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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& e5 v5 }* w( Q" m. `. Q& `GONADOTROPIN5 j' y: x. W, k
RICHARD C. KLUGO* AND JOSEPH C. CERNY
$ k: q% w! _% }) `/ kFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: W" b: o" D! _ q
ABSTRACT
2 D( p3 _, O5 x8 l* V* P1 `/ lFive patients were treated with gonadotropin and topical testosterone for micropenis associated# ^ H6 Z0 c0 [
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
! E8 F3 I' m3 qtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
( v6 y4 {) ]. u- ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 Q5 U! _% P$ s# ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% t, }- @0 W4 ~9 E8 Vincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) j3 Q) O9 K( R9 x6 ~& qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 l/ @7 R1 ~/ ~1 e( l
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ d, R Y7 i. ?+ ~6 V, Y) [# K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
5 k# B" C9 s9 n5 m- Agrowth. The response appears to be greater in younger children, which is consistent with previ-4 @' }1 a( }+ ^& j' J7 u
ously published studies of age-related 5 reductase activity.
6 S! w, b1 b# X5 k* HChildren with microphallus regardless of its etiology will% ]- v* ?# U& |' h& k" C
require augmentation or consideration for alteration of exter-
5 W$ v* P7 `5 ^7 Hnal genitalia. In many instances urethroplasty for hypo-
4 ]) F; C) }) Qspadias is easier with previous stimulation of phallic growth.
, R: y$ w' Q. ~( ~3 t# v* E: KThe use of testosterone administered parenterally or topically* x: U: m8 ?" c' ?% @
has produced effective phallic growth. 1- 3 The mechanism of# ^# `1 K% a& P# @6 e
response has been considered as local or systemic. With this
3 c6 ~5 | g- b2 @$ ~; e7 Z2 I. {in mind we studied 5 children with microphallus for response7 K5 O8 ?9 l8 x+ T2 Z
to gonadotropin and to topical testosterone independently.
* o; P: i& y7 {- F% S! C& RMATERIALS AND METHODS4 F" y* T2 V: L9 A1 D
Five 46 XY male subjects between 3 and 17 years old were: S' o5 H2 `' \' D q. z7 s/ u
evaluated for serum testosterone levels and hypothalamic
: u( T. u5 z [% Sfunction. Of these 5 boys 2 were considered to have Kallmann's
# n* n& l( a: n( E" W* G0 usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ \' s0 |: i9 G5 X" P
lamic deficiency. After evaluation of response to luteinizing$ k- E2 L/ I5 C$ H# V5 ^5 a5 U$ j
hormone-releasing hormone these patients were treated with
8 l- F4 {, j: ~5 T3 D4 F" i. G( f. O4 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks0 I1 j8 P, s; [& E7 q% s0 I& S
after completion of gonadotropin therapy 10 per cent topical
0 U2 M' \6 r& q& gtestosterone was applied to the phallus twice daily for 3 weeks.: o$ r. O1 ^6 i1 R1 K( U ?" ?
Serum testosterone, luteinizing hormone and follicle-stimulat-
- L9 }+ z- x8 A2 ]* P. ]1 Fing hormone were monitored before, during and after comple-
; S9 n4 r) r! U) {2 r# ^6 g( d. D4 _tion of each phase of therapy. Penile stretch length was& v7 L" h# K, j7 I
obtained by measuring from the symphysis pubis to the tip of3 Z! t& a1 h# b( n# D& _$ A8 s) S
the glans. Penile circumferential (girth) measurements were5 k5 c1 j, \& ^( G. ~* M
obtained using an orthopedic digital measuring device (see3 [' {9 x) q* l) S
figure).1 v6 m) ^6 I+ F" B7 c
RESULTS, _- M9 J H3 q
Serum testosterone increased moderately to levels between1 n' U: ~" q! c* d+ K
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ ?3 |) e0 j- f; K/ nterone levels with topical testosterone remained near pre-
8 M# O( `6 `8 |5 Jtreatment levels (35 ng./dl.) or were elevated to similar levels9 p4 t0 \$ h9 v, s* E
developed after gonadotropin therapy (96 ng./dl.). Higher) L+ D# I- L2 s4 p9 j$ D1 B# v
serum levels were noted in older patients (12 and 17 years old),% X; _. A" l0 j
while lower levels persisted in younger patients (4, 8, and 10+ Z; j; ?+ E# v0 | r
years old) (see table). Despite absence of profound alterations
8 \1 {1 D# G5 L. j: [- ^( R$ Pof serum testosterone the topical therapy provided a greater
* S/ o, B- z. b' h$ ~. sAccepted for publication July 1, 1977. ·
9 |! T* F; ^( W+ k" P2 H8 sRead at annual meeting of American Urological Association,
5 ?: l r% H4 QChicago, Illinois, April 24-28, 1977.
