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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ U" E- \% {) ^' zGONADOTROPIN
) R4 d, U+ ~8 l* e$ H- D9 k7 mRICHARD C. KLUGO* AND JOSEPH C. CERNY
1 y/ u8 Y( f% a! t- S; wFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan" t! w2 B; ]( g2 B; b; _
ABSTRACT' [1 E$ D6 t9 }. g
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 J" B. K5 S3 _with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ J5 \$ m9 F9 Utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ _. o% n; t1 R' \* P
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 g! A! v8 Z% u5 V$ o( D
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. K6 k3 x' d% q. Z' m! d; w6 n
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 U8 H% N% K7 S7 g! d7 g
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% c; F! ^4 M3 }2 _- U2 ]: G
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 |+ @7 @' L- W }$ z2 T5 v, qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile2 |! d/ E' @6 Z& n$ S
growth. The response appears to be greater in younger children, which is consistent with previ-( I" }6 U* m5 X9 |3 U2 O
ously published studies of age-related 5 reductase activity.
5 T2 @* W/ g; r! N* y1 ]+ {Children with microphallus regardless of its etiology will
( P% Z. U+ \4 i- [' y' qrequire augmentation or consideration for alteration of exter-
, J: Y. a0 O) d" ?5 xnal genitalia. In many instances urethroplasty for hypo-" v. F9 Z) Y4 ]" }# M& I
spadias is easier with previous stimulation of phallic growth.
, _9 A) {3 `* H& RThe use of testosterone administered parenterally or topically; l h! U: h6 n9 m! X; }, K( p
has produced effective phallic growth. 1- 3 The mechanism of9 s; m& i+ q( {' ?: n5 q% L
response has been considered as local or systemic. With this
/ n+ u7 x/ s- b; k& `% Jin mind we studied 5 children with microphallus for response
& R- e# _+ L6 h# H$ H+ y dto gonadotropin and to topical testosterone independently., S) c9 [2 w& K8 R- V3 Z' E
MATERIALS AND METHODS3 {& I' E9 B0 b3 M8 b3 k
Five 46 XY male subjects between 3 and 17 years old were+ Y4 _ b& _3 \: v5 s1 Z# a# G
evaluated for serum testosterone levels and hypothalamic
- I F# Z9 r+ C! D2 m3 E0 ~. yfunction. Of these 5 boys 2 were considered to have Kallmann's
; Q- f& E% A4 y$ X# X5 c2 }syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 |6 P8 V& Q$ l
lamic deficiency. After evaluation of response to luteinizing
$ U7 S* J' E, ~5 n, i2 Ehormone-releasing hormone these patients were treated with( V7 `0 s8 ` z: T8 X2 Y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks% J# p. j" r4 [& J. N
after completion of gonadotropin therapy 10 per cent topical
$ v1 M8 {3 q' i/ K% }( {. ttestosterone was applied to the phallus twice daily for 3 weeks.
0 ?' p7 v( y8 ^! `# @0 G+ D: aSerum testosterone, luteinizing hormone and follicle-stimulat-
/ I( U$ R* ~) Y3 Zing hormone were monitored before, during and after comple-
% o8 ?' C2 I9 Ttion of each phase of therapy. Penile stretch length was
2 |$ M. e U5 s) g) n+ [) R- ~obtained by measuring from the symphysis pubis to the tip of( a6 Y* v, G9 E, z. X
the glans. Penile circumferential (girth) measurements were$ f9 n- o- \' z
obtained using an orthopedic digital measuring device (see8 E3 Y. f F0 g, c! o
figure).
! }0 Q. F2 y6 B; ~" Z1 x; gRESULTS
b. d& d$ [% Q# f* @$ R3 |4 PSerum testosterone increased moderately to levels between1 p0 w2 q! C# ^3 P! T
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ W' m- \2 E5 ^- r& N7 |terone levels with topical testosterone remained near pre-
$ U& e* F. Z% G Ytreatment levels (35 ng./dl.) or were elevated to similar levels
7 ]) Z8 Y# |0 l) h0 c P6 r1 ideveloped after gonadotropin therapy (96 ng./dl.). Higher
5 ^. H# x2 j) M. h7 r& ?+ H( Wserum levels were noted in older patients (12 and 17 years old),' X. a$ N- p% J4 y- y
while lower levels persisted in younger patients (4, 8, and 10+ A+ |* B" x& o( [9 W7 n' C
years old) (see table). Despite absence of profound alterations8 H, U. n w4 W9 X( W: |% X! c
of serum testosterone the topical therapy provided a greater
2 U9 @* v% [1 |0 o% `: f$ jAccepted for publication July 1, 1977. ·$ F. O ~$ O1 D" {+ j6 i0 y
Read at annual meeting of American Urological Association, {( m, t7 h" G1 m- O% `
Chicago, Illinois, April 24-28, 1977.
