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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% q6 r7 F2 Z+ WGONADOTROPIN- G+ P, m" j% v, f& k. \ u! B
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 d6 G& z/ R8 R! tFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ s* k/ F" E2 i7 `; a5 L7 c
ABSTRACT
) R" ^4 F3 T' @/ ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 U- K' t7 E; c: W" o, Vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 r- q$ a' l7 ^- W8 Y$ h
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% K8 H7 y: W7 A y# E9 m9 G9 r
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 L4 l) }- r+ D/ s5 C/ ~/ i5 Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% S- T% Y4 ?! h2 ?! L5 d8 O+ O+ s- Gincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 i6 I" U1 N3 g% N3 m S
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ A% e! I, D9 G6 {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ W: H1 G% x1 I# B2 }
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ r3 P* _' s# T, z! C
growth. The response appears to be greater in younger children, which is consistent with previ-. P9 K9 G+ Y4 G) u( R
ously published studies of age-related 5 reductase activity.
3 y& ?* q4 p+ G- [0 Q+ b* UChildren with microphallus regardless of its etiology will
# I1 U0 _; N" f' ~8 W7 V, ~# {require augmentation or consideration for alteration of exter-# E8 P3 `# R) m' M+ I4 D# h
nal genitalia. In many instances urethroplasty for hypo-' u+ P6 M5 `4 _+ C q
spadias is easier with previous stimulation of phallic growth.& J: v$ t# J4 I' i) M
The use of testosterone administered parenterally or topically
3 H, m% {% e4 }9 y+ ~& xhas produced effective phallic growth. 1- 3 The mechanism of& ~. w4 c# K+ x( T# |/ ]
response has been considered as local or systemic. With this) [! e% o( ~( ^ j, {
in mind we studied 5 children with microphallus for response
( R4 P7 g& Y! A: U. K4 Q Jto gonadotropin and to topical testosterone independently.1 ~! `1 ^" K S; V6 W
MATERIALS AND METHODS( b- ^* ]. t0 q% \6 Q; J$ [) T/ e
Five 46 XY male subjects between 3 and 17 years old were
4 q2 e( D; f% p; m2 yevaluated for serum testosterone levels and hypothalamic
5 S( B; `* K4 w/ nfunction. Of these 5 boys 2 were considered to have Kallmann's! o& N0 G! ~" [" a4 G
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% w7 O& j$ A0 V: p/ H0 u Q( W" d
lamic deficiency. After evaluation of response to luteinizing9 ]) [8 c* k2 k8 S& d# Z
hormone-releasing hormone these patients were treated with
$ n- {6 f' a! Q1 L1,000 units of gonadotropin weekly for 3 weeks. Six weeks
4 C& q+ J! V5 i) h' mafter completion of gonadotropin therapy 10 per cent topical! s$ w8 C) P$ P T& |" e
testosterone was applied to the phallus twice daily for 3 weeks.
) z& Z3 H- Y' S# xSerum testosterone, luteinizing hormone and follicle-stimulat-
' D( b# x8 @" ding hormone were monitored before, during and after comple-4 {) c" P5 u9 M) p6 W
tion of each phase of therapy. Penile stretch length was
0 t2 C* a( f2 |3 p1 s/ w) w1 Zobtained by measuring from the symphysis pubis to the tip of) E$ Y- {% g" ?. p
the glans. Penile circumferential (girth) measurements were
6 m* n4 U3 _$ z* Y- j! oobtained using an orthopedic digital measuring device (see- V: L! o: ^( ~) s" w4 h8 [) ?9 l% m
figure).: f( f5 t- z2 Z( F, _
RESULTS5 b; J: I z5 \+ d7 h
Serum testosterone increased moderately to levels between
5 z) s4 E4 R4 z- v/ R1 T% u1 E50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 s, q! F2 i# f9 B1 K& f+ I4 wterone levels with topical testosterone remained near pre-
- J+ u* f6 G% X! ^/ h! ktreatment levels (35 ng./dl.) or were elevated to similar levels# X$ ^' W7 E& d/ B
developed after gonadotropin therapy (96 ng./dl.). Higher* D& F# P6 }/ u4 \
serum levels were noted in older patients (12 and 17 years old),( y1 |! v+ U) V9 ]! Q6 M
while lower levels persisted in younger patients (4, 8, and 10
, H4 ~. H- P+ l# u7 c0 r9 Z( iyears old) (see table). Despite absence of profound alterations8 \( A- A3 P( Z- q6 I) n
of serum testosterone the topical therapy provided a greater
7 q. {* Z9 a5 J' V2 S2 TAccepted for publication July 1, 1977. ·- _' \, E5 H6 ?6 }
Read at annual meeting of American Urological Association,/ m; d$ q1 n$ K* A. c V
Chicago, Illinois, April 24-28, 1977.