0 m+ Z) k* i4 p, z4 O" J* Requests for reprints: Division of Urology, Henry Ford Hospital,* s2 E( ]) u7 O3 k7 n& E0 D: d
2799 W. Grand Blvd., Detroit, Michigan 48202., j3 v4 T0 o, i9 D7 {9 ?7 E
improvement in phallic growth compared to gonadotropin.* A' U; f0 u4 `8 D0 q
Average phallic growth with gonadotropin was 14.3 per cent
3 ], {- {4 x& H V1 kincrease in length and 5.0 per cent increase of girth. Topical
/ [8 T0 C3 X3 a+ y; ~testosterone produced a 60.0 per cent increase of phallic length
+ l+ G, D$ a v u- mand 52.9 per cent increase of girth (circumference). The. k* c0 H& p. q, R) Y
response to topical testosterone was greatest in children be-
+ ~# y5 w' V" |2 @2 f, F- Qtween 4 and 8 years old, with a gradual decrease to age 17 h: \$ w. C. c' m# D9 e' v
years (see table).2 R- }, ^# d; T! F6 D, L9 X' I4 _, m
DISCUSSION
2 c" ~% p! T2 i9 l, R( R. tTopical testosterone has been used effectively by other
r# c8 @8 c3 e/ U) p2 `% pclinicians but its mode of action remains controversial. Im-
- q4 c1 R7 q/ D- pmergut and associates reported an excellent growth response
9 R+ L( f" V9 oto topical testosterone with low levels of serum testosterone,
% H: k" m2 Z) {6 V+ F. H7 tsuggesting a local effect.1 Others have obtained growth re-" s2 y9 C: J+ a
sponse with high. levels of serum testosterone after topical# Z. C6 C7 Z9 t. b" i
administration, suggesting a systemic response. 3 The use of
9 a* t' g7 l$ Z- i+ F6 \gonadotropin to obtain levels of serum testosterone compara-
' X" X$ Q5 }7 g* H7 C$ \ble to levels obtained with topical testosterone would seem to
1 k Q3 U) \( X! n% ]1 S: ], @provide a means to compare the relative effectiveness of6 W) u! v- E9 h' X( j; Q( F
topical testosterone to systemic testosterone effect. It cer-
1 X1 f# k6 P' } H- ttainly has been established that gonadotropin as well as par-( `1 }1 X" N" g. a( _# Q: T+ Z I
enteral testosterone administration will produce genital
' Y" h' |( y8 h% L3 P- ?' \growth. Our report shows that the growth of the phallus was
$ Z) T6 l" v, Fsignificantly greater with topical applications than with go-
( z% ~4 j# h8 v8 xnadotropin, particularly in children less than 10 years old.1 S1 t2 W# H4 s9 Z2 _
The levels of serum testosterone remained similar or lower
2 t3 a' t+ @) |; j% B( j+ A dthan with gonadotropin during therapy, suggesting that topi-# @" F8 V4 u& e a0 Y) L
cal application produces genital growth by its local effect as
$ |, k9 ~) W: s( cwell as its systemic effect.
