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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- O# q- e0 g/ U J$ g7 B4 i
GONADOTROPIN
2 d+ x1 H- x: k) ~2 z s, C( a hRICHARD C. KLUGO* AND JOSEPH C. CERNY
- ~6 k5 K% N2 ^: Q8 C+ ?From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' [0 I) N- K F$ o
ABSTRACT2 G$ z( D' u0 n: N3 q& F: Q8 B
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: _: j8 U3 b K V* Awith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-7 ?/ S, E7 q$ P9 p% a- I6 Q+ d
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% {. l( L& Y. c, m4 p
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' v5 q7 N7 d1 s% d: g' {
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, m$ j. c& E: F: m* B! B5 s, s2 W
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average: H* w7 N0 [& w" o% v. L' O
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" A' P3 k: H. g. Voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- |, C' z r! d2 S3 sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
' X, g( \- \0 Y0 T7 |; E: H* `1 ^) Jgrowth. The response appears to be greater in younger children, which is consistent with previ-4 a! T) I- S; |1 c
ously published studies of age-related 5 reductase activity.5 [$ K* r) }! L# q. i; p1 d% X
Children with microphallus regardless of its etiology will
! l- H& b/ t: x3 D0 ^3 g. i$ s% @require augmentation or consideration for alteration of exter-
- G! d5 G @1 |3 {nal genitalia. In many instances urethroplasty for hypo-
( i" I1 n; _/ ~4 M7 \ espadias is easier with previous stimulation of phallic growth.9 Z. H" n' T4 q- H* \1 g
The use of testosterone administered parenterally or topically Y/ |# ]3 C5 |- [. D& D
has produced effective phallic growth. 1- 3 The mechanism of! q+ B3 t- y' D& S
response has been considered as local or systemic. With this
) t# {+ x& U, a; Tin mind we studied 5 children with microphallus for response
7 T4 `4 l9 ?. A4 W8 } kto gonadotropin and to topical testosterone independently.) L. ~: u0 l% x2 n; t, l
MATERIALS AND METHODS
7 f/ Q! M0 |7 y, V3 W ], HFive 46 XY male subjects between 3 and 17 years old were. {# p, G6 T; [6 k! n1 m
evaluated for serum testosterone levels and hypothalamic
! m8 j* \0 }& ]: k$ \/ Tfunction. Of these 5 boys 2 were considered to have Kallmann's
; J* L* m* g2 p) m3 [( Z# Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' H8 U o7 f g; \. e& Q/ q
lamic deficiency. After evaluation of response to luteinizing
: }" @. U+ m }7 D5 hhormone-releasing hormone these patients were treated with
4 S3 W0 F8 ~; m1 S- b5 i# S9 C1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 d, V+ n7 @5 Y R# q" ~; z. g8 T5 S
after completion of gonadotropin therapy 10 per cent topical
R5 {0 h' ~/ Ltestosterone was applied to the phallus twice daily for 3 weeks.
, m' F7 Z3 Z, L% Y3 VSerum testosterone, luteinizing hormone and follicle-stimulat-% j( M5 a; ]2 I o1 p8 ?' x
ing hormone were monitored before, during and after comple-
% q, F: n8 d. W5 r# `$ ^tion of each phase of therapy. Penile stretch length was0 { R; G. L" K+ @
obtained by measuring from the symphysis pubis to the tip of( }7 i& I4 o. s# l! D. F
the glans. Penile circumferential (girth) measurements were& v# X/ p: v1 M3 j+ k; S: f
obtained using an orthopedic digital measuring device (see2 E* c' o+ V4 L, u! n- |
figure).
1 Y! Z) X/ F. T, f" _. YRESULTS
) I+ N7 J. ]1 m( BSerum testosterone increased moderately to levels between5 I& _. |( S ~7 G; Z& \$ ]' o b* L
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' |8 s) }2 H! V- o# D% yterone levels with topical testosterone remained near pre-
( v- ]4 f. t3 W4 d* B8 N$ Ntreatment levels (35 ng./dl.) or were elevated to similar levels
; J1 N L8 k6 P7 e: f8 xdeveloped after gonadotropin therapy (96 ng./dl.). Higher
% }& h3 v$ M) ~; tserum levels were noted in older patients (12 and 17 years old),2 O& F3 g7 {$ Z
while lower levels persisted in younger patients (4, 8, and 10
4 D7 f }& [( h+ w/ B' tyears old) (see table). Despite absence of profound alterations6 C+ r9 ^, u1 g9 J
of serum testosterone the topical therapy provided a greater9 v4 _6 P' X% V. O3 X; U/ f
Accepted for publication July 1, 1977. ·
6 Q4 ?- i. y BRead at annual meeting of American Urological Association,3 D0 c; e' { v) a6 S5 ^
Chicago, Illinois, April 24-28, 1977.
