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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* `, R# c+ A$ F: w! ^GONADOTROPIN
) s; G3 x+ o/ B% y) PRICHARD C. KLUGO* AND JOSEPH C. CERNY2 A* I+ O; `4 S& @
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: h* Z N4 k- d+ j1 w( t% \ABSTRACT& i+ }- {" Q& G; \0 j! Q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) G: _/ _5 R& s% j9 c
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 R S0 P0 i- Q( i4 {+ P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- ?1 s0 X. Y% e. }( X/ U# x
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. U% w' p1 i6 @# X. t& ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* Q5 P# e6 L4 u# ~& B5 Cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 W0 ^% v/ ?* \4 ^" x9 J% hincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
* w/ I/ i: g Y/ ]9 v: ]$ m2 s8 @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 A0 |; v7 ]' A" G1 Q( B
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ b ?7 E9 M5 k; A4 zgrowth. The response appears to be greater in younger children, which is consistent with previ-
3 [. |& h+ B; c3 ?0 sously published studies of age-related 5 reductase activity.4 i+ O) v. ^ J( T( f
Children with microphallus regardless of its etiology will8 ~; x' Y* S: S
require augmentation or consideration for alteration of exter-
- G' e5 c7 q: k4 }, dnal genitalia. In many instances urethroplasty for hypo-
g8 W( G, F+ Lspadias is easier with previous stimulation of phallic growth.
! r+ f4 n. ?* G3 ]The use of testosterone administered parenterally or topically0 E) c% Z7 U. j; K2 f1 j- C
has produced effective phallic growth. 1- 3 The mechanism of1 G3 g; W: ^: {- f+ A8 m ~/ r
response has been considered as local or systemic. With this5 g- U) i9 q, V7 q) S7 i+ n" u
in mind we studied 5 children with microphallus for response! g/ o2 E8 H6 O# Y' j8 v! t: l
to gonadotropin and to topical testosterone independently.! H6 M, A* d# M; x# p/ w
MATERIALS AND METHODS
6 q: D( ~9 t# k7 kFive 46 XY male subjects between 3 and 17 years old were' N- m' u* u$ y1 v# v
evaluated for serum testosterone levels and hypothalamic
" s H# o% M% a! efunction. Of these 5 boys 2 were considered to have Kallmann's1 b# v* `# X/ @4 \* B: G, m: N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 D- b8 D/ T4 A) A2 s& z0 _6 Elamic deficiency. After evaluation of response to luteinizing* ?- I9 V8 H5 f
hormone-releasing hormone these patients were treated with
1 c g5 w, ]/ h* V4 E5 o/ p1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 c$ _, Z7 i9 n
after completion of gonadotropin therapy 10 per cent topical
% l: B# E( @; H" w( a i0 \testosterone was applied to the phallus twice daily for 3 weeks.
/ v: l! j" [) W6 M- Y/ fSerum testosterone, luteinizing hormone and follicle-stimulat-$ S' x; Q1 w4 W( |2 e* w4 n# `
ing hormone were monitored before, during and after comple-3 l9 @; ?' w9 v% U4 G6 |/ P1 g5 C
tion of each phase of therapy. Penile stretch length was+ C9 M) Z& d3 R$ U# s( K, X
obtained by measuring from the symphysis pubis to the tip of
* [) t' s# n* P0 Tthe glans. Penile circumferential (girth) measurements were& S" E2 ~' w; ?6 M" i' G9 e4 ^
obtained using an orthopedic digital measuring device (see `+ f% e& f* v0 j
figure).
: k. j* ~/ Y: C- Y- f5 gRESULTS" b; l# Z, ^3 |& g9 k8 U# Y
Serum testosterone increased moderately to levels between6 X/ q- x' c4 G* L) F& l: l* B
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
, k8 g% \- X: e3 R! N6 eterone levels with topical testosterone remained near pre-
0 P$ K7 a' D: L! X4 n* K# W1 f& \/ D1 xtreatment levels (35 ng./dl.) or were elevated to similar levels
& B! y) N. b9 O8 d. z2 s7 p+ |developed after gonadotropin therapy (96 ng./dl.). Higher; E0 t u" B9 u* W
serum levels were noted in older patients (12 and 17 years old),: ~' l' l9 ~7 q- M8 q
while lower levels persisted in younger patients (4, 8, and 10) b q# V. F P
years old) (see table). Despite absence of profound alterations
- F* ^* A7 G4 m8 ~of serum testosterone the topical therapy provided a greater
- N( m3 x+ X1 S2 r8 U& N* D' @( CAccepted for publication July 1, 1977. ·- p& ?8 y3 m- c& \! B
Read at annual meeting of American Urological Association,2 M Y* }* D/ N/ X! s5 I( A- E2 M# E
Chicago, Illinois, April 24-28, 1977.
