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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
0 ^4 U0 N. k/ j9 ?GONADOTROPIN
# F% F+ k! I# x( ]7 g( Z6 N! zRICHARD C. KLUGO* AND JOSEPH C. CERNY
, S+ T2 `* a5 N' ~From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 b( N- I d3 v% J0 A( ]! `0 qABSTRACT' ]$ m+ o1 v6 {2 S6 \* v
Five patients were treated with gonadotropin and topical testosterone for micropenis associated& {" O8 G& I o5 K
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, x* d9 w* E% S( _: t/ w3 d/ [3 ?tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone; M5 [4 s8 w6 n9 X$ T8 s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: T7 R9 ]4 J% p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ T# W; q- t; M
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, r0 x" d" O0 c, fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 k6 c' m1 y% Q) ~ U
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ |0 A# l* |) jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 s$ ~& W$ F1 i4 ] v+ S+ Rgrowth. The response appears to be greater in younger children, which is consistent with previ-8 d0 X& b* l" a& P# l' ^
ously published studies of age-related 5 reductase activity.
$ b: |. j V( A, o1 |% i$ s( UChildren with microphallus regardless of its etiology will
9 o) T" g- A$ V! r! a. rrequire augmentation or consideration for alteration of exter-5 N% X, `0 @ D
nal genitalia. In many instances urethroplasty for hypo-1 `* A) |, O" t# r* H& D/ d
spadias is easier with previous stimulation of phallic growth.
% n2 L) `* n% J9 K3 w8 S- ?4 Q% y1 PThe use of testosterone administered parenterally or topically U/ U( b# ^, D5 V
has produced effective phallic growth. 1- 3 The mechanism of
2 D: w1 T' T7 n; k- h }) yresponse has been considered as local or systemic. With this( X4 w- F& b r9 }/ S- l3 ]. ` l
in mind we studied 5 children with microphallus for response
5 U5 t2 J. [ l* {! Vto gonadotropin and to topical testosterone independently.
: P7 v5 W& z+ r9 P: P) d+ G# C+ P! DMATERIALS AND METHODS8 V* l$ Z$ c) L. `3 z* i. G. E! t
Five 46 XY male subjects between 3 and 17 years old were
& c* c$ N1 c( ievaluated for serum testosterone levels and hypothalamic5 N2 X1 p; O5 Q+ X
function. Of these 5 boys 2 were considered to have Kallmann's
9 a0 }" D$ T' T, ]" ^/ v6 Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-2 S5 h' c; Y, _) X) P! M
lamic deficiency. After evaluation of response to luteinizing/ g. h w" ~# \
hormone-releasing hormone these patients were treated with1 f- t ?$ a5 K
1,000 units of gonadotropin weekly for 3 weeks. Six weeks& j- d. V* U! {- r. u* w9 t, k
after completion of gonadotropin therapy 10 per cent topical1 U6 A9 K" l% v
testosterone was applied to the phallus twice daily for 3 weeks.
9 T9 K v! f" v) FSerum testosterone, luteinizing hormone and follicle-stimulat-9 i. f0 i% r3 m, y
ing hormone were monitored before, during and after comple-
4 p! D f! x" S& n' Ntion of each phase of therapy. Penile stretch length was6 h% |0 U4 S) t! t K* D
obtained by measuring from the symphysis pubis to the tip of4 i- W- L' ]& w- F |
the glans. Penile circumferential (girth) measurements were H# ~3 m8 G8 ?* Z
obtained using an orthopedic digital measuring device (see, h& V- P3 a# [* R6 @3 D
figure).
0 ~8 e- m6 c3 _* ^$ w+ qRESULTS
3 u2 v9 G5 C' m! D. [Serum testosterone increased moderately to levels between' Y/ v! R0 _1 B3 _( c
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 E0 |$ V3 m, V2 a7 V& wterone levels with topical testosterone remained near pre-
) e/ i% C( f6 h+ V2 Ktreatment levels (35 ng./dl.) or were elevated to similar levels9 d8 g, c# j5 m; Y, u. p1 X
developed after gonadotropin therapy (96 ng./dl.). Higher
0 l0 N o8 K" d6 F2 g4 S ]+ P7 Fserum levels were noted in older patients (12 and 17 years old),
2 u' C+ c$ v l+ hwhile lower levels persisted in younger patients (4, 8, and 10, {$ n7 `. R" A6 Z- E" m6 x
years old) (see table). Despite absence of profound alterations
9 N; q# x+ \: D% g! _& f! A/ A% Lof serum testosterone the topical therapy provided a greater
. O+ \! {# e/ m/ ~- d4 OAccepted for publication July 1, 1977. ·& j5 I9 n; m* r
Read at annual meeting of American Urological Association,$ g7 S$ l& \3 Z0 X& R
Chicago, Illinois, April 24-28, 1977." f5 K! p# J+ f/ P& x5 T! s2 Z
* Requests for reprints: Division of Urology, Henry Ford Hospital,
: T5 Q+ |4 I6 S) y$ P( L+ {7 h' x2799 W. Grand Blvd., Detroit, Michigan 48202.) l* \- n* A$ w0 ?6 I/ O
improvement in phallic growth compared to gonadotropin.
