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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 J* J" N3 C$ I3 {4 `
GONADOTROPIN2 b0 z; |; x6 D
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 l& A g4 r: a6 l4 T) a# q8 z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan5 G9 m# H( A, s4 X
ABSTRACT- F* }9 i( z$ N1 g; T& E6 ^
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: t4 s V1 j x4 n
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* ]3 T9 R( b: Z+ Btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
2 @ H9 p. D; ]6 ^& i3 wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' D2 W( ^- y4 ~% u- n' m, V
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 Y/ F5 B5 I0 G0 N5 v! y Aincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average( w) ]0 F! [( K
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 b% V8 Y! ^/ a4 ^( v( }0 C; aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! b8 {" o8 a4 \6 Qstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile5 s) X* b5 D- U' ]1 d
growth. The response appears to be greater in younger children, which is consistent with previ-
5 }; }7 W3 @; R9 c2 Mously published studies of age-related 5 reductase activity.
! u2 R. C' c" L/ JChildren with microphallus regardless of its etiology will: Z( a8 C% z! s, O) v( O1 [( M
require augmentation or consideration for alteration of exter-9 ?9 r6 M9 q0 k: [
nal genitalia. In many instances urethroplasty for hypo-$ D/ E; V. k6 }0 R
spadias is easier with previous stimulation of phallic growth.
5 @. x7 O9 E4 Z5 j# ZThe use of testosterone administered parenterally or topically
" `( T- K3 }9 i) L9 ~8 [; Thas produced effective phallic growth. 1- 3 The mechanism of
?7 A$ K" o% [% g) fresponse has been considered as local or systemic. With this
% ~* E4 ?1 ^2 lin mind we studied 5 children with microphallus for response
' G0 g) F+ h1 _. k( qto gonadotropin and to topical testosterone independently.2 q) ^' X* u Y/ k5 Q+ E; ^/ G
MATERIALS AND METHODS
- J* F# m1 v3 ?+ i* A0 F0 c4 L! b4 QFive 46 XY male subjects between 3 and 17 years old were9 x1 M9 c5 }- K- z* v! h
evaluated for serum testosterone levels and hypothalamic. C: X6 f! V% T; [3 K
function. Of these 5 boys 2 were considered to have Kallmann's2 D9 K3 [. \& t6 R
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 j& Y- l5 n; ?' ?! b' q7 i& p1 T
lamic deficiency. After evaluation of response to luteinizing
j2 M5 ^* j3 i `8 H; q3 Mhormone-releasing hormone these patients were treated with
$ B# O) ^( m) v# i. m) y1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ r* z" _# W+ `$ o
after completion of gonadotropin therapy 10 per cent topical0 @' t q. z; t, n1 D- ]
testosterone was applied to the phallus twice daily for 3 weeks.6 @4 ?' \3 q: r7 F# }# F
Serum testosterone, luteinizing hormone and follicle-stimulat-
, [! g4 u2 C$ }9 c+ _4 o5 A( ~8 `ing hormone were monitored before, during and after comple-3 H* O" ^" P0 T, |$ b/ I
tion of each phase of therapy. Penile stretch length was# S# O# X$ p# R& c9 \% q, G
obtained by measuring from the symphysis pubis to the tip of
1 S. Y: _( `) b. f- \ Pthe glans. Penile circumferential (girth) measurements were: A6 T) e, S1 @ J6 M/ c
obtained using an orthopedic digital measuring device (see. x, q3 F# F A% R+ y. C1 M
figure).
