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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 R, l( n9 d9 D) IGONADOTROPIN
' F# W) }1 ^( i+ A( kRICHARD C. KLUGO* AND JOSEPH C. CERNY
! ^( j) U0 y' e4 qFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, u2 Q! T/ V% V) W' C8 mABSTRACT
- w  `0 D4 k  b; EFive patients were treated with gonadotropin and topical testosterone for micropenis associated
/ V4 v8 `4 Q# x3 M2 B7 iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' e, Y( r0 }1 C; R1 ltropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' l1 I, k5 c1 G  l4 T
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 m5 N; K+ x: T1 ^
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent7 k# |  x  o9 |8 d5 |' I, a% a8 c
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 @0 |5 }& C+ X- x% a
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: X! Q* I9 [7 n; C4 C2 H! S
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ p' i1 H6 h) Z# o6 t& n# C2 g; I9 l+ zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; k! l9 K- B& I. L  ?9 T' \growth. The response appears to be greater in younger children, which is consistent with previ-
8 z3 S* ^6 X( m0 nously published studies of age-related 5 reductase activity.
, n. ]; I; O0 M$ _9 a, D9 @( oChildren with microphallus regardless of its etiology will" S& }# m3 [9 C  u3 J* f: q
require augmentation or consideration for alteration of exter-' i' L: U# `- U: r7 }
nal genitalia. In many instances urethroplasty for hypo-+ C0 ?0 v' L7 `9 t1 r
spadias is easier with previous stimulation of phallic growth.: c# n( H5 }0 I2 K6 B- M% d
The use of testosterone administered parenterally or topically* [$ p: A6 R4 A
has produced effective phallic growth. 1- 3 The mechanism of
3 g: d( ~- k$ O2 K& X% Y  O, j4 yresponse has been considered as local or systemic. With this8 j% B+ w* K+ J3 Z
in mind we studied 5 children with microphallus for response! c4 [+ O8 I6 q1 @0 i9 P
to gonadotropin and to topical testosterone independently.
3 ]9 K9 m' W" b( [3 hMATERIALS AND METHODS
+ \3 N7 W1 u5 N! cFive 46 XY male subjects between 3 and 17 years old were
3 ]6 [8 b9 _: b+ P/ gevaluated for serum testosterone levels and hypothalamic
/ a* X% ]  O, q( ]( g0 X2 \! O! v( Ofunction. Of these 5 boys 2 were considered to have Kallmann's
' U- f: g& ]+ ~syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 [/ G* N8 {- ]; c6 Z: U
lamic deficiency. After evaluation of response to luteinizing
, Y0 g  M7 J4 j% c- e2 {hormone-releasing hormone these patients were treated with
: [- @5 A/ }9 R3 u/ a9 ]1,000 units of gonadotropin weekly for 3 weeks. Six weeks& Y) z: Y# n: {0 }1 n0 M, @- z
after completion of gonadotropin therapy 10 per cent topical7 L& a) i! Z( o, _& N
testosterone was applied to the phallus twice daily for 3 weeks.$ D+ Y7 ]- m8 I% r1 \1 \7 n
Serum testosterone, luteinizing hormone and follicle-stimulat-
) T9 t5 P5 f" B5 o, }ing hormone were monitored before, during and after comple-, j$ h; r, ?9 K8 m
tion of each phase of therapy. Penile stretch length was; {+ R1 c! h# _+ A9 T
obtained by measuring from the symphysis pubis to the tip of
) v1 C& s2 c5 }3 `% k5 y9 }" p; bthe glans. Penile circumferential (girth) measurements were
2 p2 b9 s) H' T) sobtained using an orthopedic digital measuring device (see. s7 L0 U: d# u- O& J% E! t! V
figure).
8 N6 ]9 O0 G1 p5 u7 pRESULTS
2 Z% f& R# v6 f& |/ J% ^Serum testosterone increased moderately to levels between
7 u5 G# N" b2 K% R; y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 _, f' c% R7 V  ?% T
terone levels with topical testosterone remained near pre-
9 c& _, Z# l/ Q5 M) Ttreatment levels (35 ng./dl.) or were elevated to similar levels
; t0 P1 t  f: u  i% Zdeveloped after gonadotropin therapy (96 ng./dl.). Higher& @* }, ~! I! x+ Z% `
serum levels were noted in older patients (12 and 17 years old),6 K7 |1 l; [) O* l) k' Q! K$ E
while lower levels persisted in younger patients (4, 8, and 10( @/ y* [- Q7 [& f5 j0 z& M* I
years old) (see table). Despite absence of profound alterations2 G( d: f- Y: M3 a( y3 E
of serum testosterone the topical therapy provided a greater
1 ?! V8 Y* T+ _# U: IAccepted for publication July 1, 1977. ·9 ?) X. q5 C% C
Read at annual meeting of American Urological Association,6 P- W. q: T- s7 [" Q' W% |9 i
Chicago, Illinois, April 24-28, 1977.
