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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ l* R0 o! P% W9 h
GONADOTROPIN/ E* J, Z( L- i& R
RICHARD C. KLUGO* AND JOSEPH C. CERNY
6 b/ N/ K+ X! A" w% P1 u; \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan6 [9 Z3 S3 c; D" B
ABSTRACT6 S( y. q9 Z/ Q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 h. Y1 E# K. n/ B0 vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! s2 ^' Z2 U1 l! B% R% P
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" i, ]( O' g% c# R' n1 A) Ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
& O" S5 m) O. o. X! Mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 x' e# h$ \# w% p4 u' Wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
' M6 J- Y: e; o% ^1 G* r" eincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 N. `5 v" a0 }& X7 D$ `
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& J/ }7 z) n9 E: m3 ^; m9 A. ?
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
7 ?" [4 C8 o5 Vgrowth. The response appears to be greater in younger children, which is consistent with previ-2 f% }5 P3 p% o, h: i C
ously published studies of age-related 5 reductase activity.
9 u7 e' j: g {2 R# y- m# B' sChildren with microphallus regardless of its etiology will0 o: b4 z2 R" @. m* |% y* y7 P- e
require augmentation or consideration for alteration of exter-7 u1 R: H% d& U# M
nal genitalia. In many instances urethroplasty for hypo-
& p! o! i: F" @9 u+ Uspadias is easier with previous stimulation of phallic growth.. N8 S0 ~/ i5 m- I1 q
The use of testosterone administered parenterally or topically# X* r" d0 \" u2 }* f( P& H1 K; C
has produced effective phallic growth. 1- 3 The mechanism of
: J* d, v7 m- nresponse has been considered as local or systemic. With this* a4 _2 E# G: K9 w) |
in mind we studied 5 children with microphallus for response
% }, K5 \% n; T$ ^& E# @to gonadotropin and to topical testosterone independently.
; J0 ]# u5 p+ cMATERIALS AND METHODS: t+ ` U% K, ?4 _$ j; e
Five 46 XY male subjects between 3 and 17 years old were
" c! q1 u) S. i- C1 Cevaluated for serum testosterone levels and hypothalamic
4 A: C' s6 ?" [1 W: l. }3 qfunction. Of these 5 boys 2 were considered to have Kallmann's
$ b2 l- Y8 q2 ]! K. V# b$ `syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-. L+ G2 [. V. N/ S, N0 D( B- |
lamic deficiency. After evaluation of response to luteinizing
" L* q1 }( c3 y \ e( j# Xhormone-releasing hormone these patients were treated with
, D* N8 G/ ?" t1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& L3 B" S0 o* L* ]/ D+ q4 Jafter completion of gonadotropin therapy 10 per cent topical" L7 c/ ]2 n ?- ^5 J. g: p: ^% C
testosterone was applied to the phallus twice daily for 3 weeks.
- [3 z ~ N! tSerum testosterone, luteinizing hormone and follicle-stimulat-: K8 S0 Y1 P9 P% O$ K, ^) a
ing hormone were monitored before, during and after comple-
' Q* K; \) o1 D+ ttion of each phase of therapy. Penile stretch length was
8 h( h$ V6 N( z9 B" M. Zobtained by measuring from the symphysis pubis to the tip of" |- T( z7 A0 ~+ d. _! A v
the glans. Penile circumferential (girth) measurements were
g% M" K. G) s! Zobtained using an orthopedic digital measuring device (see
1 C+ F! e0 P0 F- K* r8 Q+ Q/ A9 Rfigure).
2 i" w# \( O8 W6 `2 {5 _RESULTS
: J! x( B4 p% U& E9 h8 mSerum testosterone increased moderately to levels between: P! c4 T" P. R. J( r: x. ?9 ?
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-1 E+ V* l: X3 s, a) B) _
terone levels with topical testosterone remained near pre-8 j. J) [& S% q! c6 @6 P
treatment levels (35 ng./dl.) or were elevated to similar levels
2 ^4 j2 Z c" s& j, O- }6 \developed after gonadotropin therapy (96 ng./dl.). Higher. n g8 O9 Y/ |* l3 M0 z
serum levels were noted in older patients (12 and 17 years old),
! ?8 A2 B8 l2 [% P6 e2 V, k4 O2 a' Lwhile lower levels persisted in younger patients (4, 8, and 10) L, r/ D/ Y7 d h+ B" N
years old) (see table). Despite absence of profound alterations
; p% [1 `0 I6 f U' q$ K: L/ ?of serum testosterone the topical therapy provided a greater
+ }+ _. G* A" {+ jAccepted for publication July 1, 1977. ·. L6 `3 {8 b; x+ |5 ?
