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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- }6 N; I4 g3 A# gGONADOTROPIN: u h/ H$ i8 C, n3 r) a' R) {# l
RICHARD C. KLUGO* AND JOSEPH C. CERNY
' L) ~; E, R2 }1 q- o% QFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan: H6 H4 U! E' @% _* i b
ABSTRACT2 F6 d8 _9 i+ K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
D) c3 E. p3 G* e) `$ Ywith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) _: Q& r3 O _& p5 otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone9 B& y/ \" M" |
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 O# k6 X+ @% r- N6 afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ L5 N! L1 q6 K( W/ p3 P$ T" ^
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
- b% t' q6 u' Z+ A$ `% zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 \( F! P8 B L2 |% Z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- P$ s; j1 N) `3 Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 W8 S# h6 N" \; |: g, u- j& X% P
growth. The response appears to be greater in younger children, which is consistent with previ-# L) c# |/ f& m7 l
ously published studies of age-related 5 reductase activity.
" [2 \3 l- S& b! b TChildren with microphallus regardless of its etiology will
0 V$ K9 M! h. r( mrequire augmentation or consideration for alteration of exter-
W4 P) |) \7 u9 w0 m7 [nal genitalia. In many instances urethroplasty for hypo-. Y7 M. q1 W) s7 F& q5 D D
spadias is easier with previous stimulation of phallic growth.
+ B! G1 G; X$ Y& V8 ~( bThe use of testosterone administered parenterally or topically
! \0 }3 ^; c( Q- J2 G7 p5 Rhas produced effective phallic growth. 1- 3 The mechanism of
3 D4 h+ m; s, r$ mresponse has been considered as local or systemic. With this
3 O9 I" C2 n* ?8 B8 O! t$ lin mind we studied 5 children with microphallus for response+ v" k! d9 M8 o( j
to gonadotropin and to topical testosterone independently.; b9 _, L" C* M* N1 R, W" ?( s$ i; L
MATERIALS AND METHODS' e% _/ p! W/ Y/ J. `
Five 46 XY male subjects between 3 and 17 years old were
6 y" R' c2 v& ^0 e. M1 kevaluated for serum testosterone levels and hypothalamic m; F& b9 t. ^3 ?
function. Of these 5 boys 2 were considered to have Kallmann's
. c6 E6 a' Q: nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 E7 q6 d% L; m9 @lamic deficiency. After evaluation of response to luteinizing
4 L) `: d9 C. u0 S8 V3 Jhormone-releasing hormone these patients were treated with$ P; l: L; `4 n3 y$ l! \& B& ^
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% o3 o7 G' \" G% j# X& {after completion of gonadotropin therapy 10 per cent topical
& X1 C. T" J$ ?+ Ttestosterone was applied to the phallus twice daily for 3 weeks.( ]) \# R3 a5 q, ]
Serum testosterone, luteinizing hormone and follicle-stimulat-
) H! ^) S- p [7 e+ hing hormone were monitored before, during and after comple-4 Q% i& I* w5 W5 _9 j
tion of each phase of therapy. Penile stretch length was4 ?, I) _3 B$ l3 n
obtained by measuring from the symphysis pubis to the tip of
4 R8 |& l0 P7 b" v0 b) B Wthe glans. Penile circumferential (girth) measurements were
; w7 |0 s. r- _obtained using an orthopedic digital measuring device (see
- l' Z, z9 y* `1 x) Hfigure).