, q+ V3 z; V0 ORESULTS& F0 B; f8 @9 ]: J1 E, R
Serum testosterone increased moderately to levels between
, n1 D1 [& M& b; [4 p50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 ?0 `# q: Z' H
terone levels with topical testosterone remained near pre-
) I! W% h1 J& x4 d+ Ktreatment levels (35 ng./dl.) or were elevated to similar levels }2 \- \: X8 h/ {+ ~% O
developed after gonadotropin therapy (96 ng./dl.). Higher9 B. g+ _1 S7 d# D
serum levels were noted in older patients (12 and 17 years old),$ ]8 L! t, ?4 k, `* v& t3 {; X
while lower levels persisted in younger patients (4, 8, and 103 P$ G7 d0 v, Y& D
years old) (see table). Despite absence of profound alterations! ^6 }* E( O: v6 g
of serum testosterone the topical therapy provided a greater
7 v+ E! r1 x( D6 A* R ~Accepted for publication July 1, 1977. ·
0 {7 t4 V D3 O1 \7 YRead at annual meeting of American Urological Association,
: s& I) @, K( Z3 d$ ~Chicago, Illinois, April 24-28, 1977.& y% } |3 B3 i+ W) |
* Requests for reprints: Division of Urology, Henry Ford Hospital,; w3 p9 E/ }2 j/ n
2799 W. Grand Blvd., Detroit, Michigan 48202." b( @+ y- j/ `% ~/ l
improvement in phallic growth compared to gonadotropin.1 D6 u4 P; W u: O/ T) m
Average phallic growth with gonadotropin was 14.3 per cent3 |0 m) M& H: y& ?4 E! x
increase in length and 5.0 per cent increase of girth. Topical3 i x8 x, c" D7 r3 e G
testosterone produced a 60.0 per cent increase of phallic length; w" R8 u4 |# ]5 q, {! G0 i
and 52.9 per cent increase of girth (circumference). The
& b7 z5 e! X: ~2 Hresponse to topical testosterone was greatest in children be-
w# s+ W5 B- N7 ?) g* o: ltween 4 and 8 years old, with a gradual decrease to age 17
8 u6 _/ _$ m L. _( X" f6 Ryears (see table).* p& W+ Q" \ u+ Z; y. v
DISCUSSION0 v5 j' Z+ y+ }+ e9 k
Topical testosterone has been used effectively by other
6 p# }; u' s3 ~9 Fclinicians but its mode of action remains controversial. Im-
7 c; r4 a+ R0 v8 u! L* Ymergut and associates reported an excellent growth response
( ?0 _2 I' d, [+ |; }8 uto topical testosterone with low levels of serum testosterone,
5 m$ ^& E; @' |4 \0 Usuggesting a local effect.1 Others have obtained growth re-9 D1 o# `2 \, k, y3 c
sponse with high. levels of serum testosterone after topical
: A* n1 P7 X% n7 o, Z, L Wadministration, suggesting a systemic response. 3 The use of; y( @8 \8 g8 T' l
gonadotropin to obtain levels of serum testosterone compara-: {9 C# c+ G, c4 r
ble to levels obtained with topical testosterone would seem to
) R+ ] e$ s5 M2 cprovide a means to compare the relative effectiveness of! a8 z* W( q: R* p( {1 M
topical testosterone to systemic testosterone effect. It cer-
' N& i9 g0 k, A; E2 atainly has been established that gonadotropin as well as par-, h" g) u5 X, y# P
enteral testosterone administration will produce genital
$ s! Z- f4 J' B T# x( u' Rgrowth. Our report shows that the growth of the phallus was# j" ^6 m! N2 k5 m5 @/ ?; d
significantly greater with topical applications than with go-
5 m! R# l, \; }+ @nadotropin, particularly in children less than 10 years old./ I) E$ F/ Z2 U. A$ _, R( |
The levels of serum testosterone remained similar or lower! t- t. s0 a# G& v0 }) J4 j3 b
than with gonadotropin during therapy, suggesting that topi-- e8 q7 q6 G) J3 N
cal application produces genital growth by its local effect as: x3 F! w4 w% P$ F5 K( L& W
well as its systemic effect.+ A) R- }) E8 _, N% R7 V. r" q
Review of our patients and their growth response related to$ w- T# H4 @' D. J- I- D0 _
age shows a greater growth response at an earlier age. This is
: ^# M T- `( M' g m2 I! lconsistent with the findings of Wilson and Walker, who. N2 W4 M2 G- P2 L% T
reported an increased conversion of testosterone to dihydrotes-4 H+ S% r" L0 Y" t, O; v" ?/ l9 q
tosterone in the foreskin of neonates and infants.4 This activ-+ b+ A& C2 a% w, m! U& @
ity gradually decreases with age until puberty when it ap-( D$ _# C1 A* u7 ?! M- c
proaches the same level of activity as peripheral skin. It may, ]% t z3 \- f) v: R
well be that absorption of testosterone is less when applied at' F/ F' c4 W0 j9 d
an earlier age as suggested by lower serum levels in children! ]9 {0 K; c! A3 }+ y
less than 10 years old. This fact may be explained by the
: I5 i$ M( x8 `greater ability of phallic skin to convert testosterone to dihy-
* K7 m' t ?- W$ I& Idrotestosterone at this age. Conversely, serum levels in older, ?1 u/ A0 r' Z8 l. _5 N1 z+ m; }