) Q& c3 s2 \/ z; z8 B1 L( s* Requests for reprints: Division of Urology, Henry Ford Hospital,! N! J; b* R) m! R( r1 }( Q
2799 W. Grand Blvd., Detroit, Michigan 48202.) Q4 M4 T3 x% [8 p2 h1 W
improvement in phallic growth compared to gonadotropin.% q& g7 s) @( _' _% }6 K
Average phallic growth with gonadotropin was 14.3 per cent
) u( k, h- x8 J$ E) Y. `increase in length and 5.0 per cent increase of girth. Topical& D0 W9 T. \0 q
testosterone produced a 60.0 per cent increase of phallic length: [0 i4 h* z, I* s
and 52.9 per cent increase of girth (circumference). The
6 U% H8 O7 o9 j7 Gresponse to topical testosterone was greatest in children be-9 y! l/ `6 D. M& H" c
tween 4 and 8 years old, with a gradual decrease to age 178 n# ?6 X/ A& i2 D8 ]* O
years (see table).9 W2 |1 G" k8 I; z4 j
DISCUSSION5 C* q! a: p, G6 X0 P  P1 ~
Topical testosterone has been used effectively by other
* I; q3 \) ^) K( O; Yclinicians but its mode of action remains controversial. Im-
! H% p4 w% S! B" x; g8 Dmergut and associates reported an excellent growth response( a3 f. O- [5 s: D9 Q* t
to topical testosterone with low levels of serum testosterone,# u- L; F/ y1 [; F; Q1 G/ G
suggesting a local effect.1 Others have obtained growth re-
' w6 v* J: }3 ?) a; S9 B9 y4 n; s3 d, Ksponse with high. levels of serum testosterone after topical
4 {+ t6 a6 V- zadministration, suggesting a systemic response. 3 The use of* g& a8 q4 g4 q/ k
gonadotropin to obtain levels of serum testosterone compara-
& h) e7 y8 @% h' a9 A1 s% @: U3 _ble to levels obtained with topical testosterone would seem to
4 o2 W3 q& o; l! j! Y% dprovide a means to compare the relative effectiveness of5 Y! u2 S5 A% N/ }0 |
topical testosterone to systemic testosterone effect. It cer-9 |& ]' y; k% d/ z! Z
tainly has been established that gonadotropin as well as par-
8 i, P2 h( I: i0 Senteral testosterone administration will produce genital
4 a  w6 k9 R6 s. e  c5 I; d1 c& }growth. Our report shows that the growth of the phallus was
3 ^( H- i8 a6 A, Z/ E) |. xsignificantly greater with topical applications than with go-: t, X+ A) w- I
nadotropin, particularly in children less than 10 years old.
& c( d: V- y+ a4 O* E4 ZThe levels of serum testosterone remained similar or lower
& K2 _9 w  [/ J' a9 j' Y3 T  x; \% Vthan with gonadotropin during therapy, suggesting that topi-! _$ P/ @. r% V& D9 U% l/ P
cal application produces genital growth by its local effect as
8 T- ~0 i( u: u- I- R: Ewell as its systemic effect.6 X  d& I& t( @& Z& w& J7 t
Review of our patients and their growth response related to
) N2 y, l1 |- V1 z; |age shows a greater growth response at an earlier age. This is
% f  `) _' [8 W: r, tconsistent with the findings of Wilson and Walker, who
' [6 {3 I1 j) k# D. T. Ureported an increased conversion of testosterone to dihydrotes-# T. O# n8 Q2 ], [6 q" p
tosterone in the foreskin of neonates and infants.4 This activ-+ m3 k+ I! z/ N1 q8 ?0 O5 `
ity gradually decreases with age until puberty when it ap-% u& Q4 i* N; E0 t" c
proaches the same level of activity as peripheral skin. It may
* I' _0 |- P; n; Z6 Jwell be that absorption of testosterone is less when applied at# g# s& y2 K7 c6 U4 D2 G
an earlier age as suggested by lower serum levels in children2 f1 X4 [9 p3 @4 n) ~5 j, S
less than 10 years old. This fact may be explained by the/ b# [, F$ W' X& Q
greater ability of phallic skin to convert testosterone to dihy-
7 ]) _8 U9 n$ d5 }) K; A. Hdrotestosterone at this age. Conversely, serum levels in older) Z9 {7 @3 F$ g+ [' U- d
patients were higher, possibly because of decreased local3 N5 D' A9 r( ]. R  B
667
" a) e1 `" o- E9 _6 T- K668 KLUGO AND CERNY: D  I' I% C, J- [; ~# p
Pt. Age
* B, `9 {! V: F- L! f(yrs.)