Read at annual meeting of American Urological Association,1 S0 k8 j: Q" q% S; T$ B! Y
Chicago, Illinois, April 24-28, 1977.1 r y ^8 _: ]0 E& }; A( o
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 \5 g; h1 _. f$ ^( ~
2799 W. Grand Blvd., Detroit, Michigan 48202.
6 L& L$ w0 j* nimprovement in phallic growth compared to gonadotropin.
9 K& }/ a) B7 X7 s3 uAverage phallic growth with gonadotropin was 14.3 per cent2 O7 m! R1 ^9 I z- Z! W! Z$ ~
increase in length and 5.0 per cent increase of girth. Topical
# y& O( z2 C# ^, _ O* ]testosterone produced a 60.0 per cent increase of phallic length
# F3 ]& x0 K+ sand 52.9 per cent increase of girth (circumference). The( r0 S# P/ f: k* M" x3 i
response to topical testosterone was greatest in children be-/ W+ O: t+ U' r* }& ~3 E
tween 4 and 8 years old, with a gradual decrease to age 17
' K) `8 p. u; Yyears (see table).& c$ o4 r: S+ i8 P
DISCUSSION0 J! ]8 z* d& M1 x2 `
Topical testosterone has been used effectively by other! O; s3 Q( q4 T
clinicians but its mode of action remains controversial. Im-! M8 x% [" n: F" Z3 [& {
mergut and associates reported an excellent growth response& P/ b. m, M0 T! V+ _0 U
to topical testosterone with low levels of serum testosterone,
$ a) Q" C8 B. g! `' L$ ]suggesting a local effect.1 Others have obtained growth re-
7 ~2 O i% J" [9 v' s. W, d) B$ Qsponse with high. levels of serum testosterone after topical; m5 w& I# H3 U- K6 s
administration, suggesting a systemic response. 3 The use of9 d$ N) e2 p, a( n2 ]
gonadotropin to obtain levels of serum testosterone compara-
* ^& h$ R7 G& P/ K# V4 ` Bble to levels obtained with topical testosterone would seem to- @) {( ^- P E
provide a means to compare the relative effectiveness of8 g0 y% m" y M6 |
topical testosterone to systemic testosterone effect. It cer-
& M+ j# A2 l H& }tainly has been established that gonadotropin as well as par-7 i0 M2 e( O# t8 ]; y" G
enteral testosterone administration will produce genital4 @4 L. Y) @5 n- a6 }& i
growth. Our report shows that the growth of the phallus was2 _, w! b# ?& d, V) z* y* `
significantly greater with topical applications than with go-
+ P6 {1 _# }" }& Qnadotropin, particularly in children less than 10 years old.2 `/ ?/ H7 n- s% \$ ?+ S, o6 Q
The levels of serum testosterone remained similar or lower
' |# {5 x4 M' F. g1 X( V: Z. y. a) k$ Kthan with gonadotropin during therapy, suggesting that topi-
% f* V, O9 J- C* vcal application produces genital growth by its local effect as
- o) \: s) x! A+ v% Hwell as its systemic effect.
: ^9 h: w' z4 C: eReview of our patients and their growth response related to
) T$ H2 R' J+ e7 Kage shows a greater growth response at an earlier age. This is0 h$ O. Y1 {. e$ U# ]
consistent with the findings of Wilson and Walker, who
: X2 |) L# _+ e8 Jreported an increased conversion of testosterone to dihydrotes-. Z$ j4 k. A6 p' f; \: T
tosterone in the foreskin of neonates and infants.4 This activ-
8 F5 A: l5 y- Z! x& {1 c0 _, V0 K& t' aity gradually decreases with age until puberty when it ap-
( C& G1 b# u/ ~- ?proaches the same level of activity as peripheral skin. It may/ O- [- W! R7 P
well be that absorption of testosterone is less when applied at
7 y) j- Z( v' ~& Nan earlier age as suggested by lower serum levels in children
( F- [( A: W4 b+ d# Wless than 10 years old. This fact may be explained by the
5 ^% j# t4 Q/ Z! Y- cgreater ability of phallic skin to convert testosterone to dihy-
7 @# C) K4 z9 k$ e3 Y0 i& y" H6 D, Qdrotestosterone at this age. Conversely, serum levels in older
. Y2 N" R# r/ e/ Q8 g: s, ]patients were higher, possibly because of decreased local
, p& M+ f: F- S667
6 a$ |4 H9 Z, Z7 x: O) y4 U/ G668 KLUGO AND CERNY
; m- Q6 W' q V2 p2 RPt. Age! F! N. R6 `& M7 T2 R$ i. x
(yrs.)! v x' X B+ `* ^0 u
Serum Testosterone Phallus (cm.) Change Length* V3 m: C1 x% g8 ]' ?$ }5 m, S
(ng./dl.) Girth x Length (%)