patients were higher, possibly because of decreased local
% \( `+ `. Q8 L9 ?" l ^, [$ T667
- i5 F n0 W5 E668 KLUGO AND CERNY
! A5 K( A& W1 L$ ?Pt. Age' I2 h5 O$ ?0 H n' E1 m& {8 U% e
(yrs.)2 I( ]. {1 K0 B! v7 _9 b
Serum Testosterone Phallus (cm.) Change Length
+ V; m% Z, Z8 v& H# w6 @(ng./dl.) Girth x Length (%), G0 l+ h, k T7 n+ \. P; N
41 U6 \% F) B8 ?2 B0 ?
8 x1 ^. W3 O' C- x3 T
10" R! G5 A) r) ~% W7 j) M2 T
126 q/ ]+ a/ V9 ^$ L; A9 X
17+ ]: [+ ]' }$ T1 U& A
Gonadotropin6 O1 c' D5 j# v$ m; \3 R: B, r* k
71.6 2.0 X 3 16.6( m# D$ `, Z) N* u9 C e
50.4 4.0 X 5.0 20.05 j# t5 Z5 w" Z- J0 i9 c
22.0 4.5 X 4.0 25.0/ X: y* ?0 e% n" y- H8 |- U3 a
84.6 4.0 X 4.5 11.1
1 U7 v; Q! u1 y' r1 ~85.9 4.5 X 5.5 9.0
; s6 [! ?* n1 w1 T$ U* YAv. 14.3
- d5 @$ X- X4 W' C6 X6 {1 R5 a4
& t4 J( k+ t/ S9 P8
2 C2 {! ]8 j$ S10
- W# O7 }. ^$ J& g# m6 x+ D12) {5 i& u, p. W) s
17& C- M$ c V3 V7 E* W
Topical testosterone! F7 R1 s4 ~9 Y7 d
34.6 4.5 X 6.5 85
6 ?4 v* O3 m% A1 q0 C38.8 6.0 X 8.5 70- @$ V8 U- V k) @1 }4 ?
40.0 6.0 X 6.5 62.5
5 S+ B3 L; q3 Q2 v93.6 6.0 X 7.0 55.52 J3 [9 S8 p4 |
95.0 6.5 X 7.0 27.25 m3 q' C0 I+ \% l: P/ B: |
Av. 60.06 ]5 |9 k7 E& j6 n6 {
available testosterone. Again, emphasis should be placed on
) A# ^7 W6 q' `* a" x) searly therapy when lower levels of testosterone appear to5 B& w3 O7 P6 Q1 G& ]
provide the best responses. The earlier therapy is instituted- U; O1 l. b$ V4 r, x3 H
the more likely there will be an excellent response with low0 j0 E! Z$ F% s2 P9 @; J
serum levels. Response occurs throughout adolescence as% b8 e; T9 x. H5 R Z/ x
noted in nomograms of phallic growth. 7 The actual response
; r* K' n$ D# Xto a given serum level of testosterone is much greater at birth' N. T# F2 K. L9 l/ y% d7 ], Z
and gradually decreases as boys reach puberty. This is most6 [$ J& p0 g& s2 U8 I0 Z( g, I- R
likely related to the conversion of testosterone to dihydrotes-
- s9 J+ ~/ w" ^tosterone and correlates well with the studies of testosterone
. ]6 M: g+ z, V" S8 ?4 p* J9 [9 W! Rconversion in foreskin at various ages.4 q3 ?5 ^) \5 R- Q
The question arises regarding early treatment as to whether* X# n/ d! w+ O. J1 p
one might sacrifice ultimate potential growth as with acceler-. J! ]& t4 v) x/ x5 ^1 t b) K
ated bone growth. The situation appears quite the reverse& V* _( Y7 d3 L8 X) }
with phallic response. If the early growth period is not used
7 }1 {" \. x% D& {5 ^when 5a reductase activity is greatest then potential growth8 V6 _7 \. _2 U' e& o
may be lost. We have not observed any regression of growth) f: R6 B' ^( c- w4 }5 l
attained with topical or gonadotropin therapy. It may well7 @1 o6 L$ p4 B X P, T
be that some patients will show little or no response to any8 S" b* r6 m2 d+ h2 p5 w
form of therapy. This would suggest a defect in the ability to# S+ Y% C# p: C r
convert testosterone to dihydrotestosterone and indicate that
: Q2 i( E! u% Z5 ~. e6 Aphallic and peripheral skin, and subcutaneous tissue should4 a: _& ^" ?8 d+ j# A5 P
be compared for 5a reductase activity." a4 D/ f. I! H( U% {3 Q
A, loop enlarges to measure penile girth in millimeters. B, b" L+ i# y' z# P
example of penile girth computed easily and accurately.6 n' ~8 m. v1 Q& D
conversion of testosterone to dihydrotestosterone. It is in this
- g; A0 a' r) U. V6 b7 h! S4 folder group that others have noted high levels of serum& }4 A$ C; O* g, s7 T& S
testosterone with topical application. It would also appear6 J. M. b' J3 B2 G2 o# X
