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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ U! X1 a8 ]5 p) O: w9 g- q, k* K
GONADOTROPIN1 Y8 J5 t! Q. j" ~( b2 V/ m
RICHARD C. KLUGO* AND JOSEPH C. CERNY
  M: o/ z6 X  [2 SFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& y# D  l6 k% g9 k8 y* t+ ?+ pABSTRACT
, W, r1 d$ o$ z/ p3 w  E  f: ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated
% _2 m; g; O$ hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 U6 N; y+ h- }6 I- \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 ~1 Z( g' r. v- u+ Ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
  U% T* A1 t( ^1 x' Wfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: F. P" v6 L) r3 S9 S
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
/ j! M: F& U! n! G& Xincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ z; [- m4 |( o% L* ~, ^( koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 g$ I- v: X1 q8 c! c$ z; R
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 }* l6 V* v% w' z0 vgrowth. The response appears to be greater in younger children, which is consistent with previ-
5 e, i; z4 _9 H5 d" y0 wously published studies of age-related 5 reductase activity.
' d% c3 C4 e& @6 O, u) \Children with microphallus regardless of its etiology will
/ f( r+ U& U% I5 Prequire augmentation or consideration for alteration of exter-9 K, @" y! `2 n& [" M& Q. V, ^
nal genitalia. In many instances urethroplasty for hypo-: O4 q; k! `( X2 `9 L
spadias is easier with previous stimulation of phallic growth.
6 x% S% m; G1 W9 MThe use of testosterone administered parenterally or topically! B9 Y1 f# T9 ^1 Z2 Z( |/ w2 Y* y
has produced effective phallic growth. 1- 3 The mechanism of
# `& F  W! p! S" x. wresponse has been considered as local or systemic. With this& x+ {1 B4 ~, y
in mind we studied 5 children with microphallus for response( J1 u1 z- n; j$ e' [$ Z2 P
to gonadotropin and to topical testosterone independently.
4 i8 A. G. s  N. l/ h# w7 ^MATERIALS AND METHODS/ Y; U4 \$ M7 l5 z2 e9 H' e3 s  u
Five 46 XY male subjects between 3 and 17 years old were
# O* r5 m) {% a  s8 q0 yevaluated for serum testosterone levels and hypothalamic; H8 t7 R+ Y( N: ?# `: Q
function. Of these 5 boys 2 were considered to have Kallmann's4 n2 l( Q$ x" {9 [
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  B, B0 g+ k3 [! d, n+ s9 a; k
lamic deficiency. After evaluation of response to luteinizing; q7 X! [1 j5 {1 I0 q2 Y
hormone-releasing hormone these patients were treated with
" t4 T, w& y6 q& [0 }- }1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) s$ y6 }8 D/ I2 R0 K% _: k, Qafter completion of gonadotropin therapy 10 per cent topical# I7 o8 Z: K7 h7 J6 q: R
testosterone was applied to the phallus twice daily for 3 weeks.( |8 E2 ~# D8 H
Serum testosterone, luteinizing hormone and follicle-stimulat-
" o: ~4 Y( ~+ U: w& n2 D/ l4 ging hormone were monitored before, during and after comple-+ b# l: ?2 d% O% d% d/ p
tion of each phase of therapy. Penile stretch length was
6 B6 P! a. I3 w, G& T8 p) Bobtained by measuring from the symphysis pubis to the tip of% T0 ~! L$ {2 y' D* V( v
the glans. Penile circumferential (girth) measurements were9 k8 K+ }# c8 z: c' h2 m
obtained using an orthopedic digital measuring device (see: w9 J6 u2 v/ H5 W5 p) c' R
figure).
; o( F" t9 _/ ?0 h* ~, q% X9 ~3 B9 ARESULTS7 `% d5 F4 N! v& U* j" n# S' p( F
Serum testosterone increased moderately to levels between7 _- Y% z) z3 @9 T$ i
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 p! R# c) d* l) B% ~/ D: mterone levels with topical testosterone remained near pre-
; R' g* ]/ ]* R& O* ftreatment levels (35 ng./dl.) or were elevated to similar levels
) M; W1 o/ H$ q; R. edeveloped after gonadotropin therapy (96 ng./dl.). Higher
" S; K! i5 k2 aserum levels were noted in older patients (12 and 17 years old),
; u* V7 m$ c, |4 _  x  r7 L1 ^4 }while lower levels persisted in younger patients (4, 8, and 10  o/ p& i$ @3 b( y  n2 `4 W
years old) (see table). Despite absence of profound alterations7 X% g+ z8 ]- g' g5 @" g
of serum testosterone the topical therapy provided a greater
1 A1 i( x2 g* H" WAccepted for publication July 1, 1977. ·3 p+ P# V/ J  Z3 e& V; _: U2 x
Read at annual meeting of American Urological Association,% D4 F8 S  `+ i) }% H# i7 @
Chicago, Illinois, April 24-28, 1977.