" H3 l1 ]% z( l( h, E9 C5 ~4* |! K: T. G5 z: n& U$ j" [- p
8! E8 Y+ T& D. k& W$ B( b
10' h. n% V: Q" D3 d: [2 R1 \
12& a) a8 h y2 @0 O1 S1 w, K& O
17
; ]7 N& h5 n u% }3 i# G- UGonadotropin
0 M& S8 m2 ^- F# F* O71.6 2.0 X 3 16.6$ |, M& o' A, }' B2 G- n& `( ?
50.4 4.0 X 5.0 20.02 X' W" r- h* W& Y$ `+ Z; g
22.0 4.5 X 4.0 25.0
# P$ u# M7 V1 u) y84.6 4.0 X 4.5 11.1
0 o5 l) G/ e2 D85.9 4.5 X 5.5 9.04 _; X1 s4 u+ B& A/ A" i0 M
Av. 14.30 w. @3 d: N4 @# Y: ?* m& H6 s/ o
4$ |2 F1 P, M! n( I# o( a( F9 W
8
5 d% f, o$ K% K$ a; t3 Y2 R" E; x: Q# j10
' L" x9 Y8 _* W12
3 |9 m, U$ j: R1 M2 @175 o+ F, C5 B5 H( m# |* L
Topical testosterone" Y" c7 @4 j) c) m" u( \5 W
34.6 4.5 X 6.5 85
2 ?! | M# a$ p0 q9 j9 ]38.8 6.0 X 8.5 70
; V( Y# W6 q8 c, E5 |7 D- p" B40.0 6.0 X 6.5 62.5( A1 p1 Z) \2 E) l9 W
93.6 6.0 X 7.0 55.5; m: w3 P0 a# ]
95.0 6.5 X 7.0 27.2
: J( } V6 }6 H9 \1 l8 AAv. 60.0+ ~5 J3 _: H. g$ T" a
available testosterone. Again, emphasis should be placed on
" ~; O; B) Y! x6 iearly therapy when lower levels of testosterone appear to, A; G. @, H3 f& d3 ^
provide the best responses. The earlier therapy is instituted
1 b9 }8 l8 j1 v! ]3 ^- ~+ gthe more likely there will be an excellent response with low5 d6 v! O0 m3 G! V0 u/ _" u/ f
serum levels. Response occurs throughout adolescence as/ o q1 Z8 ^1 z: W
noted in nomograms of phallic growth. 7 The actual response" L* u: d) f4 H! H
to a given serum level of testosterone is much greater at birth
, X" T, a4 G$ Q$ [and gradually decreases as boys reach puberty. This is most1 P: I% J1 f/ Q# B/ I" B
likely related to the conversion of testosterone to dihydrotes-( f) P3 K3 [% Q5 R% p) O+ [
tosterone and correlates well with the studies of testosterone
# @" i4 e' ]8 _conversion in foreskin at various ages.7 A5 W% j0 h* Z9 e
The question arises regarding early treatment as to whether
' z9 G1 d+ j! t* n3 Kone might sacrifice ultimate potential growth as with acceler-
) v: j, R5 c) b+ j# V" pated bone growth. The situation appears quite the reverse
" C8 |9 j( N6 o4 h2 Dwith phallic response. If the early growth period is not used6 D+ O' o9 q; b V5 N3 S9 S, h
when 5a reductase activity is greatest then potential growth7 \4 ^( H9 Z* ~. H
may be lost. We have not observed any regression of growth9 T: y% y6 x/ X, t4 M+ s
attained with topical or gonadotropin therapy. It may well
5 u- \2 V( s( }- k+ K6 pbe that some patients will show little or no response to any0 r& V% j2 j4 D2 x5 p: C
form of therapy. This would suggest a defect in the ability to
- Z$ b- j# N; q! \, _" ?+ Gconvert testosterone to dihydrotestosterone and indicate that- S% `" ]; \' Y/ p; r2 M' l. L
phallic and peripheral skin, and subcutaneous tissue should% v% j3 e$ j L B3 h% Q- F
be compared for 5a reductase activity.: A2 o( m; ]9 e) p
A, loop enlarges to measure penile girth in millimeters. B,
4 S& }% u7 d3 U% v) g5 ^. A' u# |' ~example of penile girth computed easily and accurately.0 H; ^$ r* ^9 D6 P
conversion of testosterone to dihydrotestosterone. It is in this$ m7 p, m* M, m6 I. f
older group that others have noted high levels of serum
1 u0 G. O4 U0 F6 I" O F, Xtestosterone with topical application. It would also appear9 E' R- D! e4 v
that phallic response during puberty is related directly to the$ W! F4 t' a! }7 K
serum testosterone level. There also is other evidence of local5 Q3 m. ^ W7 a% Z; ]( d6 v, k; H