; R+ l7 @( A+ I1 x" AAverage phallic growth with gonadotropin was 14.3 per cent
, V0 e+ O2 r% I. W9 z% Kincrease in length and 5.0 per cent increase of girth. Topical
5 f5 Q" V" ~. J9 ztestosterone produced a 60.0 per cent increase of phallic length
% f5 o9 W6 y- y+ r7 ]& ?( sand 52.9 per cent increase of girth (circumference). The1 }' `+ ^, S% x* @$ }7 W5 g
response to topical testosterone was greatest in children be-
5 |$ i& m& H, ^) Vtween 4 and 8 years old, with a gradual decrease to age 176 C ?+ y! D6 I0 D8 F* o0 P6 o
years (see table).0 x2 l" v, q* Q1 V
DISCUSSION2 W1 ^* p9 o; _9 ^& O
Topical testosterone has been used effectively by other
8 Y* ]) x; ?" wclinicians but its mode of action remains controversial. Im-
: A9 r! L) f! Umergut and associates reported an excellent growth response3 s) \* ]" m- p2 L) G8 H
to topical testosterone with low levels of serum testosterone,
+ @: ~7 U. Y- r! Isuggesting a local effect.1 Others have obtained growth re-7 }9 ?1 }! ^, O. \2 c1 v
sponse with high. levels of serum testosterone after topical9 L+ O b. K; O3 k9 I# @" O
administration, suggesting a systemic response. 3 The use of @2 Y4 v' A) v/ S0 b3 N3 z
gonadotropin to obtain levels of serum testosterone compara-
; a. {, ?) \; R5 L9 L% s( P# Kble to levels obtained with topical testosterone would seem to
. d, H+ W2 B/ b4 X& K' f6 o4 Mprovide a means to compare the relative effectiveness of
& V7 ?# e& {& ?. J% p1 Jtopical testosterone to systemic testosterone effect. It cer-$ l# Z7 p+ u& v6 u- {5 j% P) ?
tainly has been established that gonadotropin as well as par-
2 b1 E! ~5 H9 v6 h6 a- d+ zenteral testosterone administration will produce genital( x, ]! a5 q5 J* p! W, O
growth. Our report shows that the growth of the phallus was9 L/ m5 N9 F4 W. l3 N! @5 u; G6 g @/ x# i0 K
significantly greater with topical applications than with go-1 o5 V% w- Y. t2 R. R+ M; g2 ^
nadotropin, particularly in children less than 10 years old.5 ?- m' Z3 L; ~* T
The levels of serum testosterone remained similar or lower$ u2 ^* j u. S# X7 H: t
than with gonadotropin during therapy, suggesting that topi-
6 _2 B& y3 d5 Q/ dcal application produces genital growth by its local effect as
* S7 `2 f/ c5 X' m: vwell as its systemic effect.
6 v: U* e O# `: }Review of our patients and their growth response related to. G/ O, O5 H- {" O% ~5 [/ v
age shows a greater growth response at an earlier age. This is Q7 ~* I- t% M) B! a' X
consistent with the findings of Wilson and Walker, who
6 O, n5 a* l% mreported an increased conversion of testosterone to dihydrotes-8 z! d7 [- m( |" f+ [ a: j7 Q
tosterone in the foreskin of neonates and infants.4 This activ-
. Z0 J! i* p: q0 D7 W+ z# f5 l9 iity gradually decreases with age until puberty when it ap-8 ]9 h" @9 D0 j0 Y4 H+ Q9 |3 Q
proaches the same level of activity as peripheral skin. It may/ J% _' Z, f+ R1 V: {) Q! p$ J
well be that absorption of testosterone is less when applied at
" M1 v8 R* [$ Ran earlier age as suggested by lower serum levels in children
$ ?* B" {5 x5 _less than 10 years old. This fact may be explained by the
& g0 k5 M8 B5 l" Mgreater ability of phallic skin to convert testosterone to dihy-
! b0 Z3 R8 u- Kdrotestosterone at this age. Conversely, serum levels in older2 D {$ T( f) Y- f
patients were higher, possibly because of decreased local
* ]; X7 a/ _, L4 R! W2 M; q667% O: p4 p; k- M: u3 f# [
668 KLUGO AND CERNY! @' L4 X; s& Q* m! P$ k0 K
Pt. Age
, h, g2 A% |7 I0 a(yrs.)