' `. z: H- h- b# x0 V0 W3 E* ?* Requests for reprints: Division of Urology, Henry Ford Hospital,1 e4 c; h* J+ o8 D8 f
2799 W. Grand Blvd., Detroit, Michigan 48202.8 H$ @9 }' j6 r$ C& ?$ G) J! p, f  D1 o
improvement in phallic growth compared to gonadotropin.6 R7 q8 N+ n4 U; \' f* ]2 h4 v
Average phallic growth with gonadotropin was 14.3 per cent
1 y) {6 A' S/ dincrease in length and 5.0 per cent increase of girth. Topical2 z: n9 d2 g7 j/ ]; z) n
testosterone produced a 60.0 per cent increase of phallic length4 `$ k6 B' F$ d: N% n
and 52.9 per cent increase of girth (circumference). The
; z' I" k# b( Y. x# f$ y# g4 oresponse to topical testosterone was greatest in children be-
& w: j( y- ~  k, d: F$ j4 ztween 4 and 8 years old, with a gradual decrease to age 17
: T, X* u2 K! f* t. I% ^years (see table).
0 _. [8 C" N. w9 R0 |- t& N3 fDISCUSSION
0 S& l7 k8 X& OTopical testosterone has been used effectively by other
+ Z/ [& S8 R. J, [. v$ @5 f6 pclinicians but its mode of action remains controversial. Im-
6 J+ h2 V; ]% l2 z0 y" E- o  _mergut and associates reported an excellent growth response. Y6 D! [0 ]& l# v& ~3 V, s7 h
to topical testosterone with low levels of serum testosterone,. ]' U8 {* U; l" E& i7 [, y
suggesting a local effect.1 Others have obtained growth re-
+ `9 V5 X! g# o) psponse with high. levels of serum testosterone after topical# }4 |  K7 S+ e
administration, suggesting a systemic response. 3 The use of: W4 h) g8 D1 _$ k  T
gonadotropin to obtain levels of serum testosterone compara-- x  [9 l& O: V1 C; K4 q8 R
ble to levels obtained with topical testosterone would seem to  H9 a4 m7 o2 l1 \- U6 o# x5 t9 s& \
provide a means to compare the relative effectiveness of
( L, }+ o& t% ]$ X! m0 ]topical testosterone to systemic testosterone effect. It cer-+ \2 P: L1 i2 S" x
tainly has been established that gonadotropin as well as par-
/ q5 y) {. b* ]# [; ?' }$ K8 Ienteral testosterone administration will produce genital! y3 L' r  f+ X7 o" [
growth. Our report shows that the growth of the phallus was
) F, {" }: a: ^3 }; E- ]) f  Usignificantly greater with topical applications than with go-2 w3 Z( N: \0 _% t
nadotropin, particularly in children less than 10 years old.
) S* n1 p" a3 g: K! I/ p% XThe levels of serum testosterone remained similar or lower
0 s( M7 z; K5 ], @( ~0 q/ {2 Ithan with gonadotropin during therapy, suggesting that topi-
4 C* V- C3 D% Y, M& bcal application produces genital growth by its local effect as
7 w6 q+ L6 `! Z- z3 F- Owell as its systemic effect.