. S2 U! ^& ]6 W: s, W* Requests for reprints: Division of Urology, Henry Ford Hospital,( w6 g* I# R* \
2799 W. Grand Blvd., Detroit, Michigan 48202.
~; V. n6 N$ t, }; l, }improvement in phallic growth compared to gonadotropin.
0 k, S# V7 f" {3 TAverage phallic growth with gonadotropin was 14.3 per cent5 C7 I% x/ ^' R# v% E
increase in length and 5.0 per cent increase of girth. Topical7 a2 g1 x1 a6 W4 {
testosterone produced a 60.0 per cent increase of phallic length7 z3 z- R" N" y0 @4 ]
and 52.9 per cent increase of girth (circumference). The) Q( y4 T! v/ J( j
response to topical testosterone was greatest in children be-, F+ e: }% J5 X1 _) ^
tween 4 and 8 years old, with a gradual decrease to age 17* H! c; {2 ?, [) s3 d S* l
years (see table).' `' l, m% n3 H9 M8 G H
DISCUSSION
5 T- a- w! G8 eTopical testosterone has been used effectively by other0 W% m3 A- V" [
clinicians but its mode of action remains controversial. Im-% o3 j8 E( n: d' o3 w
mergut and associates reported an excellent growth response5 f5 w5 n. V2 F4 s+ J- N7 p- I
to topical testosterone with low levels of serum testosterone,* V) u8 n4 o& b6 B% v
suggesting a local effect.1 Others have obtained growth re-
6 b7 x% U2 o% h8 c5 a$ K7 N' ksponse with high. levels of serum testosterone after topical ^4 l+ B7 w8 U1 B( a
administration, suggesting a systemic response. 3 The use of
, O& G* j S5 y2 J- P$ ngonadotropin to obtain levels of serum testosterone compara-
2 \3 c( R. @/ m4 B4 Y& dble to levels obtained with topical testosterone would seem to v7 C7 [1 n* m% N7 \
provide a means to compare the relative effectiveness of
8 a: F% x N7 ]: Q7 `topical testosterone to systemic testosterone effect. It cer-
4 w0 O" d$ W; E, g. ~* ltainly has been established that gonadotropin as well as par-% g1 h; [' Y! O
enteral testosterone administration will produce genital% E% V" C$ Q i. ]( K, [* s p+ n
growth. Our report shows that the growth of the phallus was6 B! j/ O$ K+ E! O8 b& f
significantly greater with topical applications than with go-
$ h8 L0 ^9 T3 I( [ unadotropin, particularly in children less than 10 years old.
) T0 g( \, l7 Q9 rThe levels of serum testosterone remained similar or lower, ?* [$ a2 |1 x7 Y6 L3 M" \$ T; G% [9 T
than with gonadotropin during therapy, suggesting that topi-! t5 S. M0 Z& }1 {& D
cal application produces genital growth by its local effect as
, h, w: ]: f* zwell as its systemic effect.# g' ?0 ~0 y! ]" [, R
Review of our patients and their growth response related to; R1 Z( \" Y2 e8 _
age shows a greater growth response at an earlier age. This is2 l$ W3 H' n# Z( b+ |4 ~+ z& Z
consistent with the findings of Wilson and Walker, who
) J' Z" e0 T" E4 u! E$ Lreported an increased conversion of testosterone to dihydrotes-