6 o4 A3 D, K9 u" _* Requests for reprints: Division of Urology, Henry Ford Hospital,# t! B) b5 Z2 ?0 t, f, P2 |% W/ F
2799 W. Grand Blvd., Detroit, Michigan 48202.
8 L) ?# x( [& s# @2 Z/ Y$ kimprovement in phallic growth compared to gonadotropin.
1 L, X( {" l" t0 I3 Y" cAverage phallic growth with gonadotropin was 14.3 per cent
1 P( i Q5 W( _) l6 l8 Pincrease in length and 5.0 per cent increase of girth. Topical8 w1 \9 K2 W% k9 U( o+ U0 f3 N( O
testosterone produced a 60.0 per cent increase of phallic length: x0 E/ v5 p9 z) q1 s
and 52.9 per cent increase of girth (circumference). The2 J8 J2 J- q7 t
response to topical testosterone was greatest in children be-
, p- f+ K6 O6 z; r2 H& ftween 4 and 8 years old, with a gradual decrease to age 17 Q, g& j p* X, U
years (see table).2 K9 n; t1 \. Q! H! {* s
DISCUSSION
1 g9 ^. Q* G C! J; E& QTopical testosterone has been used effectively by other
8 r' ^! A4 P& r3 wclinicians but its mode of action remains controversial. Im-& t7 r) V2 R3 K5 S: z8 o
mergut and associates reported an excellent growth response; ~3 S2 K! J. L; [5 h% m5 T
to topical testosterone with low levels of serum testosterone,: l/ q( U0 L- m! D j d/ L9 z
suggesting a local effect.1 Others have obtained growth re-/ ] u: `7 Z+ l: i+ Q0 X
sponse with high. levels of serum testosterone after topical9 Q4 F `: Z" i6 a3 W
administration, suggesting a systemic response. 3 The use of
. m/ W# z2 f9 f8 [% w1 d% R& ?; \. bgonadotropin to obtain levels of serum testosterone compara-4 F7 f0 F3 e4 c, ^. p4 k4 `) r
ble to levels obtained with topical testosterone would seem to# j0 l8 X% x( x
provide a means to compare the relative effectiveness of/ x5 |8 d; ~5 }) ]
topical testosterone to systemic testosterone effect. It cer-
+ \2 f! u9 \ n' O" Itainly has been established that gonadotropin as well as par-
, p5 X, }9 Y {& G! u' l& kenteral testosterone administration will produce genital. b* R$ s: E; }# [$ T8 M# l9 L% s1 [
growth. Our report shows that the growth of the phallus was
6 G3 `3 d$ z$ k; W7 M4 n) m& usignificantly greater with topical applications than with go-- g- S" H0 B# J
nadotropin, particularly in children less than 10 years old.
1 K( H' M& W1 a/ F6 I7 D/ y7 lThe levels of serum testosterone remained similar or lower
- [. u% s9 k9 H$ y* ?+ Z# bthan with gonadotropin during therapy, suggesting that topi-; H, C1 h+ _3 r, t
cal application produces genital growth by its local effect as7 ~6 J# b5 k9 ?' ^4 y# K; E' D; W
well as its systemic effect.
6 Q, ?( l% e* f1 C3 _4 _Review of our patients and their growth response related to7 N2 P+ c8 G: I1 Y
age shows a greater growth response at an earlier age. This is4 N9 @ B5 N3 M* U+ C- |+ y3 S7 \/ W
consistent with the findings of Wilson and Walker, who$ d7 k- j7 X2 d* Z1 [
reported an increased conversion of testosterone to dihydrotes-
+ G5 E6 u+ A D7 I4 c# C7 ktosterone in the foreskin of neonates and infants.4 This activ-3 c3 R4 Q, @" m0 N1 n- o
ity gradually decreases with age until puberty when it ap-1 V- C( v0 P% M" K. \9 T
proaches the same level of activity as peripheral skin. It may. c9 t( q& A8 }8 d' W
well be that absorption of testosterone is less when applied at
% P3 X m6 ?& s) Y, C0 V wan earlier age as suggested by lower serum levels in children
5 g% I0 O, @2 H& E" K6 `) gless than 10 years old. This fact may be explained by the
. x1 F( B; p7 S x4 k. Kgreater ability of phallic skin to convert testosterone to dihy-
( [$ e- i/ X( |- P4 ?1 Edrotestosterone at this age. Conversely, serum levels in older6 l8 v7 D" Y8 g8 k( ^
patients were higher, possibly because of decreased local# t# h5 |6 U- v8 m8 |* [
667& R. t; C2 `4 o1 V4 T" Z' [) L
668 KLUGO AND CERNY
/ [7 Q0 r( x7 kPt. Age4 H0 o! j% P$ T6 g1 u
(yrs.)