. D* i8 o. {/ ?8 P1 Y/ }* Requests for reprints: Division of Urology, Henry Ford Hospital,5 f1 r, d7 j* s4 i" w- {
2799 W. Grand Blvd., Detroit, Michigan 48202.
+ ?7 d+ C8 r. `. L8 X& Y) `improvement in phallic growth compared to gonadotropin.8 l1 n& v2 @* V2 ^. h
Average phallic growth with gonadotropin was 14.3 per cent
7 k% D/ P% d0 F4 Tincrease in length and 5.0 per cent increase of girth. Topical
7 I. G* |% C0 f( N0 z' @testosterone produced a 60.0 per cent increase of phallic length
1 W4 }2 `3 e V6 J: `7 d7 Aand 52.9 per cent increase of girth (circumference). The
! i+ t+ j$ o; {) K' I& Rresponse to topical testosterone was greatest in children be-
0 V3 b) C& t$ p* f; ]) h+ a8 q2 gtween 4 and 8 years old, with a gradual decrease to age 175 l5 `" W: D! G3 `* v6 O
years (see table).
8 V$ F$ ~5 b, }DISCUSSION
0 G% W8 N7 ^! q3 T3 o5 h1 KTopical testosterone has been used effectively by other3 n* { b5 I3 M. x) l
clinicians but its mode of action remains controversial. Im-
* p9 y- ~0 d1 W. }2 Smergut and associates reported an excellent growth response
, V. E7 v3 z4 a9 b; xto topical testosterone with low levels of serum testosterone,
2 K& v" g- J6 Hsuggesting a local effect.1 Others have obtained growth re-
' S0 B" N, |) @' T5 d. Nsponse with high. levels of serum testosterone after topical; v. X. t) [8 k8 C2 S- b* J
administration, suggesting a systemic response. 3 The use of5 |7 k3 P4 l- {( l2 |
gonadotropin to obtain levels of serum testosterone compara-5 U. f* w1 Y! D' {/ B; F
ble to levels obtained with topical testosterone would seem to
8 [5 Z* a4 v! F$ T: K2 o lprovide a means to compare the relative effectiveness of
7 `( `$ X6 x/ \# mtopical testosterone to systemic testosterone effect. It cer-: C5 b# v( E, A# b8 P' g o: L1 e5 F
tainly has been established that gonadotropin as well as par-
0 V" m U9 d) `, Q! I" r6 eenteral testosterone administration will produce genital
/ ^7 [$ G0 l. W4 Bgrowth. Our report shows that the growth of the phallus was
+ L/ h, k+ b: v1 F' hsignificantly greater with topical applications than with go-/ C' }: s6 ^% R; u
nadotropin, particularly in children less than 10 years old.
I/ Z$ p( R; `6 c! Z0 T7 sThe levels of serum testosterone remained similar or lower
9 |( |: q1 D3 O4 _6 E% v: jthan with gonadotropin during therapy, suggesting that topi- q- r! T0 k1 w9 L& F
cal application produces genital growth by its local effect as: j) W, T# H4 e% w! n) S! Q+ z
well as its systemic effect.% U0 K1 \1 T7 v. Q- C
Review of our patients and their growth response related to
8 `1 x: Q9 o' I gage shows a greater growth response at an earlier age. This is
5 g+ |; ~+ N9 [ K2 x( J. xconsistent with the findings of Wilson and Walker, who) t* C7 w% S X$ Z5 ?/ H6 D. V
reported an increased conversion of testosterone to dihydrotes-5 L" D7 O+ C- O; \$ H0 w6 n
tosterone in the foreskin of neonates and infants.4 This activ-
, M: g- ]( i0 t( q% n2 bity gradually decreases with age until puberty when it ap-2 P5 d+ u$ |# f' O
proaches the same level of activity as peripheral skin. It may0 v' ^* e; ^ m: c# f+ R7 Q0 |1 z6 j
well be that absorption of testosterone is less when applied at, {. u* W$ `6 s. [4 v2 J1 |
an earlier age as suggested by lower serum levels in children
9 @8 u; W- h, X) B0 }3 \less than 10 years old. This fact may be explained by the
" A* i' n# d' l( agreater ability of phallic skin to convert testosterone to dihy-- ?/ _$ L6 z8 J$ ~* b/ L5 C. h) r3 ]
drotestosterone at this age. Conversely, serum levels in older
! }: s1 t Z( S$ |2 a# z! d1 Kpatients were higher, possibly because of decreased local, s* F4 ?8 Q. c+ S
6678 ~4 T. w1 N+ z, t/ m
668 KLUGO AND CERNY$ t# D! A( D: q( z
Pt. Age* n7 D) r; o4 t2 k' x
(yrs.)
