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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% s. f$ f! k2 ]9 x# K3 EGONADOTROPIN$ V2 h. a! o; s/ \0 B
RICHARD C. KLUGO* AND JOSEPH C. CERNY
9 d% R" ?) p: _6 {& s, r8 zFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 ]) s, `0 O% _# ~% R' Q1 HABSTRACT) P3 e2 W: h2 i
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
& G' [% j6 k0 T) F: X( j5 hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-) T/ b; c$ w5 q Y
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ U) w3 l; F; [7 icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 v: T7 _, C2 {) b+ A# Yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: b4 o) {; S+ r* I
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average, Q6 P. ?0 S) s9 p5 G3 S& }
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 m _7 P* C" `' j: i0 k$ q5 s. V
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 S* m; z; D3 ~study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
. ]) B; h1 V: }# s" Q; z2 @5 o5 Rgrowth. The response appears to be greater in younger children, which is consistent with previ-
6 y/ B* V" H: _9 Pously published studies of age-related 5 reductase activity.; ~" [) F7 y) }
Children with microphallus regardless of its etiology will h" t n# X1 y( z% s. F
require augmentation or consideration for alteration of exter-
5 [9 N/ O4 K: x5 dnal genitalia. In many instances urethroplasty for hypo-9 ~2 J, X* \& h4 d( M, `
spadias is easier with previous stimulation of phallic growth.
; Q+ N9 ^0 [3 B4 kThe use of testosterone administered parenterally or topically
+ E% S$ @0 g5 P! x2 m; c2 P7 B& J: chas produced effective phallic growth. 1- 3 The mechanism of4 O' L1 \7 W0 ?& }; N
response has been considered as local or systemic. With this
( \( c' _! r* \5 P W7 Win mind we studied 5 children with microphallus for response
. I9 R" p6 z3 Mto gonadotropin and to topical testosterone independently.7 {3 x' m8 H6 `6 O' M7 d
MATERIALS AND METHODS& X8 Y: ?& |& J& O: _1 P: ?) L
Five 46 XY male subjects between 3 and 17 years old were9 X8 [- Y# L1 E h* C7 ]. W
evaluated for serum testosterone levels and hypothalamic! }+ c9 L- K* U4 i* }
function. Of these 5 boys 2 were considered to have Kallmann's
9 u7 L: y! ` B7 ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; l' l$ r3 u; O: ^1 {3 `lamic deficiency. After evaluation of response to luteinizing
! Z4 B2 v) |2 `- Chormone-releasing hormone these patients were treated with
/ b: z% B) G* q* @5 T1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 h( Y0 s! ]" I! H& lafter completion of gonadotropin therapy 10 per cent topical
9 P5 l. r0 \$ @1 |8 f8 n+ E6 ptestosterone was applied to the phallus twice daily for 3 weeks.
$ k+ M* j9 J5 M1 KSerum testosterone, luteinizing hormone and follicle-stimulat-9 m7 j% Y3 h& F+ s$ h- `3 k
ing hormone were monitored before, during and after comple-* v3 p$ F" W* T. v+ N5 }! v2 A
tion of each phase of therapy. Penile stretch length was
+ a, G+ F# G, U2 |. u: ^obtained by measuring from the symphysis pubis to the tip of
6 ^: z' @0 a- s0 hthe glans. Penile circumferential (girth) measurements were
+ J$ a# H2 {$ x5 |' X; Aobtained using an orthopedic digital measuring device (see
' o" |- B6 e [3 E1 Tfigure).