6 p: g$ @/ P; Q3 WSerum Testosterone Phallus (cm.) Change Length
+ X' G7 A: M- c/ ^0 z' K(ng./dl.) Girth x Length (%)- l; `4 h$ L- \3 `6 f  ?
4
3 Y3 ^; O! C, l3 o3 g, C" L8' [3 v6 H3 d, s: k2 D$ ?
10
( `- s/ G8 y) N2 i124 C& d, J# d* x& b$ `& G8 o
171 a; g2 F) N% _* i$ f
Gonadotropin$ a7 o6 V; f5 C- o% ~, d
71.6 2.0 X 3 16.6
- F7 Q, `+ J7 X) W50.4 4.0 X 5.0 20.0, o! i$ N2 Z. S1 ?
22.0 4.5 X 4.0 25.0/ ?; M3 H7 e2 |( x
84.6 4.0 X 4.5 11.1" k6 {2 K. V8 l
85.9 4.5 X 5.5 9.0
& p7 F, O0 V; G7 u$ _  d% dAv. 14.3( c# @) Z  d0 _, U
4
7 p3 m( L# c; y8) ~# ^- M( ~1 a: K3 U
10$ a$ A# @# ]9 Z3 u3 g3 L9 Y2 e
123 I. P, \6 p) e3 S9 @( C9 w
17
9 ^, J" D( y5 C% T; tTopical testosterone
7 B; J  x, L5 ]. {) a34.6 4.5 X 6.5 85
$ z* S* {$ I2 u5 i' `0 F# G38.8 6.0 X 8.5 70
" h, G" |3 c" ?  w$ v2 N" t40.0 6.0 X 6.5 62.52 o8 ^% A+ E; V
93.6 6.0 X 7.0 55.5
! `% |3 {( M) D7 |6 N95.0 6.5 X 7.0 27.2
4 P2 [& q# ~/ `2 N; KAv. 60.0# l& f% f( m4 p1 ?3 O
available testosterone. Again, emphasis should be placed on
/ M+ I+ H. g' [' x* l8 s/ qearly therapy when lower levels of testosterone appear to3 y4 [6 L9 I/ @" n
provide the best responses. The earlier therapy is instituted  j/ U; o0 A! }" G, |" u& x
the more likely there will be an excellent response with low
5 s; ^' D: m  a7 @$ f2 h' z& cserum levels. Response occurs throughout adolescence as
# x: m8 R5 t$ C8 L+ N. s) rnoted in nomograms of phallic growth. 7 The actual response
/ a; z$ D& j  ]4 b* I4 `; Xto a given serum level of testosterone is much greater at birth
* n5 _3 Z. d6 Kand gradually decreases as boys reach puberty. This is most
7 w% V* V/ Y! u$ G( R2 F; _likely related to the conversion of testosterone to dihydrotes-" Q/ A* \( q( A/ [  I! V
tosterone and correlates well with the studies of testosterone$ Z  \; k, W) Z5 J
conversion in foreskin at various ages./ f. C: ^# Q9 o
The question arises regarding early treatment as to whether0 d3 N) Y' ]. Q8 r! ^9 S0 h: h+ h
one might sacrifice ultimate potential growth as with acceler-" D3 G- u/ I+ K( ?