8 K$ N- K# z7 A tReview of our patients and their growth response related to
9 d. l2 y( I2 Q$ P- wage shows a greater growth response at an earlier age. This is1 H8 _& Q7 @5 V
consistent with the findings of Wilson and Walker, who
& W2 L* @9 E" i* Z4 {reported an increased conversion of testosterone to dihydrotes-
/ q) u0 B% U& _% `' P6 X& ^& B% itosterone in the foreskin of neonates and infants.4 This activ-
9 [- k- v4 ~* }ity gradually decreases with age until puberty when it ap-* r1 o7 k! b. F
proaches the same level of activity as peripheral skin. It may. I- t1 P1 X* y o
well be that absorption of testosterone is less when applied at3 G' k2 C* l5 b" X
an earlier age as suggested by lower serum levels in children
& V; N- ?2 e: z' n+ |+ Pless than 10 years old. This fact may be explained by the
; R, f) a5 Z2 k/ S4 ^1 kgreater ability of phallic skin to convert testosterone to dihy-
2 ~5 ^5 q; J. z sdrotestosterone at this age. Conversely, serum levels in older
( u, e, _; u7 c* spatients were higher, possibly because of decreased local8 o8 D5 C2 l) Q
667
" K6 u% B5 F4 A- b668 KLUGO AND CERNY
: }. w$ X" H+ z3 F LPt. Age
4 ^! A6 z+ l3 K a( c(yrs.)) P/ B4 B& u$ s# C1 g- s# `
Serum Testosterone Phallus (cm.) Change Length+ q& c! e. X; R; L9 r
(ng./dl.) Girth x Length (%)% W: V5 I+ V7 H3 E* [
4
& M! H0 s+ z+ [/ q: P' y. F8
% l* Z- }' p9 c2 Z* z ^10
5 h$ X+ M2 R3 J. }* H$ E12# J1 E6 ^& T4 o- x4 F/ u
17
" R/ y+ U! }6 J$ oGonadotropin* `3 ]% O% a5 O9 m& {3 \
71.6 2.0 X 3 16.6
+ @/ U* R: Z6 D! k50.4 4.0 X 5.0 20.0' ?, t6 n F# P+ d/ f- r+ C9 M
22.0 4.5 X 4.0 25.0 O7 d7 r' _) G6 n7 ]5 l- W
84.6 4.0 X 4.5 11.1
6 T1 P8 Q6 z. j* m \# ]85.9 4.5 X 5.5 9.03 l: x$ l1 N+ I) S1 U
Av. 14.3
6 {+ ~+ I% d2 [. T0 v' f4
3 J9 a2 o* s0 G2 t0 u* _8" u* Z$ _7 Z4 Q
10
$ L% o8 R) c8 n+ I) ?9 }; R12
9 ]6 w; c8 K% Q3 u+ D2 ?( J17) B A8 S5 a" J# m' [1 W
Topical testosterone
, F3 P9 D/ [. M$ ^( P8 U8 C/ n34.6 4.5 X 6.5 853 Y. w" w" R- P! j
38.8 6.0 X 8.5 701 Y! @9 k& \# A8 P# A
40.0 6.0 X 6.5 62.5) \+ V# D% L) g& U
93.6 6.0 X 7.0 55.5! @8 z; u+ R3 r& _
95.0 6.5 X 7.0 27.2- [+ J1 Q6 G. e
Av. 60.0
. V) x" R( ~- c3 bavailable testosterone. Again, emphasis should be placed on
( ^( n9 s5 ^$ F( x+ H( ]# zearly therapy when lower levels of testosterone appear to
/ ]" h2 ?$ ^: p( ^: n3 Fprovide the best responses. The earlier therapy is instituted
1 a, H, e8 L6 rthe more likely there will be an excellent response with low
2 D9 w: d# A3 [8 A3 H+ L: Aserum levels. Response occurs throughout adolescence as3 \7 X0 \! ~- q
noted in nomograms of phallic growth. 7 The actual response, |; e" w% M3 X, a
to a given serum level of testosterone is much greater at birth
9 P. V7 R' p/ R/ \/ q2 i/ c/ vand gradually decreases as boys reach puberty. This is most+ c1 a; X8 \# Y& F" F
likely related to the conversion of testosterone to dihydrotes-" p# v1 R) F2 O' C
tosterone and correlates well with the studies of testosterone' D6 w/ n' c6 ~2 w
conversion in foreskin at various ages.) h% e+ W9 c8 h" d
The question arises regarding early treatment as to whether
3 X6 K x! k: F# k( m5 Lone might sacrifice ultimate potential growth as with acceler-
/ _5 P' M& y+ y% q- u0 I" tated bone growth. The situation appears quite the reverse
/ h9 Q5 x" L& W) @4 gwith phallic response. If the early growth period is not used
. F# L7 z+ r5 q" p' S3 i0 Ywhen 5a reductase activity is greatest then potential growth- j }+ [) s' U9 V; S
may be lost. We have not observed any regression of growth
T0 I# V @$ _* {& Kattained with topical or gonadotropin therapy. It may well
$ f) m' U: y' e3 } Qbe that some patients will show little or no response to any$ F3 e4 K3 o3 O/ V8 L6 `
form of therapy. This would suggest a defect in the ability to5 P/ |& g. b% E! j8 y2 h) r+ E
convert testosterone to dihydrotestosterone and indicate that! f' w8 D* n" a* [- z. }
phallic and peripheral skin, and subcutaneous tissue should+ X6 ~# K* m. o7 T- a. r6 k# a
be compared for 5a reductase activity.: H1 l, h% u8 |5 ^1 \
A, loop enlarges to measure penile girth in millimeters. B,- y5 |) a& P0 _
example of penile girth computed easily and accurately.