. P- r4 l( U! N4 h! ~( N* Requests for reprints: Division of Urology, Henry Ford Hospital,8 {2 Y$ `& ~/ U4 u7 w! d
2799 W. Grand Blvd., Detroit, Michigan 48202.
; X: N2 {1 r5 m9 P4 Yimprovement in phallic growth compared to gonadotropin.
/ y5 U& Q$ [% E0 d) [( oAverage phallic growth with gonadotropin was 14.3 per cent3 }4 O0 T$ y# h, D' m/ @; n; g
increase in length and 5.0 per cent increase of girth. Topical% i# Y& ~, A. K8 h3 G
testosterone produced a 60.0 per cent increase of phallic length4 P: k" @1 F- f p, _ G' W
and 52.9 per cent increase of girth (circumference). The/ O( P! q7 W0 R+ \
response to topical testosterone was greatest in children be-
0 @1 x; V; o3 N: i0 Itween 4 and 8 years old, with a gradual decrease to age 17
+ L V0 V" c% B5 N2 A" Dyears (see table).
0 D; }. G3 p' Z) ~DISCUSSION( f( U+ h% c" O4 n! Q; Q* n; y
Topical testosterone has been used effectively by other
: y' I8 w# ?1 X( }clinicians but its mode of action remains controversial. Im-
" d3 `; L1 h. k8 M) j, zmergut and associates reported an excellent growth response1 R& t& }# x( E/ q z# A
to topical testosterone with low levels of serum testosterone,
6 J) A5 [: L( [% F. k. nsuggesting a local effect.1 Others have obtained growth re-
! Q8 x2 i3 Y$ s, C4 {, lsponse with high. levels of serum testosterone after topical
/ o% i6 z, A' p& Wadministration, suggesting a systemic response. 3 The use of' d2 C' s$ ^$ J9 X+ b+ a! b
gonadotropin to obtain levels of serum testosterone compara-5 S% ]) z5 a9 Y& G
ble to levels obtained with topical testosterone would seem to
9 x; l4 |- e4 g9 Hprovide a means to compare the relative effectiveness of9 j& v4 a5 m9 w$ i8 k: n# M
topical testosterone to systemic testosterone effect. It cer- ?& p5 d8 {2 p% @( l8 E- O* K
tainly has been established that gonadotropin as well as par-
' Q* m @* o. y: Penteral testosterone administration will produce genital
2 p1 P% t2 n" S! U$ ]$ f$ }growth. Our report shows that the growth of the phallus was
7 g" E, g1 }- U$ k( W6 ^" Tsignificantly greater with topical applications than with go-
5 q4 B8 n) V5 n+ ^9 u) T$ Bnadotropin, particularly in children less than 10 years old." h& t& I( Y% h* I3 |& b
The levels of serum testosterone remained similar or lower. r9 m% q! @/ G/ F; q
than with gonadotropin during therapy, suggesting that topi-8 d: I/ y% J8 n @5 b$ J
cal application produces genital growth by its local effect as. A& ~ Z" s7 v' ^ _
well as its systemic effect.* S! l" @; y, a) |
Review of our patients and their growth response related to9 I) X. C% W2 U5 R
age shows a greater growth response at an earlier age. This is1 \& N. t- Y8 i, C2 {- U5 e
consistent with the findings of Wilson and Walker, who$ p5 n' K+ |3 B o% |- C* ^
reported an increased conversion of testosterone to dihydrotes-
( m. A5 K0 G7 b2 P0 S) U3 {tosterone in the foreskin of neonates and infants.4 This activ-
a" i" ?7 [6 i! n9 w Iity gradually decreases with age until puberty when it ap-% h5 G7 m0 |! C$ n7 n
proaches the same level of activity as peripheral skin. It may; J! n( s5 F8 U* z
well be that absorption of testosterone is less when applied at
3 M3 s# ^& k }; oan earlier age as suggested by lower serum levels in children
6 F2 Z6 m' u' h. k! ~. o1 Bless than 10 years old. This fact may be explained by the