& t+ q1 ]; K4 p2 JSerum Testosterone Phallus (cm.) Change Length }* Z+ \, ^: ?6 R
(ng./dl.) Girth x Length (%)
D& w9 D* S; m# @' k0 I* ?( E4' r W' [9 W1 v! p7 ?
8; { [7 f7 s B% o: E
10
2 r: g9 A1 L, L4 R5 A% |5 }; M12. V8 u2 j i Q3 K/ l) a @( W+ o5 j# x
17; h3 |. t4 s. y4 l0 w
Gonadotropin
) M7 C. y9 w3 w8 f71.6 2.0 X 3 16.6
6 _* D+ I: e4 `50.4 4.0 X 5.0 20.04 u- }0 h! a5 T* S- z
22.0 4.5 X 4.0 25.0
3 f6 m4 }9 u$ d# i* o84.6 4.0 X 4.5 11.1; o, V0 o& c; \2 f% ~! O; s: F
85.9 4.5 X 5.5 9.0
4 F, J2 x3 b! N. P1 z9 O% RAv. 14.3 X/ }$ {$ ^8 g# \4 _
4
% S, P* t* z! t1 y5 M9 Z- \6 F& O8( s5 n7 B3 W% s+ E# @9 c& P
10
f% [3 b: M% Q& ^* J) |12
; F# J8 t7 S9 W" g( Q1 N/ b17
' J4 I. o$ M. a4 w& h7 D2 BTopical testosterone& J: W3 X* M: s r
34.6 4.5 X 6.5 85
9 O+ n! R$ ]/ {) T5 R38.8 6.0 X 8.5 70
6 d" o! a+ b- B1 ` h40.0 6.0 X 6.5 62.5; r! [& P! H6 E/ O9 B* s' x
93.6 6.0 X 7.0 55.5/ \) n, n8 C5 w1 H
95.0 6.5 X 7.0 27.2
: E, p! W4 O$ a8 k8 S" J. l, |Av. 60.0
/ m6 `- w6 h! ]6 c: ?2 {$ |3 Vavailable testosterone. Again, emphasis should be placed on
% ^( W: H, E1 Xearly therapy when lower levels of testosterone appear to+ E t' F3 p4 G7 m7 b7 R- b
provide the best responses. The earlier therapy is instituted
6 P% P: t4 Q7 `4 R5 p7 Q8 dthe more likely there will be an excellent response with low3 \& a7 c' Y- A. T% P
serum levels. Response occurs throughout adolescence as# o# E- ]5 \$ y) W$ o/ G6 S1 U
noted in nomograms of phallic growth. 7 The actual response
( d; M, D7 }" }; f$ t# bto a given serum level of testosterone is much greater at birth0 b' S+ h a) u* U! x& a
and gradually decreases as boys reach puberty. This is most
& c) r* x- F! E! A$ glikely related to the conversion of testosterone to dihydrotes-! x7 E- }+ K+ Y |, O% ]$ k
tosterone and correlates well with the studies of testosterone$ G8 z' d) a0 Q" v1 T% _
conversion in foreskin at various ages.
2 r5 W5 r* b- K, r$ k7 \. C1 JThe question arises regarding early treatment as to whether
2 J& z8 D$ M. pone might sacrifice ultimate potential growth as with acceler-
0 R: k- P* [8 E+ S. y) fated bone growth. The situation appears quite the reverse
- @2 g4 K" K4 Q. d, D# k5 J% x9 W) mwith phallic response. If the early growth period is not used! d7 }$ {: m z7 w4 T, r
when 5a reductase activity is greatest then potential growth, P& q9 S/ J& j6 H3 G
may be lost. We have not observed any regression of growth
: P7 h1 d' V1 l' i; e& Tattained with topical or gonadotropin therapy. It may well
/ K& J. A8 J v$ a/ W5 u) T/ Abe that some patients will show little or no response to any, E- k" N8 Z+ u& ?7 s" d* n
form of therapy. This would suggest a defect in the ability to9 K! s9 M! j/ t) M6 R) z* ]
convert testosterone to dihydrotestosterone and indicate that8 a9 ]' z- s" M0 G! S
phallic and peripheral skin, and subcutaneous tissue should j# o' F' Q0 |! E2 W: b1 \. n
be compared for 5a reductase activity.& y9 V5 Y1 h7 E0 N" j. ^
A, loop enlarges to measure penile girth in millimeters. B,; n1 Q: ^ I. V9 ?/ @
example of penile girth computed easily and accurately.