+ v" H) d* V& ISerum Testosterone Phallus (cm.) Change Length
2 [2 D% I: u2 H# o(ng./dl.) Girth x Length (%)
. s+ P+ ~# w- R L/ G. ?: f4) G# V. P# i6 c; |- x3 ^
8' f7 }. s6 S& ~ O3 ]
10- r. N$ m' O# h# t3 h; |: J
12
q4 J2 @- l5 C( z* @! B171 y }2 W& w3 D0 A1 ]# N$ Y
Gonadotropin
# W' p2 E4 @" A- s0 \& W U71.6 2.0 X 3 16.6
9 ?# m, b! b! s+ z; i50.4 4.0 X 5.0 20.0* M6 Q# m4 E: j4 h% B6 t6 A: T7 Z
22.0 4.5 X 4.0 25.0
1 V: _2 J! R$ s4 A( o84.6 4.0 X 4.5 11.14 c" }7 T' ?9 t D
85.9 4.5 X 5.5 9.0
' u _" V5 Q, H; T& @5 }5 lAv. 14.3% X+ f. T+ c3 _9 i1 R
4
; ~- o$ t5 j) j: f* V8
0 P( s2 O: E9 |" z0 I. \& I10
; v) R# _7 l# t12
1 m/ E; |* P" J, U* g6 k17
( @# i2 v/ g, D/ Y" l* ^Topical testosterone
/ s2 _2 T' X: l9 [34.6 4.5 X 6.5 85
' n# c9 o1 d8 k& C/ F. s6 E* Y38.8 6.0 X 8.5 70
, y! s: P$ z/ `0 [, {) u( ~4 ?40.0 6.0 X 6.5 62.5/ V& O' P1 |- I1 K$ e, G" J. j
93.6 6.0 X 7.0 55.5
( i F& q$ O& a95.0 6.5 X 7.0 27.2- H5 o& ]! P5 [$ x ^! {/ s
Av. 60.0# x0 ?" |' h# E% m) v, }4 E- C
available testosterone. Again, emphasis should be placed on
4 _) L0 P' }6 R/ dearly therapy when lower levels of testosterone appear to# u. T& v# s" a# J% x9 l+ O
provide the best responses. The earlier therapy is instituted
5 ` y9 [5 M: O) d! X, w; rthe more likely there will be an excellent response with low
6 P6 ]0 v( X6 K! A Q6 q/ @serum levels. Response occurs throughout adolescence as
* N. @8 g( {7 Hnoted in nomograms of phallic growth. 7 The actual response
4 R) M3 t; A3 |* n$ p/ [' tto a given serum level of testosterone is much greater at birth
8 y$ s3 ~0 o% jand gradually decreases as boys reach puberty. This is most, ~) P0 C' E! G$ ]
likely related to the conversion of testosterone to dihydrotes-
% s6 L+ W$ s# I/ R" Ytosterone and correlates well with the studies of testosterone
' B. c; x; `. I t+ d/ Y, a" X/ Mconversion in foreskin at various ages., q$ t# y2 @5 \, H, t. f8 R
The question arises regarding early treatment as to whether
8 s1 T9 }; \0 k8 {* X" L3 i. gone might sacrifice ultimate potential growth as with acceler-
$ O# i% R# j9 T; l4 K* \+ Rated bone growth. The situation appears quite the reverse: W! V+ o3 k5 U* v; `
with phallic response. If the early growth period is not used
8 j8 ~ u! A/ t) U) E! `" |when 5a reductase activity is greatest then potential growth
1 _5 U2 N/ c& Y! u( W, Cmay be lost. We have not observed any regression of growth/ F% G6 _ s {+ f4 z& E3 i
attained with topical or gonadotropin therapy. It may well( G6 m6 v$ C R t' ?