6 @7 B9 {6 j) H2 j! a( s; Qgreater ability of phallic skin to convert testosterone to dihy-+ N# r' Q" N) w9 U" T% w+ M
drotestosterone at this age. Conversely, serum levels in older
/ U" n* @' I* E% Xpatients were higher, possibly because of decreased local
' `6 ^2 Q8 `' Y! Y* V667
: |; O" t) S) v0 t; r' ]8 i7 v, C x668 KLUGO AND CERNY
* d% I, M; P7 }4 H9 q* pPt. Age
" n& z" S8 x+ b p: _+ H& k(yrs.)/ B1 E5 X: Q3 J" }+ G
Serum Testosterone Phallus (cm.) Change Length& n0 T* H( D! [8 d
(ng./dl.) Girth x Length (%)
1 ]" i0 |& q, g$ i45 x6 C! u) n8 f% u; K; E: C
8% {4 X: u! c5 K1 j$ l
10
' L6 q0 ~; M; D8 h7 [( g! | t2 r( Q12
1 Q ^& n" s d7 U" a17
+ U' M$ X3 L# z! q6 SGonadotropin
2 d. @( ~& Q! x# h9 d71.6 2.0 X 3 16.6' A- l' g2 _# C* G2 _) _
50.4 4.0 X 5.0 20.01 B; }/ A6 ?& N$ i7 U. f2 v
22.0 4.5 X 4.0 25.0' a% v2 V" Q" n8 m( }
84.6 4.0 X 4.5 11.14 O. e6 k: S a, m+ x/ D
85.9 4.5 X 5.5 9.0& r/ k* G3 \! s @! F; l) v4 g" E( g: O
Av. 14.3
$ J A; p; ^4 K, d+ r7 p% s. e7 D4
- N' R0 ?; e& L& f L8
9 z2 t% G0 o6 W10
0 P5 S. t- M/ ]1 r) G# o12
# g4 y" s! ^+ {7 b! P170 }2 L; \7 r, c" A4 ^. V6 W
Topical testosterone
* i( o3 I6 W' W6 R" S3 y34.6 4.5 X 6.5 85$ u! d9 B# y, H& p
38.8 6.0 X 8.5 70
! A2 h' B2 w1 i40.0 6.0 X 6.5 62.5
7 X" M( L( R$ T: G: b, x {9 {93.6 6.0 X 7.0 55.5
) z4 R2 h+ a; v95.0 6.5 X 7.0 27.2
9 t( C8 ~" x% V6 ], P0 y1 @, l( KAv. 60.02 u, I1 G$ B0 p3 w+ `2 s7 b
available testosterone. Again, emphasis should be placed on
5 d: H6 ]( _4 N4 G3 I [" {$ iearly therapy when lower levels of testosterone appear to, ]( `) q& w8 I# F/ D
provide the best responses. The earlier therapy is instituted
. Y9 T- q2 [' s8 D* P' bthe more likely there will be an excellent response with low9 y# j7 t- z# o1 k
serum levels. Response occurs throughout adolescence as
6 j% C/ e1 l% m7 l9 g. l( enoted in nomograms of phallic growth. 7 The actual response. ?+ b/ T0 l6 Z( W
to a given serum level of testosterone is much greater at birth y# u( }+ U6 S# W+ t% b. p
and gradually decreases as boys reach puberty. This is most- |* x+ W% [9 ?: `8 \! Z
likely related to the conversion of testosterone to dihydrotes-3 Y) O$ ^ z5 I. b2 v4 I$ o% ^' A! ]
tosterone and correlates well with the studies of testosterone
# u1 u b/ ?' s4 h: ]conversion in foreskin at various ages.' R' r# ]0 V. z! M3 N
The question arises regarding early treatment as to whether
/ ~* o$ F& Y" r4 B# R' F2 hone might sacrifice ultimate potential growth as with acceler-* M2 }, I5 h9 `0 x6 x* O; C( B8 E
ated bone growth. The situation appears quite the reverse
' e9 ^& r3 i/ s+ B5 _with phallic response. If the early growth period is not used: i( w6 q, T% B0 X, I
when 5a reductase activity is greatest then potential growth$ q+ u( w/ u" K+ q& h, A) D
may be lost. We have not observed any regression of growth
6 \8 ~+ m* J7 lattained with topical or gonadotropin therapy. It may well
# a: k- |& c0 \1 q1 A5 Q' c! O' Ibe that some patients will show little or no response to any
: D& a* {+ s" ~form of therapy. This would suggest a defect in the ability to# P& B4 C7 ]. G4 j
convert testosterone to dihydrotestosterone and indicate that
+ ~2 @9 H+ V/ Ophallic and peripheral skin, and subcutaneous tissue should9 u2 ~5 O, t1 K" e8 V; e
be compared for 5a reductase activity.