& M: r: ~7 V( @; ~' s5 {2 Jtosterone in the foreskin of neonates and infants.4 This activ-8 R# `) ~7 b Q8 t. z
ity gradually decreases with age until puberty when it ap-# Y I, w2 O/ o8 Q8 C% @( \- l* V
proaches the same level of activity as peripheral skin. It may
B7 E% a2 W( S, x6 G1 Owell be that absorption of testosterone is less when applied at" g' ^, o" F: ~7 I; `$ e+ B" W
an earlier age as suggested by lower serum levels in children* B( _5 T+ C5 y( \* l/ F; [+ j
less than 10 years old. This fact may be explained by the
" e) `8 G! d( G& I7 b% @) }greater ability of phallic skin to convert testosterone to dihy-
+ u: f# v- _5 `drotestosterone at this age. Conversely, serum levels in older
B. W! X" e- Tpatients were higher, possibly because of decreased local
" Z" t3 V% C4 x: _667
) x$ X3 r7 r9 i+ W/ s m- G1 `668 KLUGO AND CERNY3 \$ g5 ]' I1 d# c
Pt. Age* L1 M: ^/ c8 O# |
(yrs.)% W' V- a. U- ]0 o% v7 E- }- u
Serum Testosterone Phallus (cm.) Change Length$ e3 U0 Q( u* J1 a
(ng./dl.) Girth x Length (%)* h& O k9 w# T- |) F2 Z& y( Z; T
4! E! n$ e% J' V' i8 t% X
8% x# V/ y* V Z, l
10
; _8 v) n: D: v7 m12; D" o( {& [: m0 C7 k: x0 c: O
17
}- j9 r3 P4 n. m% `4 Z" v$ T! aGonadotropin
, K8 z: x& b6 k1 ~0 t! x71.6 2.0 X 3 16.6
* a: ~1 e$ J( e. `50.4 4.0 X 5.0 20.0, ]6 S/ Y# @: h9 ~$ n2 M5 A) w9 H1 E! n
22.0 4.5 X 4.0 25.07 @1 k# }0 l* w7 @( Z1 h& l
84.6 4.0 X 4.5 11.1
- D* M8 n! u; Z85.9 4.5 X 5.5 9.00 Y1 D. }! L/ ^ D0 W8 l$ Y
Av. 14.3% x7 T& p, e u
4
?- d. D. `5 M; G# c8
1 d! J- `# n- n" ~' f7 \& l109 q+ g Y8 u1 I' i, d& P
12% S6 ~/ Z7 H( b& T
176 ]6 i" _& \9 E u8 ^5 e
Topical testosterone
/ v7 s8 K: Q( \- c34.6 4.5 X 6.5 85
1 z. b9 S. T* j& r M% r38.8 6.0 X 8.5 70
; ?6 `7 P5 }" s40.0 6.0 X 6.5 62.5* T/ D, o# ? L3 X- x1 R2 {
93.6 6.0 X 7.0 55.5$ L: f4 S: a/ ]2 m: L% i! e
95.0 6.5 X 7.0 27.2, n1 l* R& ~8 r3 v
Av. 60.0
4 j. o9 f& g4 |' |: v3 u" @# @3 ^available testosterone. Again, emphasis should be placed on( M/ `% M- s2 l7 l$ R/ {. f
early therapy when lower levels of testosterone appear to
# e9 Z0 M( {6 P- L' Aprovide the best responses. The earlier therapy is instituted0 H' [: T" p; M$ H. C; R2 d
the more likely there will be an excellent response with low
* v4 ~0 `1 M6 ?/ V m( k3 tserum levels. Response occurs throughout adolescence as0 x! u& \* d5 {
noted in nomograms of phallic growth. 7 The actual response" {0 G8 a8 y; j7 j
to a given serum level of testosterone is much greater at birth" e. O0 S) Y8 V$ @0 ^2 s
and gradually decreases as boys reach puberty. This is most
$ `; N, G: K6 b% ?# L; glikely related to the conversion of testosterone to dihydrotes-8 G$ p1 z% N* n3 l
tosterone and correlates well with the studies of testosterone! G+ H0 p! x( ]# u
conversion in foreskin at various ages.