' M% ?* g3 F4 L, ?Review of our patients and their growth response related to8 o1 c% f# U2 h. [- t
age shows a greater growth response at an earlier age. This is
: \% U: n: ^/ d6 P# [consistent with the findings of Wilson and Walker, who& o$ h8 u& Y$ C" |' l
reported an increased conversion of testosterone to dihydrotes-% L* V: H$ J$ \
tosterone in the foreskin of neonates and infants.4 This activ-  \6 h* q& D  o" C9 C) a7 u6 n
ity gradually decreases with age until puberty when it ap-( M. a0 c3 Z* ]
proaches the same level of activity as peripheral skin. It may; h4 d+ d! e/ h6 C! u" X, \. b. U3 W
well be that absorption of testosterone is less when applied at. L, N2 W4 s( F% f
an earlier age as suggested by lower serum levels in children
4 A2 w( _6 _; M9 g8 W% Qless than 10 years old. This fact may be explained by the
; `$ Y7 j5 O: N* S' Ugreater ability of phallic skin to convert testosterone to dihy-
  h+ G4 ~; H0 `; r7 X- a6 bdrotestosterone at this age. Conversely, serum levels in older: p7 p% i) V  m! B
patients were higher, possibly because of decreased local% L. l& U, I- C
667
- r6 V5 X, \9 I; A) C, s, O668 KLUGO AND CERNY! O! }- `4 J2 @0 k
Pt. Age# j" Z: F6 f" @$ s* g/ y8 d2 f7 z
(yrs.)5 ]# b1 C) Z& v  C, r+ a
Serum Testosterone Phallus (cm.) Change Length: y/ N- H. r+ m% w, e/ C' [" ~
(ng./dl.) Girth x Length (%)
3 \' M$ ?, {) y+ _+ N  _  D- \4
$ O% I; S- h1 K) a8
0 v' X" e$ n! Y6 ~% Z% K# \10& E, {0 U+ L# Z# \8 X  m
12
7 e9 T8 D( @5 J/ z) Y17$ B7 C  Q' t  i- x
Gonadotropin
5 U( l7 y  T6 {$ Z71.6 2.0 X 3 16.65 o& B: y5 t: m( ~
50.4 4.0 X 5.0 20.0# H0 _) \( R% p0 B, \0 V- H
22.0 4.5 X 4.0 25.0
. H6 ^: ~7 q* W- {8 O$ N9 v& `84.6 4.0 X 4.5 11.1
) @/ V$ @3 `8 \85.9 4.5 X 5.5 9.0
7 x: J6 _% v/ Y& L1 D9 J+ CAv. 14.3
) ^) P) _* a" r0 d6 d' T4
* H9 t+ q# k* m( R  h/ B( }8# r" c& z- C) H3 K2 [
10
/ @7 x3 v4 T4 Y) y: ^% S: w2 j, C9 A12
: _' V. |  {' `% I5 H- ?1 {17( E* p( B+ B9 M5 \  J
Topical testosterone
' G: ]* E; b2 V6 z/ \. w) s7 A7 T34.6 4.5 X 6.5 85( P$ b- {3 D: w4 m
38.8 6.0 X 8.5 703 X4 F" ^: ?1 [7 J6 ]
40.0 6.0 X 6.5 62.5$ J" t8 [+ H' V; b' `: }5 g! b
93.6 6.0 X 7.0 55.5
. @$ M- N6 P0 }& c% ~, h- v+ R95.0 6.5 X 7.0 27.2
; w$ @& a' d0 Y  ^. g$ `  PAv. 60.0
/ ~. T7 ?/ u7 A. w: ^available testosterone. Again, emphasis should be placed on# K4 w* G( i# ~. X+ \
early therapy when lower levels of testosterone appear to
6 a8 w3 Z' A# aprovide the best responses. The earlier therapy is instituted1 H* M# [+ l5 `; j
the more likely there will be an excellent response with low
; u, X: a6 d7 f1 g/ n9 x( cserum levels. Response occurs throughout adolescence as
0 A8 B+ e, N; f" X' r/ P, lnoted in nomograms of phallic growth. 7 The actual response$ A$ r; Q$ k: n+ C' T( p
to a given serum level of testosterone is much greater at birth
+ l, H) v; w# d- H/ r+ N+ D2 Aand gradually decreases as boys reach puberty. This is most
) J. ]: b/ E7 s- Hlikely related to the conversion of testosterone to dihydrotes-$ k7 y8 i: z  \+ T- [% L6 F& }
tosterone and correlates well with the studies of testosterone/ q7 r3 T9 K4 y, Q, [
conversion in foreskin at various ages.