; _" Q" c3 v" b2 e) l* `; p4 EA, loop enlarges to measure penile girth in millimeters. B,4 |2 [" |9 {3 m( |' l r6 p1 @' l: g
example of penile girth computed easily and accurately.
- X# V$ z; ]8 K1 {/ W4 K3 @conversion of testosterone to dihydrotestosterone. It is in this
: ^ ]+ q9 }( o" \, N* {" q. Zolder group that others have noted high levels of serum) t! k( o0 s9 w( D0 X3 B, Q
testosterone with topical application. It would also appear) R5 ]+ e" [) [/ z& E
that phallic response during puberty is related directly to the
9 \7 M d. I5 ?, Nserum testosterone level. There also is other evidence of local
- t+ a4 B$ x& e" Gresponse to testosterone with hair growth and with spermato-
$ o/ N, ?" M+ r8 M& Fgenesis. 5• 6; p, q( y5 q0 M) L8 T. T! M
Administration of larger doses of gonadotropin or systemic, \& v6 k( B3 i$ r, H/ M- f6 k
testosterone, as well as topical applications that produce, _7 Y# u. ~# B+ u3 | o: z! {
higher levels of serum testosterone (150 to 900 ng./dl.), will; T! [3 X4 I- W0 w
also produce phallic growth but risks accelerated skeletal
" T8 ^4 q+ N8 p$ Y+ ~# T( q1 Fmaturation even after stopping treatment. It would appear; K/ h. X8 a8 k0 O0 ?
that this may be avoided by topical applications of testosterone
3 l$ J1 U+ ~! e) S# rand monitoring of serum testosterone. Even with this control
0 w0 e4 f( n. P- f( W, X! p0 d f! Tthe duration of our therapy did not exceed 3 weeks at any
: K9 _- m$ q) k$ r/ jtime. It is apparent that the prepuberal male subject may0 T0 v* k% f2 p: P) f$ G
suffer accelerated bone growth with testosterone levels near: m$ ^3 g% X6 M) z+ d$ E
200 ng./dl. When skeletal maturation is complete the level of
# o9 a* x0 V# p- B: Hserum testosterone can be maintained in the 700 to 1,300 ng./
* \& e$ b# c- p6 O$ U& w% }dl. range to stimulate phallic growth and secondary sexual& G+ D( |4 n' R1 e; Z+ C
changes. Therefore, after skeletal maturation parenteral tes-
0 R+ V$ Y* k* N2 ztosterone may be used to advantage. Before skeletal matura-
# w! d/ O: N7 \1 i0 Ktion care must be taken to avoid maintaining levels of serum
6 w6 A- D$ x- a3 @. c- htestosterone more than 100 ng./dl. Low-dose gonadotropin! T6 ]: h/ ^. ]' Y1 @0 [) b1 S, U
depends upon intrinsic testicular activity and may require
# C+ _2 P2 K3 ]# g- nprolonged administration for any response.. T& b5 o' P- L! d
Alternately, topical testosterone does not depend upon tes-, h# f; T6 S8 L- H s; N8 D4 R
ticular function and may provide a more constant level of- Z0 s9 v% U* D2 g+ i
REFERENCES7 K* R. h( y; T( @! d
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- Y( f9 L7 V4 b y5 S% V5 N
R.: The local application of testosterone cream to the prepub-+ f* S3 ~. ]5 p6 O
ertal phallus. J. Urol., 105: 905, 1971.
8 i5 T+ S3 Q) {* N0 c1 u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
4 ]; w/ f; j! B$ F1 G6 o8 `2 ctreatment for micropenis during early childhood. J. Pediat.,/ a3 y$ z/ b$ C, [0 [
83: 247, 1973.
) F0 `& u* U5 C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 @! G- _& k; A& J: xone therapy for penile growth. Urology, 6: 708, 1975.
0 }! H/ V7 _* Q* S4 W* S4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 z7 ]. y& P- Z
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* w3 Q+ i1 x4 A$ Z2 q
skin slices of man. J. Clin. Invest., 48: 371, 1969.% s$ R" M0 O. X: j/ G# K) w/ H
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, Q; W) V) @: L3 h) p$ O$ A5 ~by topical application of androgens. J.A.M.A., 191: 521, 1965.9 C% Y( s. q: ^
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ i. _8 n5 R3 D& \' m! Sandrogenic effect of interstitial cell tumor of the testis. J.
# `7 t7 z; h: F" j' E0 C$ Q8 O4 YUrol., 104: 774, 1970.* Z1 l. X! e( `2 X) z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 c# X& @: j+ g. H
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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