S r9 f' Q6 G1 N/ q3 u# @conversion of testosterone to dihydrotestosterone. It is in this
8 e; G- n% k% L8 K3 B0 T7 oolder group that others have noted high levels of serum
i; D n& P; ~1 `: g* r+ G0 Etestosterone with topical application. It would also appear& g* ?% }+ \: ], \
that phallic response during puberty is related directly to the3 P9 w7 H. A6 {! `9 V" [
serum testosterone level. There also is other evidence of local
. O) [: } W! R* v; O, u- cresponse to testosterone with hair growth and with spermato-
x3 s/ I+ a+ n; N1 T% {genesis. 5• 6
/ k1 [$ H. W6 Q* B0 i6 D$ J; qAdministration of larger doses of gonadotropin or systemic$ v7 I" J$ V6 `2 k. U) m+ B
testosterone, as well as topical applications that produce
4 `8 {# W% q& f+ t* Xhigher levels of serum testosterone (150 to 900 ng./dl.), will
# k7 U, m* l) X6 ^also produce phallic growth but risks accelerated skeletal( N4 V7 Q2 Z3 `- R
maturation even after stopping treatment. It would appear
: E% r$ a& s( }" A1 G9 n+ L0 fthat this may be avoided by topical applications of testosterone
: Y7 w g) h7 p( i2 z- M+ K, Hand monitoring of serum testosterone. Even with this control
0 r* c3 M$ }, d$ _the duration of our therapy did not exceed 3 weeks at any5 C9 ?9 S1 F: [
time. It is apparent that the prepuberal male subject may8 x$ F6 a# D: c5 b% u. ~! X2 L
suffer accelerated bone growth with testosterone levels near
2 |9 Z' S3 f/ o: O200 ng./dl. When skeletal maturation is complete the level of
) R; p7 p- B' p8 ~% J. L/ L, Wserum testosterone can be maintained in the 700 to 1,300 ng./) P/ r% f0 O) w' ?4 H1 m
dl. range to stimulate phallic growth and secondary sexual3 k% @ g8 r) k, }8 j; W: v
changes. Therefore, after skeletal maturation parenteral tes-
( b6 V' E+ _& n( u! n+ f( Jtosterone may be used to advantage. Before skeletal matura-
0 z2 a- P' G4 h9 Ation care must be taken to avoid maintaining levels of serum
; n! j1 X! p2 H+ `2 vtestosterone more than 100 ng./dl. Low-dose gonadotropin
# h* e( `/ c6 @0 \9 o) m# Ddepends upon intrinsic testicular activity and may require4 h4 }: W) H" |9 `2 T m/ A; n ]6 o
prolonged administration for any response.1 [! B9 L/ h) a/ a4 t
Alternately, topical testosterone does not depend upon tes-$ X+ S. K: K0 X" b' o2 C4 g8 _
ticular function and may provide a more constant level of
/ b9 \9 a* H) \REFERENCES
3 ~7 d3 G8 f. o2 H" h$ v1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; j" k/ `' C% x4 o& HR.: The local application of testosterone cream to the prepub-! A2 R0 g4 c. [' m& Z( u. D
ertal phallus. J. Urol., 105: 905, 1971.' U! F4 [/ V+ B7 p* u
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" W+ C8 A1 r9 `9 C6 r
treatment for micropenis during early childhood. J. Pediat.,/ n. O, @. [$ ]/ v5 Z5 t
83: 247, 1973.$ s) h8 @. M: n
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 G8 t! Y3 u5 J0 F0 zone therapy for penile growth. Urology, 6: 708, 1975.1 R% S2 Q8 A0 N6 f/ z& r/ F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone% z# Y# c% M, r* q- P
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by0 ~4 T( |: V+ a6 F3 P+ N
skin slices of man. J. Clin. Invest., 48: 371, 1969.+ m, G- d4 |, l% Q# b
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 {+ g x/ N6 W# M6 T Fby topical application of androgens. J.A.M.A., 191: 521, 1965./ Q) o# Q" B* U, {
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
( S" ?$ q/ |) J z+ ^& h2 landrogenic effect of interstitial cell tumor of the testis. J., u0 D- R4 u! h% j, I
Urol., 104: 774, 1970.2 d' c2 i `, l. D/ f% v
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
% l9 L4 c& w8 h( N6 k$ Wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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