0 V, d# V# z0 t. t- vRESULTS
( Z, a6 Z* L, VSerum testosterone increased moderately to levels between( e: f$ c/ n/ c4 v, S, Y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 m. ? t& ]3 \$ n! K5 y: oterone levels with topical testosterone remained near pre-8 V D% c' r6 V, k
treatment levels (35 ng./dl.) or were elevated to similar levels
1 M8 e+ H8 A5 ]9 g& h! ~developed after gonadotropin therapy (96 ng./dl.). Higher
; c# e7 u5 Z- v* q9 t$ g$ i8 Sserum levels were noted in older patients (12 and 17 years old),. {2 {6 B- {, @% B9 `2 b% k0 Q C& R
while lower levels persisted in younger patients (4, 8, and 10" X$ m, T9 i h/ y
years old) (see table). Despite absence of profound alterations
9 M- x4 _, C$ H# dof serum testosterone the topical therapy provided a greater
8 ]/ y, [6 N2 c& k- p* R. oAccepted for publication July 1, 1977. ·9 J( m+ u A6 z: ~
Read at annual meeting of American Urological Association,9 y- k; U- C/ w9 U2 o% U; f& T' q9 |
Chicago, Illinois, April 24-28, 1977.1 w5 Z* L, i' _7 w
* Requests for reprints: Division of Urology, Henry Ford Hospital,
" L' E' @4 Y& k; d& V2799 W. Grand Blvd., Detroit, Michigan 48202.& y" H ?* X/ g0 b
improvement in phallic growth compared to gonadotropin.8 M0 g; u' [* v* D0 ~2 s" N
Average phallic growth with gonadotropin was 14.3 per cent
$ g7 s& Z$ Q) ~7 ]& ^increase in length and 5.0 per cent increase of girth. Topical
" N: ~5 W( [7 p9 \( e& \4 r D. z$ a0 dtestosterone produced a 60.0 per cent increase of phallic length
8 w/ F' ~7 \; e7 cand 52.9 per cent increase of girth (circumference). The
2 B# P8 X. m. Q( k4 Dresponse to topical testosterone was greatest in children be-* b1 R! C+ C$ e; E* [
tween 4 and 8 years old, with a gradual decrease to age 17: s4 k$ y9 B$ G$ Z" B
years (see table).# B h6 }" \5 p i6 F
DISCUSSION+ w* z# _$ Y) b; Y
Topical testosterone has been used effectively by other4 j; x+ I3 L- A* I
clinicians but its mode of action remains controversial. Im-
; P1 ?! p# @# ~" ]1 `# q0 K# Y: Bmergut and associates reported an excellent growth response
1 V4 r* A0 h% T# ^, R: Bto topical testosterone with low levels of serum testosterone,
% b9 m- P4 x% Y6 r( Hsuggesting a local effect.1 Others have obtained growth re-8 j( G+ W! }( I5 v5 a; M. w- X
sponse with high. levels of serum testosterone after topical
$ n& ?! |6 a. W) u9 Kadministration, suggesting a systemic response. 3 The use of
: C5 g8 e/ |) H6 l' Vgonadotropin to obtain levels of serum testosterone compara-- n V: C0 `0 c8 L* [+ {
ble to levels obtained with topical testosterone would seem to8 h5 Q7 d! D$ b* |1 x9 M
provide a means to compare the relative effectiveness of! Q' S2 n- R8 Z' d
topical testosterone to systemic testosterone effect. It cer-
- @$ }# ~: {) F: ]tainly has been established that gonadotropin as well as par-9 @$ a' D4 B; J/ D$ O
enteral testosterone administration will produce genital
7 {% T5 f' U \. `growth. Our report shows that the growth of the phallus was5 p4 h* K( \% }" m
significantly greater with topical applications than with go-4 o: O/ \& }# x/ r2 s7 `
nadotropin, particularly in children less than 10 years old.
, W- A% }$ g2 e9 C# ZThe levels of serum testosterone remained similar or lower
2 M! \4 @! J. u0 i+ e* v% gthan with gonadotropin during therapy, suggesting that topi-
5 o. R6 `8 L! m& ecal application produces genital growth by its local effect as
& U( w& c0 U% }0 Iwell as its systemic effect.
' k8 a" b/ [/ [" c) E# L: w$ MReview of our patients and their growth response related to
2 D2 w8 |- ]% U6 N5 @( h& zage shows a greater growth response at an earlier age. This is
% ~& x0 M& c- B# |. r7 fconsistent with the findings of Wilson and Walker, who! u7 P& {: c8 r4 y# ^! n$ ^
reported an increased conversion of testosterone to dihydrotes-' W4 b& c( e5 I9 g
tosterone in the foreskin of neonates and infants.4 This activ-) U1 o5 {: T% a
ity gradually decreases with age until puberty when it ap-! F$ Z3 z0 @3 {* G1 n4 U
proaches the same level of activity as peripheral skin. It may" c4 ?! n, b. m% g" _6 C
well be that absorption of testosterone is less when applied at
4 K7 }' a3 N* h/ can earlier age as suggested by lower serum levels in children
4 U9 n- N# w" ~less than 10 years old. This fact may be explained by the+ N9 E8 T4 I, u. w9 q3 X' |
greater ability of phallic skin to convert testosterone to dihy-
+ ?- L1 M5 g' e) [drotestosterone at this age. Conversely, serum levels in older
# m& }" v4 [0 D' v- ypatients were higher, possibly because of decreased local
7 O0 z7 k8 g" l1 W: i667. X7 U+ l/ P6 A4 r8 x
668 KLUGO AND CERNY- y* |, m& r" ^2 l) q2 s
Pt. Age
: b6 G! ] A o5 o* r7 b(yrs.)