4 |( ~+ S6 R8 k& @The question arises regarding early treatment as to whether
! x9 u2 H2 W9 s! G5 lone might sacrifice ultimate potential growth as with acceler-
6 S Z7 h7 S3 o* @$ V# u1 {ated bone growth. The situation appears quite the reverse
# P2 |1 E' f; P7 n# ~with phallic response. If the early growth period is not used; F) c0 j1 b' v8 G0 I
when 5a reductase activity is greatest then potential growth/ B7 Z e Z. n0 ?' a4 e3 i/ Y+ ~
may be lost. We have not observed any regression of growth
4 O3 q- V% b" jattained with topical or gonadotropin therapy. It may well
2 y! W0 a; q2 n. D+ ibe that some patients will show little or no response to any
( i/ O- U8 {0 [0 bform of therapy. This would suggest a defect in the ability to
* H8 x3 z( a2 O- X" @* r1 Cconvert testosterone to dihydrotestosterone and indicate that% x6 z8 V5 d, H, n
phallic and peripheral skin, and subcutaneous tissue should, G" A! O: s. ^3 l/ `( a
be compared for 5a reductase activity., I' x, y4 D& B1 ^9 }1 s3 L% ~# t
A, loop enlarges to measure penile girth in millimeters. B,
2 q0 g$ C4 V% _8 Lexample of penile girth computed easily and accurately.- K& b2 [- D- c3 ?; O- i
conversion of testosterone to dihydrotestosterone. It is in this
9 m. m( r4 a8 j' D, Molder group that others have noted high levels of serum' W5 J$ `) I3 }
testosterone with topical application. It would also appear
9 T) S8 T" f( h# X6 Y; ]8 }; o% pthat phallic response during puberty is related directly to the
2 E5 w, C' X; S+ E" D9 o$ w4 I4 Lserum testosterone level. There also is other evidence of local
# t* D7 n- f' { N# I5 W& u$ lresponse to testosterone with hair growth and with spermato-
; w+ ?" H* E9 N. t5 j; \0 P5 mgenesis. 5• 64 a+ E9 g8 A, Y1 S) F0 M
Administration of larger doses of gonadotropin or systemic7 f3 {2 f: M8 X, w( T" U1 t
testosterone, as well as topical applications that produce
; h. r% J, A* k; Mhigher levels of serum testosterone (150 to 900 ng./dl.), will* V$ R4 V& v) L6 x
also produce phallic growth but risks accelerated skeletal
0 _) \# x3 e; H$ q) B7 mmaturation even after stopping treatment. It would appear5 K6 o/ g- l$ K8 _4 H+ X/ A
that this may be avoided by topical applications of testosterone
# [$ M* z- t. F R& n/ X" {and monitoring of serum testosterone. Even with this control
V$ e" c5 Q8 s& L, `5 t% @the duration of our therapy did not exceed 3 weeks at any
! H |; _0 O7 Stime. It is apparent that the prepuberal male subject may
3 F" l( l( Q9 D+ P+ }0 r' H3 o! o% Msuffer accelerated bone growth with testosterone levels near
1 a4 z# M. q. l4 R! C200 ng./dl. When skeletal maturation is complete the level of
- h [+ P3 P6 d) w: _3 Xserum testosterone can be maintained in the 700 to 1,300 ng./
! c; z5 n( g- Y* c" B) B- Ldl. range to stimulate phallic growth and secondary sexual8 H0 ?4 a. x5 d2 G4 Q) X0 Q! F
changes. Therefore, after skeletal maturation parenteral tes-
% I- V! t4 `# H1 Ctosterone may be used to advantage. Before skeletal matura-
8 j P: {; ^6 ^3 D; Jtion care must be taken to avoid maintaining levels of serum2 y; _/ x; E( P0 o0 u; l4 K8 k
testosterone more than 100 ng./dl. Low-dose gonadotropin5 [1 J- Q( R3 G6 T
depends upon intrinsic testicular activity and may require
) l/ F& N* |4 V( Dprolonged administration for any response.
( P9 X* C6 Q v% bAlternately, topical testosterone does not depend upon tes-" G: J/ {+ T( m1 j
ticular function and may provide a more constant level of
% [9 o: T( k# l* VREFERENCES
; }, K- D# ^+ k# l* l1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 K3 G3 l; h$ v# W+ P" v' FR.: The local application of testosterone cream to the prepub-
/ \4 x/ J5 P# _5 E& d6 i- A1 a$ Zertal phallus. J. Urol., 105: 905, 1971.
+ V' d& J$ z. N. x- y2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( L N8 T+ p, }- y( {& K
treatment for micropenis during early childhood. J. Pediat.,
* B: M: {+ u4 Q& c83: 247, 1973.
% K7 ?5 `+ L- P/ V& K' R) A3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 n* S" J+ y5 E: U) m+ _
one therapy for penile growth. Urology, 6: 708, 1975.
! k* c) V k$ T | p4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ P- `8 B* a. X G
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 K7 A1 W, h- h, H! \
skin slices of man. J. Clin. Invest., 48: 371, 1969.: E2 @$ d" J* _ X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth7 x/ T; H, h P! N3 |9 y# e. l
by topical application of androgens. J.A.M.A., 191: 521, 1965.& O% A z9 S: A1 M. B3 r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
6 P5 m3 A0 E& x% T0 Tandrogenic effect of interstitial cell tumor of the testis. J.
) q& |2 N6 d% o$ HUrol., 104: 774, 1970.
2 k3 g1 f2 |; j& Z' g7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& u( o3 |7 B8 m u, L3 Vtion in the male genitalia from birth to maturity. J. Urol., 48: |
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