' r( W- A2 x9 x7 O9 W, u1 l$ fconversion of testosterone to dihydrotestosterone. It is in this/ {: S. |! I) ~' t+ h% e. h
older group that others have noted high levels of serum0 D4 H m( q( y8 R2 _6 x. F
testosterone with topical application. It would also appear
6 ] t% h+ n- ~that phallic response during puberty is related directly to the
" p- _) @5 a+ o/ A6 j" ?% f# Zserum testosterone level. There also is other evidence of local6 \- N' A1 g3 T, f& ? o8 r% W
response to testosterone with hair growth and with spermato-- `! y l5 Q/ p( t( {1 _6 l0 A, |
genesis. 5• 6
1 t3 r' \$ r9 v( M, ]Administration of larger doses of gonadotropin or systemic" W7 ^2 Z( e* I5 D* }* D
testosterone, as well as topical applications that produce
+ T2 a" F$ C6 o0 u# hhigher levels of serum testosterone (150 to 900 ng./dl.), will) p: d+ b) v3 w: ~
also produce phallic growth but risks accelerated skeletal
# i5 \$ a# _8 e) g) Nmaturation even after stopping treatment. It would appear
1 ]( `9 K" e! n. ^that this may be avoided by topical applications of testosterone4 y# o, ] W. R
and monitoring of serum testosterone. Even with this control
' X; M+ t. i; H8 a* Bthe duration of our therapy did not exceed 3 weeks at any
' w( X. C* E$ F( I3 wtime. It is apparent that the prepuberal male subject may( y0 ?& n3 B9 R# ~
suffer accelerated bone growth with testosterone levels near3 O ^% i% W8 j/ O
200 ng./dl. When skeletal maturation is complete the level of9 l4 A. L4 S# Q% ?# ^- v1 J
serum testosterone can be maintained in the 700 to 1,300 ng./+ _% H( e, o x
dl. range to stimulate phallic growth and secondary sexual
t2 P$ e& O0 _+ T! zchanges. Therefore, after skeletal maturation parenteral tes-
# J. m- k( u2 H( q# Q3 k9 L1 ztosterone may be used to advantage. Before skeletal matura-
4 `/ ?+ O2 u; Stion care must be taken to avoid maintaining levels of serum% B! c" }; M/ {' h
testosterone more than 100 ng./dl. Low-dose gonadotropin
9 o; _6 e& }) ?+ ldepends upon intrinsic testicular activity and may require
# N6 j) J; m3 {2 ?) zprolonged administration for any response.
2 H/ Q! C9 d5 l- S, wAlternately, topical testosterone does not depend upon tes-
) c( Q6 s6 z3 ~7 {. A7 _. pticular function and may provide a more constant level of
7 f' j! y4 M2 |5 T7 uREFERENCES. \" Q. t+ u# z0 t9 R6 e* r! |( A
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,: ]+ k1 }( C: d
R.: The local application of testosterone cream to the prepub-8 g6 o& Q5 Y3 T
ertal phallus. J. Urol., 105: 905, 1971., q6 |7 E X& S4 R
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& Q; H. n" K4 w ^0 l
treatment for micropenis during early childhood. J. Pediat.,: d/ b7 E0 `6 s% F- T- z# g
83: 247, 1973.
6 F& s' F3 M: s( H3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster- ?1 [+ m) p- e# ~2 Z; u8 ^( Z) M. R, ?
one therapy for penile growth. Urology, 6: 708, 1975.
( u* Q5 o, X8 Y; d+ s5 |1 J' p9 m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
6 m3 a/ a W+ K/ Fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* \! z# \# }2 v: M j# y
skin slices of man. J. Clin. Invest., 48: 371, 1969.
- f x" ] e- L+ f5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: Q- N$ E# m& j$ f1 Aby topical application of androgens. J.A.M.A., 191: 521, 1965.
, j# A; H1 [, Z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
: H, J% C4 D6 v" xandrogenic effect of interstitial cell tumor of the testis. J.
0 ?3 n! S$ |( c! Q* U$ a9 wUrol., 104: 774, 1970.
/ {9 r9 o1 u. m; E7 x7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 Y$ N% }; s c7 P8 s! f) Ttion in the male genitalia from birth to maturity. J. Urol., 48: |
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