! l, M4 M) h( o& S) l% QRESULTS! E; ~0 X/ o0 V- k% q
Serum testosterone increased moderately to levels between
7 R# S5 w3 A# m: r) l50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-# P0 i9 T3 m2 D$ z- `0 M) H1 e! n& O
terone levels with topical testosterone remained near pre-% f9 d' Q ]$ f! ]4 ^* i) B0 b
treatment levels (35 ng./dl.) or were elevated to similar levels
& P# A, {. n/ n. }# W3 C- rdeveloped after gonadotropin therapy (96 ng./dl.). Higher; O; [3 `8 O/ M5 y$ N
serum levels were noted in older patients (12 and 17 years old),
6 T- u; v* C8 Iwhile lower levels persisted in younger patients (4, 8, and 10, e7 [+ v7 C5 ~" m4 P) B
years old) (see table). Despite absence of profound alterations# ]9 q6 o( Y9 i8 u, x4 p
of serum testosterone the topical therapy provided a greater
" i& e1 v5 h8 c& _# SAccepted for publication July 1, 1977. ·; v) i3 J$ p6 j; Z" ~& X
Read at annual meeting of American Urological Association,0 `, K1 A, y( `0 e+ r+ e" Q6 k) m0 {
Chicago, Illinois, April 24-28, 1977.
' ~" j, W& }' o" Y* Requests for reprints: Division of Urology, Henry Ford Hospital,6 p% j) n$ \, Y/ w4 v
2799 W. Grand Blvd., Detroit, Michigan 48202.' m% i; D: @# j- h6 T
improvement in phallic growth compared to gonadotropin.
% J6 z: x* ~/ K* o! i! IAverage phallic growth with gonadotropin was 14.3 per cent
* t2 Y# L" b/ a1 p# @, g9 }! xincrease in length and 5.0 per cent increase of girth. Topical
2 @& Y7 S) p# B3 I( j( t2 r. Jtestosterone produced a 60.0 per cent increase of phallic length) [ f7 h* V! ]. O) \" ]* S
and 52.9 per cent increase of girth (circumference). The
' p8 }$ E) B% f( H0 f+ B; ]) Presponse to topical testosterone was greatest in children be-
% f! x; Z: d, [/ J1 Wtween 4 and 8 years old, with a gradual decrease to age 17
: e2 A; a8 ~0 k! yyears (see table).# o* u; j; L( y# ]+ f
DISCUSSION
0 g7 b% X$ J9 v( d2 |Topical testosterone has been used effectively by other
$ m2 F* [" D. ]clinicians but its mode of action remains controversial. Im-
9 K6 k4 A7 }7 R0 {9 Q+ Tmergut and associates reported an excellent growth response
5 b! E2 ]8 q+ k' f+ d& d! Kto topical testosterone with low levels of serum testosterone,/ m9 y, _5 V9 ? z8 k" g3 s
suggesting a local effect.1 Others have obtained growth re-, T9 j; `; z. f& R& ]* r& e+ v
sponse with high. levels of serum testosterone after topical
5 q1 W" R; @' _- A6 f: r. @% _administration, suggesting a systemic response. 3 The use of! w; z( u: q2 f, i& j) Q# V& r
gonadotropin to obtain levels of serum testosterone compara-* E) i" R3 T: H) B) z% b! j
ble to levels obtained with topical testosterone would seem to" ?1 c6 X0 n3 Y( ?( u z
provide a means to compare the relative effectiveness of
! N. Z& l% A* ^8 |2 R3 n" K; Stopical testosterone to systemic testosterone effect. It cer-
! v% }5 f+ B9 Y [2 d5 K" u& z" Htainly has been established that gonadotropin as well as par-7 f3 c' K( q4 z/ @$ a5 J
enteral testosterone administration will produce genital2 e h' L/ q" |8 X
growth. Our report shows that the growth of the phallus was
`4 N6 a! n' ]5 ]& s% k& [significantly greater with topical applications than with go-, v r- `. H: l' a+ \
nadotropin, particularly in children less than 10 years old.: }8 C* Q! U! d* z( @- A
The levels of serum testosterone remained similar or lower2 Y( ~% u$ v9 Z1 m: o
than with gonadotropin during therapy, suggesting that topi-
' g* T9 F# ?) G, Ecal application produces genital growth by its local effect as
1 j$ I% @, A! W/ r- `1 Owell as its systemic effect.