8 i. x% ]# I! i! T/ D7 lSerum Testosterone Phallus (cm.) Change Length
+ U' h; K0 e+ R+ b- A5 ](ng./dl.) Girth x Length (%) Y+ O1 P* J( e1 m6 [6 Z2 A
42 R( e7 G2 C3 M" w! d- v* q, i% k
8% @2 a8 ^* X) l6 V2 V8 d/ K
108 b2 f2 e4 ~4 N( _4 F, y4 s
12
; \+ ^8 W; A7 M$ c5 ~17( [0 s5 Y: R7 P4 w" u/ y
Gonadotropin
. v2 g& e7 s8 D. l4 A9 U6 w! i71.6 2.0 X 3 16.6( c5 K' [* h3 c
50.4 4.0 X 5.0 20.0
. R$ H' ~1 x7 r% V0 h7 f# z22.0 4.5 X 4.0 25.0
6 Q1 j3 R* v; O84.6 4.0 X 4.5 11.1
1 ]7 x: z6 W0 F1 V6 G85.9 4.5 X 5.5 9.0
* E4 H+ ~0 {' U! ]9 @1 aAv. 14.3
6 U2 |. ?- C _6 Q0 k4
- E! c" ]3 r( a# T88 Q' p3 R8 ]( n& k' D8 i
10
9 _2 {4 Z. o; m3 ?12
2 e M2 v3 [; ^3 X- {6 u17# P/ p! H& o& s* _7 _+ n6 ^9 _' K
Topical testosterone" L( Y+ E( @2 H8 N% s
34.6 4.5 X 6.5 85
% \# Y% c7 K; m: t; [& j38.8 6.0 X 8.5 70, H# z6 ^+ k: _+ x
40.0 6.0 X 6.5 62.5
3 G8 u9 {& u; a93.6 6.0 X 7.0 55.5* h- O$ ~. W( D5 p8 Z
95.0 6.5 X 7.0 27.2
7 z& I+ b/ a$ f* }+ a* ^5 @Av. 60.0
' q9 U U6 E' C: `& h* Uavailable testosterone. Again, emphasis should be placed on
' {+ M/ `( O' u6 z1 nearly therapy when lower levels of testosterone appear to8 ^ _3 _+ v3 G5 N
provide the best responses. The earlier therapy is instituted& D" Z) f r a' H$ S& H. S
the more likely there will be an excellent response with low
: X K+ }! d. j/ N* s6 Mserum levels. Response occurs throughout adolescence as' l* |) M7 y$ E" x6 A
noted in nomograms of phallic growth. 7 The actual response1 W! ^7 j) r# V9 q- d7 k
to a given serum level of testosterone is much greater at birth W& A6 V* R; ~- J
and gradually decreases as boys reach puberty. This is most
W o, X" s; Q- X2 y1 slikely related to the conversion of testosterone to dihydrotes-
4 ] d# V) r1 y$ M, @tosterone and correlates well with the studies of testosterone1 n0 q. e! ]$ Q" y% S
conversion in foreskin at various ages.% S4 O3 ?1 j( H3 i# N. J' ~, x
The question arises regarding early treatment as to whether
% _- ]/ ]: m. i7 {4 H" Xone might sacrifice ultimate potential growth as with acceler-
8 T4 X( |7 J J9 s3 G: U! [/ Iated bone growth. The situation appears quite the reverse( d; V. p7 J0 d* Q( e5 G6 t1 S
with phallic response. If the early growth period is not used
w& t1 M, h, H" _/ vwhen 5a reductase activity is greatest then potential growth
( f9 a" N8 }+ J7 i/ S% M: Pmay be lost. We have not observed any regression of growth* G2 ~( h; O9 O! S: }7 c! X2 y
attained with topical or gonadotropin therapy. It may well
( D5 d4 S( g3 Y A' I( z/ ]: |be that some patients will show little or no response to any
0 \5 O, k$ z, u4 eform of therapy. This would suggest a defect in the ability to, B% n# w( I8 A5 G9 {! Y
convert testosterone to dihydrotestosterone and indicate that
+ ~* d1 Z2 v6 @4 ~, Q0 O; cphallic and peripheral skin, and subcutaneous tissue should
/ M; R/ d6 r" k: `* Ube compared for 5a reductase activity.