response to testosterone with hair growth and with spermato-2 b( Q, I1 J! t* t% U/ ^7 K
genesis. 5• 6
* a/ A8 {$ A3 u# hAdministration of larger doses of gonadotropin or systemic
7 z- J E- D8 ]/ T% _' Gtestosterone, as well as topical applications that produce
6 l5 h& u* i9 V) H: W7 x' Jhigher levels of serum testosterone (150 to 900 ng./dl.), will" {; B* r1 O5 A }" b. s
also produce phallic growth but risks accelerated skeletal
+ ~; i& j$ L1 X, Xmaturation even after stopping treatment. It would appear
1 \6 [( F& W4 [( }( D# b: Q; }! U& }4 z/ Zthat this may be avoided by topical applications of testosterone5 \0 v$ y; Z3 I7 k/ Q$ B
and monitoring of serum testosterone. Even with this control B T/ ], Y' e% S! c% a5 D' }
the duration of our therapy did not exceed 3 weeks at any! |6 E2 j+ k0 u5 i8 A, M' x0 C k& v
time. It is apparent that the prepuberal male subject may4 D; F* T9 o) @' A9 v$ n; }3 U
suffer accelerated bone growth with testosterone levels near
6 ^% s9 ~. ?* o* n' c" [: o200 ng./dl. When skeletal maturation is complete the level of1 o, \+ Q/ d* B4 h! F
serum testosterone can be maintained in the 700 to 1,300 ng./' W$ S. x- h/ A# F- W
dl. range to stimulate phallic growth and secondary sexual
# \ c( J* S1 A! n2 i$ h1 y5 D. R: zchanges. Therefore, after skeletal maturation parenteral tes-
" h7 D& P C4 Otosterone may be used to advantage. Before skeletal matura-
' c# N6 `9 Y8 Q! d0 S$ d4 z' ation care must be taken to avoid maintaining levels of serum
7 d( e! p5 V& c7 l# K, T4 l9 E# mtestosterone more than 100 ng./dl. Low-dose gonadotropin" g0 P5 v* A) u; }
depends upon intrinsic testicular activity and may require* [3 i1 y! h, U0 U4 F* G+ M
prolonged administration for any response.7 Z+ m/ A" l: P! Q- d1 U; j
Alternately, topical testosterone does not depend upon tes-
4 n7 S; c* p4 zticular function and may provide a more constant level of s# `: w" R( h |8 _
REFERENCES* D) b O7 h; R1 R! o+ P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: p% p( A+ s5 w/ m& q' @1 jR.: The local application of testosterone cream to the prepub-
% _. f9 j) a6 V% a6 O4 y, p+ Jertal phallus. J. Urol., 105: 905, 1971.+ R( a& ^0 J* W* Z& z
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# I2 X( [+ h+ [' N7 M
treatment for micropenis during early childhood. J. Pediat.,
3 _3 @' W7 f& _: k$ M/ c; M- ?) I83: 247, 1973.
" V- P- J. H8 v3 G3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
4 \! \: z/ p& p% u, Zone therapy for penile growth. Urology, 6: 708, 1975.3 o4 c# B' w) e3 o1 ~
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* U: ]0 |9 e s0 A6 q# v
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" O0 i' k# k- G# q1 j
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, p3 A- j% l; W9 [- w4 A) P1 h5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ R; a* u4 w( \$ D6 q
by topical application of androgens. J.A.M.A., 191: 521, 1965.5 [, }7 ^: v$ S; E+ u
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 V3 F/ A/ l' V" h) s5 A- X' eandrogenic effect of interstitial cell tumor of the testis. J.
3 O3 y- R" h0 s: Y8 k/ SUrol., 104: 774, 1970.
& p" |2 u4 n0 t: n" t& L+ |4 Q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; j0 M, n& C8 q/ F. I5 M" |tion in the male genitalia from birth to maturity. J. Urol., 48: |
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