application of testosterone cream to the prepub-/ _- v* ^5 s8 B7 _# z
ertal phallus. J. Urol., 105: 905, 1971.
c* j; k8 Q; @3 }5 ]- g2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( [% f; g. L4 f2 I8 N7 etreatment for micropenis during early childhood. J. Pediat.,; k' c' v/ O/ K( P/ x9 \
83: 247, 1973.3 H$ ^- X% R$ u! j, a; u! q$ [5 J
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-! b+ e# k2 G. t- ?; k- t9 u
one therapy for penile growth. Urology, 6: 708, 1975.
: l2 o) ]" @: T3 a4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 E4 `2 p+ o3 Mto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 b$ R. R+ v9 T
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 g8 L1 a) [( w1 n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# o+ }. [8 T) b) o wby topical application of androgens. J.A.M.A., 191: 521, 1965.# B) E% J( _- Y9 ?8 Q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 X) t6 N, o; ?% Dandrogenic effect of interstitial cell tumor of the testis. J.4 e7 l1 I$ ^2 z$ i( [
Urol., 104: 774, 1970.
; U8 X4 M' y2 {- H7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
% g* g' ]0 P6 |7 H9 T# a8 mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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