9 c' e& Y6 J2 pA, loop enlarges to measure penile girth in millimeters. B,
! Q3 f* U8 i& a; ]$ b( qexample of penile girth computed easily and accurately.
, c" `' s# B4 I o8 X( m% o: Aconversion of testosterone to dihydrotestosterone. It is in this8 l* s; C7 ~: p" I4 }" f9 h
older group that others have noted high levels of serum+ V+ e& ~" B0 U& Y+ }* k
testosterone with topical application. It would also appear
" _7 k1 c' |! U' n5 y5 D7 Xthat phallic response during puberty is related directly to the* V! k6 K6 m5 i7 Y
serum testosterone level. There also is other evidence of local ]) {8 |' m) W6 q
response to testosterone with hair growth and with spermato-/ u2 E( X3 t P; m; X6 V
genesis. 5• 6
- b$ v# |5 B) G- A0 Z8 ~Administration of larger doses of gonadotropin or systemic
+ K+ P6 m& a% r) g) Vtestosterone, as well as topical applications that produce5 G' q, z9 } a& ?4 r
higher levels of serum testosterone (150 to 900 ng./dl.), will
; s% d: p$ E5 D4 w calso produce phallic growth but risks accelerated skeletal
9 C! \: C: `7 j# M2 L: Z* smaturation even after stopping treatment. It would appear
7 R0 U% a# w( G$ e8 ?that this may be avoided by topical applications of testosterone
% V2 ^$ D" f; C! l8 Hand monitoring of serum testosterone. Even with this control* u0 {; Y: \* V% D! W& p0 ]
the duration of our therapy did not exceed 3 weeks at any! H* y/ b# `) R3 i3 B; | ^0 q( D
time. It is apparent that the prepuberal male subject may
5 o/ \% [* Z T9 N: zsuffer accelerated bone growth with testosterone levels near
& i6 Z" |2 R; {" C1 }' |200 ng./dl. When skeletal maturation is complete the level of8 T; h2 c* x5 c$ K
serum testosterone can be maintained in the 700 to 1,300 ng./* Y* X4 Z$ c& |7 j# O
dl. range to stimulate phallic growth and secondary sexual
3 L3 Q+ o: B* X0 R+ Gchanges. Therefore, after skeletal maturation parenteral tes-
7 P, h" {" F& ltosterone may be used to advantage. Before skeletal matura-
: ~" z9 K0 R$ E" etion care must be taken to avoid maintaining levels of serum
6 |) \7 ^- N+ r6 v/ [" Ytestosterone more than 100 ng./dl. Low-dose gonadotropin
% S* s# `7 ~. i1 F7 Wdepends upon intrinsic testicular activity and may require
" X2 ]) J) i# B1 j0 ` uprolonged administration for any response.4 G) V! Z4 K1 ~4 l3 y; @
Alternately, topical testosterone does not depend upon tes-% j9 n! ]% i ?$ S( L- m
ticular function and may provide a more constant level of' y% G( \: B2 y2 I: {/ ~3 b' _: L
REFERENCES/ C1 E1 K Y( {4 n
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ @" D1 D: X# i
R.: The local application of testosterone cream to the prepub-% }+ L4 r* R7 F% u% L
ertal phallus. J. Urol., 105: 905, 1971.
4 E, S8 A6 K( A1 \3 l: Q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ m4 w$ _, N3 \, y. c
treatment for micropenis during early childhood. J. Pediat.,
( o! z2 A/ Z0 `83: 247, 1973.; i' ?& X0 ^4 ~4 X+ V0 l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# f! G# \' B: a
one therapy for penile growth. Urology, 6: 708, 1975.
6 v M2 Q# t" f# N7 x* t4 a8 q, _4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* D& j/ N8 y' E0 z- G) Rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% E! g7 C2 [& S3 `( J
skin slices of man. J. Clin. Invest., 48: 371, 1969.* I% T7 O* V6 ` H; N; \5 g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 z7 v O2 X/ L: y8 Wby topical application of androgens. J.A.M.A., 191: 521, 1965.. Q, Q- ~! @1 E. N" }$ Y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 n4 ?# _( r: L P# Nandrogenic effect of interstitial cell tumor of the testis. J.
$ N; e: ]+ k% L' Y2 o: ?Urol., 104: 774, 1970.7 D1 m2 c% |& V6 a2 i- E9 w8 n
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! T- _ w: R7 H& @2 }& u' O
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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