6 k5 P& A7 g( j; C: @& ASerum Testosterone Phallus (cm.) Change Length, H( e; o# t. G; m% k* T
(ng./dl.) Girth x Length (%)- ]1 c( t1 G; S; C
42 `) K$ h# d1 s: K% N4 q
83 g, q: Q8 ]" j1 d* X1 b. C
10
! @) W; ?9 x( k2 C* l( A1 Z' Y- x12
4 A5 k3 a1 E! s* r+ \$ g175 v2 _/ L; H+ l2 k2 R2 a
Gonadotropin
" A: F0 b' }0 u# `+ f" J% l+ U1 u% K71.6 2.0 X 3 16.6+ ^' R9 m5 b9 ~, i# w- `
50.4 4.0 X 5.0 20.0
0 h( F& X) \3 v: p& u22.0 4.5 X 4.0 25.02 o: V, l0 D8 a5 y! n+ q$ a2 e0 P$ y
84.6 4.0 X 4.5 11.1
+ d) C$ F0 V& q @: e85.9 4.5 X 5.5 9.0
# g* d, ~3 U) CAv. 14.3
7 L4 e, @9 I) Q4: W: x) y, N/ q. t* Y8 H
86 c, y2 G' M! H9 C
10
' x9 B( ?" d. i) C12
$ d, z$ Q+ ]1 e V; r17
l3 M( x6 @; u! w5 [Topical testosterone
# K, n9 l O, O0 W2 z34.6 4.5 X 6.5 85
5 E( { j% b( R3 ]4 J0 X+ w38.8 6.0 X 8.5 70
P9 ~. z1 ?: Z9 C) ?& E& v7 z40.0 6.0 X 6.5 62.5
. k& W5 M/ y" X: j3 x/ l$ H93.6 6.0 X 7.0 55.5
# n8 s/ j& Y7 ^$ M! G95.0 6.5 X 7.0 27.2
- ?" ^( T7 E0 @+ b! N' P& q) YAv. 60.0# |- D2 @4 v* m$ _* P
available testosterone. Again, emphasis should be placed on
" P4 k, |+ C$ p- q* d( }early therapy when lower levels of testosterone appear to4 ]- L9 x7 [8 I; I# `% N
provide the best responses. The earlier therapy is instituted
3 r% a: F, A: q+ Qthe more likely there will be an excellent response with low
1 T. ? B# D- J1 d, kserum levels. Response occurs throughout adolescence as$ c- o6 K' m0 K2 m1 j/ o
noted in nomograms of phallic growth. 7 The actual response+ x* v1 _: Q5 I' d* _2 g
to a given serum level of testosterone is much greater at birth, p H, t. E' b: b0 H8 a
and gradually decreases as boys reach puberty. This is most4 U7 ]% }# U, W3 o6 l! T. a; M6 n
likely related to the conversion of testosterone to dihydrotes-8 B6 Z; [' i7 |: l
tosterone and correlates well with the studies of testosterone
) _* }3 d1 O# econversion in foreskin at various ages." H$ u$ q+ F+ d+ H/ {, g' ]4 s
The question arises regarding early treatment as to whether
; V- ^; K0 {5 G( U3 l! \one might sacrifice ultimate potential growth as with acceler-1 R% s8 B3 _3 H+ W6 ^
ated bone growth. The situation appears quite the reverse# d5 j, I5 Y# P
with phallic response. If the early growth period is not used
+ L$ S7 i, N' U( M( Swhen 5a reductase activity is greatest then potential growth
# B$ P, L& C: x* G' l: omay be lost. We have not observed any regression of growth
$ a4 x5 L4 P3 fattained with topical or gonadotropin therapy. It may well1 O$ E( j3 L% G% C
be that some patients will show little or no response to any
0 q; b; C+ a9 }$ y- M3 j% n# Vform of therapy. This would suggest a defect in the ability to& ]5 a: o, x# U) J R$ X* A
convert testosterone to dihydrotestosterone and indicate that/ g2 f9 ^6 I/ {+ L9 A0 }9 D* ]
phallic and peripheral skin, and subcutaneous tissue should
& L% W8 s; c- C) \7 g! pbe compared for 5a reductase activity. V: O( |* e$ `/ E# @& }
A, loop enlarges to measure penile girth in millimeters. B,
P0 F1 p+ M2 kexample of penile girth computed easily and accurately.