# R% P9 g* k8 k0 }5 @* zThe question arises regarding early treatment as to whether
: H$ f6 K* i9 k1 Q- p# d5 ?one might sacrifice ultimate potential growth as with acceler-) s  x; Z& U# `4 P. ?2 c7 K
ated bone growth. The situation appears quite the reverse
) T/ s$ b1 p$ x. H$ u" mwith phallic response. If the early growth period is not used
: d4 u. p) C  y4 `( G2 a2 p0 A5 qwhen 5a reductase activity is greatest then potential growth
/ S  ~1 v3 m* k6 x, B) Amay be lost. We have not observed any regression of growth( n4 e! x4 m+ ?% k2 Z
attained with topical or gonadotropin therapy. It may well
9 G; A! }0 x0 x/ }be that some patients will show little or no response to any1 Q0 g$ ]5 K" w) w2 k4 t
form of therapy. This would suggest a defect in the ability to8 }+ }3 u) G# }' C! |* M
convert testosterone to dihydrotestosterone and indicate that2 m# g5 _$ S! R0 {
phallic and peripheral skin, and subcutaneous tissue should
6 {$ j5 s. s5 R1 C& }- _2 w! {4 vbe compared for 5a reductase activity.# J8 A" E) t" b; b
A, loop enlarges to measure penile girth in millimeters. B,6 z, |4 G$ Q7 K0 W9 t1 w
example of penile girth computed easily and accurately.1 S  u9 P; g0 [' b" P/ p6 [
conversion of testosterone to dihydrotestosterone. It is in this
0 B" d- W4 z8 @3 c" v+ tolder group that others have noted high levels of serum
% i6 \) c7 t4 w6 R1 J9 l" I) htestosterone with topical application. It would also appear1 ?" y8 Z% S( l6 ?3 B  w! ^
that phallic response during puberty is related directly to the
+ s  E' H% Q( X6 w" }* U+ bserum testosterone level. There also is other evidence of local
7 {% r9 U$ f) {- ]4 x4 A3 bresponse to testosterone with hair growth and with spermato-
" X1 L( q) h: F1 I( Vgenesis. 5• 6
& O# T1 }5 `. U, z8 sAdministration of larger doses of gonadotropin or systemic
' s' m- R5 V5 I& [" p2 l, jtestosterone, as well as topical applications that produce! i% |" G5 L9 i1 r& T0 k
higher levels of serum testosterone (150 to 900 ng./dl.), will9 r: T* a7 M' I* {  S
also produce phallic growth but risks accelerated skeletal# ^! |2 C' Y# P& [% K
maturation even after stopping treatment. It would appear
  Z+ H7 Q' e, s1 f* @that this may be avoided by topical applications of testosterone, D, W9 d$ [9 U& E+ w
and monitoring of serum testosterone. Even with this control
1 C$ _/ r: `, l& \the duration of our therapy did not exceed 3 weeks at any
+ n1 J" W4 }3 K' L3 V8 i4 t$ Gtime. It is apparent that the prepuberal male subject may
2 M: ]! a; a9 L" Asuffer accelerated bone growth with testosterone levels near
- p, K! [9 ^) Z1 j5 r200 ng./dl. When skeletal maturation is complete the level of/ ~* _( x" H5 j  L# [# Y$ ^+ c
serum testosterone can be maintained in the 700 to 1,300 ng./$ W' |" P8 N7 ]. a, l7 ^- d
dl. range to stimulate phallic growth and secondary sexual
& @, M$ O$ U( W/ z& z7 Bchanges. Therefore, after skeletal maturation parenteral tes-
! [9 {; }" U9 J/ k3 D) x: w& {tosterone may be used to advantage. Before skeletal matura-" \6 K+ z0 g+ n. v# @
tion care must be taken to avoid maintaining levels of serum
$ l+ H2 |% x2 r2 W& o8 K. f; g; Ytestosterone more than 100 ng./dl. Low-dose gonadotropin7 X4 `1 t/ b& p( _+ q
depends upon intrinsic testicular activity and may require
, p, }: l$ g7 ^2 h; I0 cprolonged administration for any response.
' _6 f( f& a8 i, U( ?1 j* Y, r  U- \Alternately, topical testosterone does not depend upon tes-" e9 f, ~" ?. f4 \0 z/ E7 T4 L1 R
ticular function and may provide a more constant level of- O3 V( d  w# N  I. U+ A
REFERENCES( V/ y/ Z, K. B- l( z; ^7 B
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 n: {( v7 [# ]9 @/ b1 {. o' e' H
R.: The local application of testosterone cream to the prepub-
- B% d6 r8 H' p: r5 Qertal phallus. J. Urol., 105: 905, 1971." J) g) Z8 P6 n* z) U/ ?
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 \+ a: g* |. b% S2 z' A
treatment for micropenis during early childhood. J. Pediat.,
7 t+ Z& T) o. S( Y+ b$ t4 C83: 247, 1973.7 n9 d) X' R: D! I0 Q. D1 j0 g
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; g/ d  m6 i* @9 L0 L* P7 Cone therapy for penile growth. Urology, 6: 708, 1975.
4 m$ a% _0 Z4 @; z3 F9 ?7 ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, d) e! j9 z: M, e3 xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! R' b4 ~) S, x0 I* G- W6 iskin slices of man. J. Clin. Invest., 48: 371, 1969.7 o  {( f9 W) c+ I
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 K& W/ c- W5 W1 aby topical application of androgens. J.A.M.A., 191: 521, 1965.
0 J& J0 C- i" J+ [  d# w6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( k% Z1 {7 W! `% i$ V: x* `& `
androgenic effect of interstitial cell tumor of the testis. J.3 A* f" Q1 t+ l" n( P4 i
Urol., 104: 774, 1970.. J( O) z8 Y/ I
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- ]8 G2 ]  N' O7 [4 x7 V  V0 ition in the male genitalia from birth to maturity. J. Urol., 48:
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