ated bone growth. The situation appears quite the reverse/ L) `$ e9 A0 M/ ~1 G7 w( B  J3 S
with phallic response. If the early growth period is not used8 Z% u5 J, e  j8 r
when 5a reductase activity is greatest then potential growth' M( t+ x# ]7 h5 e& V$ k( V
may be lost. We have not observed any regression of growth# u: X4 h9 o: U% R5 e- q2 S4 Z6 o
attained with topical or gonadotropin therapy. It may well
+ G. C# M' J' i6 Ube that some patients will show little or no response to any6 Q$ x* m* Q9 O5 K/ P- Q
form of therapy. This would suggest a defect in the ability to
7 U6 Z4 M; Q! w" F$ _3 y. L- rconvert testosterone to dihydrotestosterone and indicate that
6 R$ c  o% u  G0 yphallic and peripheral skin, and subcutaneous tissue should( M1 w+ \# [# e1 x$ _
be compared for 5a reductase activity.8 R5 T6 a: U4 q5 i( v" e
A, loop enlarges to measure penile girth in millimeters. B,- \3 q- M* m- ?6 r$ o4 |
example of penile girth computed easily and accurately." U$ B1 O0 q6 ~. `, @0 W& D, O
conversion of testosterone to dihydrotestosterone. It is in this- O& u+ h7 h+ u' h+ u' E
older group that others have noted high levels of serum
5 ^: L. b) q0 k' ztestosterone with topical application. It would also appear
6 I- R: Z" Q+ G0 P" [  `2 nthat phallic response during puberty is related directly to the3 W8 s* b4 n+ l9 J1 \# l
serum testosterone level. There also is other evidence of local
9 n+ n8 N: U" r9 O8 Lresponse to testosterone with hair growth and with spermato-6 Q! h1 ?, x8 F' Q* s2 A2 u; n- ^
genesis. 5• 6
5 s6 c8 G& J# u- f8 k' |Administration of larger doses of gonadotropin or systemic
0 e( H4 Y( Z( q9 \testosterone, as well as topical applications that produce
5 S- ~+ ~, m5 v; ]( E1 ohigher levels of serum testosterone (150 to 900 ng./dl.), will
" \2 Z( ~7 h, _* k) ralso produce phallic growth but risks accelerated skeletal7 ]& {; e- s- G/ W4 x
maturation even after stopping treatment. It would appear
2 B, j2 b* F" X, Pthat this may be avoided by topical applications of testosterone, U: C3 [5 C( l! w9 b! w4 d
and monitoring of serum testosterone. Even with this control
+ j- T. i6 c- d* e; vthe duration of our therapy did not exceed 3 weeks at any9 @! j* _# n1 F" q# u; o% R  y
time. It is apparent that the prepuberal male subject may
1 v6 d" F& K  ]3 d% I, Vsuffer accelerated bone growth with testosterone levels near4 e1 b4 x- q# E5 ]
200 ng./dl. When skeletal maturation is complete the level of
* A; ]! e8 m$ N, w3 Kserum testosterone can be maintained in the 700 to 1,300 ng./" q( e0 T( [; q! V. A2 [( E
dl. range to stimulate phallic growth and secondary sexual$ t9 \& i+ g, w- v& b$ Y8 r7 J
changes. Therefore, after skeletal maturation parenteral tes-; Z9 o+ d, d4 l# j& L  e* M& J
tosterone may be used to advantage. Before skeletal matura-' P# Q* A8 E+ n$ \) y( P( g; T: y
tion care must be taken to avoid maintaining levels of serum/ m5 Q% I, @. _1 U5 t& o8 B
testosterone more than 100 ng./dl. Low-dose gonadotropin: a. B1 `- N7 p7 c7 U, \" o% h
depends upon intrinsic testicular activity and may require" J; k7 x5 A: s7 @
prolonged administration for any response.3 r% j( s+ @+ j: v0 V2 P
Alternately, topical testosterone does not depend upon tes-6 Q  ^/ n/ l. D0 x
ticular function and may provide a more constant level of
" v. h  l. `$ n, yREFERENCES9 `9 G& ?# F7 G# ]
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- U6 {+ j/ z+ f8 o4 [# ?
R.: The local application of testosterone cream to the prepub-
' k( a" K/ A5 Y8 C7 |5 n# pertal phallus. J. Urol., 105: 905, 1971.5 Q3 U& G& f+ P  @
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" n2 \) Y6 @7 ^. o0 Htreatment for micropenis during early childhood. J. Pediat.,
* z7 o& Z7 {: K6 L* A% Z& {  m83: 247, 1973.
0 m7 s: t; Y/ n. L$ a- r3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. {$ R/ l% y) B+ l2 ~
one therapy for penile growth. Urology, 6: 708, 1975.& E) ~; y# W* n" H$ n
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone! v$ k7 @4 E( v* i$ w
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. c$ I1 r5 n* \/ cskin slices of man. J. Clin. Invest., 48: 371, 1969.
" y5 p) G0 G. N+ \& `5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
! n( q; Z0 n. Y. H$ Sby topical application of androgens. J.A.M.A., 191: 521, 1965.$ c7 x3 D# t" N( V2 f) j/ j
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! }& q* P3 ^1 W# @$ S  sandrogenic effect of interstitial cell tumor of the testis. J., X& x& v$ M: q
Urol., 104: 774, 1970.
. W. O2 n+ c* ~8 W4 N/ L6 {7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ X4 X6 @6 z( e) L  Z0 qtion in the male genitalia from birth to maturity. J. Urol., 48:
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