that phallic response during puberty is related directly to the1 z( h1 W- r5 d7 Z& Z
serum testosterone level. There also is other evidence of local3 x7 Y+ r |: G% K' m6 A% W* w6 M0 Y
response to testosterone with hair growth and with spermato-4 e0 J+ A4 V& Y5 w6 }+ H5 ? R
genesis. 5• 6
* m" Z4 e* u8 a; VAdministration of larger doses of gonadotropin or systemic
) D$ V0 _4 W' M7 G1 Ltestosterone, as well as topical applications that produce
: J! }( {* ?# b3 u% I) I5 L& Chigher levels of serum testosterone (150 to 900 ng./dl.), will; @4 V& \4 I. t6 R+ }. _
also produce phallic growth but risks accelerated skeletal
, d$ A; C; Y5 \3 umaturation even after stopping treatment. It would appear
: V' p4 a! c1 Rthat this may be avoided by topical applications of testosterone' u1 N- C8 f0 ^% X8 [8 a; x- ^
and monitoring of serum testosterone. Even with this control
) Q/ k& R O7 p; sthe duration of our therapy did not exceed 3 weeks at any3 j) D* m+ r) v1 |( P" ?
time. It is apparent that the prepuberal male subject may
" V |: [" \! v, n% l- Nsuffer accelerated bone growth with testosterone levels near, [& h) ?9 f) g* g8 V9 A3 U
200 ng./dl. When skeletal maturation is complete the level of
- W6 C5 d4 ~' {8 i) y1 A! wserum testosterone can be maintained in the 700 to 1,300 ng./
" }/ N) n7 p1 ^+ `9 ndl. range to stimulate phallic growth and secondary sexual& G7 O7 @8 a, N/ n
changes. Therefore, after skeletal maturation parenteral tes-
3 d D1 u. ` t/ xtosterone may be used to advantage. Before skeletal matura-/ x. x! w0 S# \6 T& d- r% y8 Z
tion care must be taken to avoid maintaining levels of serum, Z D5 _ T$ f: ~+ O. M
testosterone more than 100 ng./dl. Low-dose gonadotropin2 O# v0 p; S) J! \* W
depends upon intrinsic testicular activity and may require v3 q& [; A/ h
prolonged administration for any response.2 m3 y6 g# \; X5 E4 c! V- P% p
Alternately, topical testosterone does not depend upon tes-8 i+ ?( E! R+ z4 y1 W( z
ticular function and may provide a more constant level of
$ d; n3 D7 \5 k! Z( WREFERENCES
- m S2 X$ {1 P5 s* r: i$ p9 [2 ]1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
* J+ Q. e) J6 u$ n+ CR.: The local application of testosterone cream to the prepub-
' b' [ g0 B8 p' _+ a) [9 R, n& Mertal phallus. J. Urol., 105: 905, 1971.9 L& s4 n+ ?) Z4 y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ p v* B N$ N6 v" r
treatment for micropenis during early childhood. J. Pediat.,
+ ?! U+ C# H3 m83: 247, 1973.
) C8 ?9 F- X, d3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" T _8 r [) C! N) s7 |one therapy for penile growth. Urology, 6: 708, 1975.5 e9 a9 P$ ?6 A* a: _$ A7 O$ t
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ { C% c/ B6 z; V; jto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 U% K. O5 f" B3 D
skin slices of man. J. Clin. Invest., 48: 371, 1969.4 e# n* S; q; m; l$ g
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 h, ]0 |5 t: [" jby topical application of androgens. J.A.M.A., 191: 521, 1965.
" f3 L, s9 q. x8 y7 O6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. T6 |" F4 J) h1 T( y( ^androgenic effect of interstitial cell tumor of the testis. J.
2 O$ Q5 S( I/ e. I5 q% }Urol., 104: 774, 1970.5 s# z# s+ s9 ?* J
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 E9 k b; X2 Z- J1 `0 H1 x$ D' i6 h
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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