be that some patients will show little or no response to any/ f) [% N& b% ]: P" T. Z
form of therapy. This would suggest a defect in the ability to
$ z5 f& E2 u0 v- r: L) `convert testosterone to dihydrotestosterone and indicate that! S! g/ z# u/ o$ e2 P
phallic and peripheral skin, and subcutaneous tissue should2 z4 x6 g+ I1 b
be compared for 5a reductase activity./ R# K. z) p/ G- `$ e9 [
A, loop enlarges to measure penile girth in millimeters. B,# M( k+ D8 T' @6 D3 _4 U
example of penile girth computed easily and accurately.# ^* s) A) G" U: S& `3 z- m7 i: T5 N
conversion of testosterone to dihydrotestosterone. It is in this% N( W6 X+ D* g
older group that others have noted high levels of serum
( l, p3 ~, B$ Gtestosterone with topical application. It would also appear, ]3 |( s3 i8 O) h0 O8 l1 W
that phallic response during puberty is related directly to the/ o/ u. x/ `( z$ T
serum testosterone level. There also is other evidence of local' J. p2 x# ^9 V j
response to testosterone with hair growth and with spermato-
7 w/ d; v) Y' \2 g0 J2 Sgenesis. 5• 67 z8 k6 `1 q5 y+ j
Administration of larger doses of gonadotropin or systemic
. ?2 D% A% N- c/ U2 Z! ntestosterone, as well as topical applications that produce
8 I+ V) ~- i2 Fhigher levels of serum testosterone (150 to 900 ng./dl.), will
7 B# H: O" s1 Lalso produce phallic growth but risks accelerated skeletal
. D! Y i; L% t. \0 ^1 f3 omaturation even after stopping treatment. It would appear
7 _9 z1 z! Z" W/ w* C2 Mthat this may be avoided by topical applications of testosterone+ o6 I) s6 O4 d; _
and monitoring of serum testosterone. Even with this control
1 f: R4 B/ ?) e4 R5 G4 q/ D% Z2 v2 z8 _the duration of our therapy did not exceed 3 weeks at any
+ k; W* G1 D5 N j4 g \time. It is apparent that the prepuberal male subject may
- t3 H9 \4 i( {: L. {$ l0 Xsuffer accelerated bone growth with testosterone levels near& Z7 G9 O1 W% T
200 ng./dl. When skeletal maturation is complete the level of
o2 I5 e" }8 m! Wserum testosterone can be maintained in the 700 to 1,300 ng./
" h- u, U* |7 R8 O1 Pdl. range to stimulate phallic growth and secondary sexual
6 k% D: `. k) W% q# Tchanges. Therefore, after skeletal maturation parenteral tes-
& u* U% }* @. U( b) ftosterone may be used to advantage. Before skeletal matura-
8 B+ Z7 U) g+ U ^- c g8 Ition care must be taken to avoid maintaining levels of serum+ o+ {5 N7 [$ V) C S- K; i3 x
testosterone more than 100 ng./dl. Low-dose gonadotropin
8 C% G, C1 ~5 k, M. q1 fdepends upon intrinsic testicular activity and may require
3 d7 H% r( V: t) p! t# f7 Aprolonged administration for any response.
( \0 ^! t& Y# _; j6 x7 F1 V% VAlternately, topical testosterone does not depend upon tes-% h8 ~9 I* W6 I3 g
ticular function and may provide a more constant level of z- ?6 [5 _9 r2 L6 p
REFERENCES$ M! A6 b' r7 t" G6 v, x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 _' f2 p* J; d) M, S( ~R.: The local application of testosterone cream to the prepub-) c, O' i9 Q" s y8 c* K! r# p
ertal phallus. J. Urol., 105: 905, 1971.! ^: v5 d/ }9 ?1 G
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 H+ P* i% ^0 }3 `* streatment for micropenis during early childhood. J. Pediat.,
t$ h4 l/ I- c5 {" @* o83: 247, 1973.' F' p+ _+ |2 y6 K) _( r
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# i' G3 _" s! gone therapy for penile growth. Urology, 6: 708, 1975.. d0 L4 L+ F6 K# |5 }
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 w1 N$ h& J4 F) V% t9 ^to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: E7 C4 ?% x! U+ O$ p( W
skin slices of man. J. Clin. Invest., 48: 371, 1969.4 z2 z: j1 x8 i2 p& l
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
1 \2 f! {. h0 p& x4 {! `by topical application of androgens. J.A.M.A., 191: 521, 1965.
' O5 u( ^! T, S1 `3 ]6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 h$ O) l, O7 K$ n" ^+ U3 |androgenic effect of interstitial cell tumor of the testis. J.0 D, I8 i C) ] ~+ \
Urol., 104: 774, 1970.# ~. l |6 L6 f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 E" n% v0 t& Z% Q
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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