~4 M3 h, y& Pconversion of testosterone to dihydrotestosterone. It is in this
$ X* F* c4 U, Q+ Bolder group that others have noted high levels of serum! d; Q& n. n- M
testosterone with topical application. It would also appear$ {9 f' B1 h5 [7 s! h/ P
that phallic response during puberty is related directly to the7 B U$ G) ^- _. y6 B+ T
serum testosterone level. There also is other evidence of local& ?5 C2 R7 |1 d1 U2 q4 g# J' v, ]; u
response to testosterone with hair growth and with spermato-
% r6 p) ]: [' N8 H& x/ }genesis. 5• 60 r9 ]' ~3 ]1 G1 l) }- }
Administration of larger doses of gonadotropin or systemic
9 ~& \- J9 s2 V$ {1 ?testosterone, as well as topical applications that produce+ Q8 }5 A) ]5 L
higher levels of serum testosterone (150 to 900 ng./dl.), will
) n3 V0 X5 {5 M( a' \6 Talso produce phallic growth but risks accelerated skeletal
+ M& L% h* T7 W2 z& vmaturation even after stopping treatment. It would appear
2 ^+ V- d5 |" f8 f3 [. P, Bthat this may be avoided by topical applications of testosterone
, b* z0 d R0 w& oand monitoring of serum testosterone. Even with this control
0 L k% d" y/ _ s5 Ithe duration of our therapy did not exceed 3 weeks at any
5 D N0 P! a$ i+ E. Itime. It is apparent that the prepuberal male subject may0 E; g X1 A0 @. f9 c7 {: v
suffer accelerated bone growth with testosterone levels near1 a* ]) O; L0 J' v% I% v
200 ng./dl. When skeletal maturation is complete the level of
. `% ?1 A" {. [; ?8 Nserum testosterone can be maintained in the 700 to 1,300 ng./
/ A }6 M& k" i& D- E, W2 Cdl. range to stimulate phallic growth and secondary sexual
' e2 X, a% }' B2 O X% d+ tchanges. Therefore, after skeletal maturation parenteral tes-
& ?9 h* W; V1 b3 Qtosterone may be used to advantage. Before skeletal matura-
- f4 z0 A4 U( jtion care must be taken to avoid maintaining levels of serum
: K2 |* s L& @ ^3 c1 J6 ]8 Ptestosterone more than 100 ng./dl. Low-dose gonadotropin
; F; F8 y6 G: t: I! h. qdepends upon intrinsic testicular activity and may require! E' \2 \9 \: g+ ]8 J' d8 O0 J5 M
prolonged administration for any response.& |# r# O, W" ^; F# e
Alternately, topical testosterone does not depend upon tes-% Y. ^$ l7 T& I' Z, H- F
ticular function and may provide a more constant level of
" R: q2 ?% _6 b! kREFERENCES
, F; E; }$ w+ |- w, d/ L; B: c1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
( v8 T, `% c9 E+ @( C3 l/ NR.: The local application of testosterone cream to the prepub-6 E* K4 g5 r. `! G$ B4 ]8 \
ertal phallus. J. Urol., 105: 905, 1971.+ a$ q/ w# s' x! g
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
& c# N9 e3 a* wtreatment for micropenis during early childhood. J. Pediat.,
: L1 `+ M \* e) e3 n83: 247, 1973.
& }0 |9 K# G- {& M7 N n+ [3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% d) j j& P5 e: g! f
one therapy for penile growth. Urology, 6: 708, 1975.8 J$ d8 d0 H/ s( `( H
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone# G `' r& }3 S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by7 L$ e3 E7 f: A
skin slices of man. J. Clin. Invest., 48: 371, 1969.
( _5 E9 F1 \+ l, F5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& s+ l& s- y' }" T# m& @by topical application of androgens. J.A.M.A., 191: 521, 1965.
: v- |: Z1 [" L' v6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local2 Y- _) s: s5 T1 _. V% f
androgenic effect of interstitial cell tumor of the testis. J.' I% q. g$ _, M. j
Urol., 104: 774, 1970.
1 f* L( Q/ d6 j2 U+ r7 \ X7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, o$ ^) p x5 }+ a) k8 G/ D
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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