6 s" h( D+ i$ v% i3 n5 U6 J, c5 kReview of our patients and their growth response related to( N9 L' o' m4 F& d& r) s* X
age shows a greater growth response at an earlier age. This is. |! O' I. w6 l. b- @' [2 `
consistent with the findings of Wilson and Walker, who
# y* V2 J* b# ]$ J/ o! C9 V3 ureported an increased conversion of testosterone to dihydrotes-
- j; j& |8 |$ Y. A5 z: wtosterone in the foreskin of neonates and infants.4 This activ-+ W' C* U9 E% p
ity gradually decreases with age until puberty when it ap-
8 l* d5 E* c, Y/ C: n( D1 rproaches the same level of activity as peripheral skin. It may3 l5 b& A0 n' Y1 S" l# u
well be that absorption of testosterone is less when applied at
4 ~7 b4 o+ X* Oan earlier age as suggested by lower serum levels in children4 m. V; q1 U1 E
less than 10 years old. This fact may be explained by the" F9 K% ?4 s( D7 h% f
greater ability of phallic skin to convert testosterone to dihy-
; |* x+ x/ E8 i" I2 n4 w4 x; hdrotestosterone at this age. Conversely, serum levels in older
* _: x, f' c5 Z* ]patients were higher, possibly because of decreased local/ Z+ z* c, }' V8 l9 v! N% D
667
* t7 X0 I* t5 b668 KLUGO AND CERNY. b; R+ r$ u, L- M
Pt. Age
0 _, t& j, _% f2 P(yrs.)! F8 M5 J1 b' W8 T
Serum Testosterone Phallus (cm.) Change Length9 P9 O' o! \# j: [3 d
(ng./dl.) Girth x Length (%)
( W- n+ C8 D' a" u, n% _4
/ V+ @7 i$ x& I8
8 `( `7 |6 E4 c) C5 P1 ~10$ {5 D+ o5 e* n$ p) J
12) P1 [% X. `, S
17
) Z7 A' T7 @! P1 \! _Gonadotropin
: @) h1 q' p" V6 h71.6 2.0 X 3 16.6) e, l8 S$ _, h3 f
50.4 4.0 X 5.0 20.0
5 ^ g' S1 }0 A% G' D5 D! r22.0 4.5 X 4.0 25.0
. J! t4 G" J1 o/ D$ s! R' r84.6 4.0 X 4.5 11.1% |4 Z9 S1 n6 X
85.9 4.5 X 5.5 9.0
5 B# h# r) j6 F1 \- sAv. 14.3
' E0 k, Q* f2 _7 V2 \46 o$ n' H% D/ e# ]+ \+ {# {
8/ W) U' j( [$ {7 S. |. i
10
/ ^( P' `& B2 B% b) U1 t12
, J! y% `! W- G* m4 W H( P17
. Q. [8 t9 k+ d" j) \Topical testosterone
1 W, Z0 W$ Z3 r, X1 l34.6 4.5 X 6.5 85
9 Y p8 K! ?- M" j0 F. R38.8 6.0 X 8.5 70
- A) y( t- v2 V. g40.0 6.0 X 6.5 62.5 Y% A3 A, Q: o9 |+ M l
93.6 6.0 X 7.0 55.52 B# S& ^% z0 R: b/ b
95.0 6.5 X 7.0 27.2( r* T$ O: A$ H/ K1 O( M1 T% v9 t8 k
Av. 60.0$ ^. p5 D# a$ q6 u: d# [6 p; k! R6 Z9 z
available testosterone. Again, emphasis should be placed on/ W; h+ x5 i) K& w/ X1 ~& w0 F
early therapy when lower levels of testosterone appear to
, L- r" n a8 y+ D- m- W7 }provide the best responses. The earlier therapy is instituted c1 n, m1 d1 Y% A/ N, b2 f
the more likely there will be an excellent response with low6 z; S7 l3 ~- u
serum levels. Response occurs throughout adolescence as
! ~3 Z! [5 h: A) S8 p, p" Xnoted in nomograms of phallic growth. 7 The actual response) A6 [2 D9 V4 l ]7 R4 I4 Z
to a given serum level of testosterone is much greater at birth# w% o( _" L! U7 m) A" S
and gradually decreases as boys reach puberty. This is most
) x" t1 G/ h( U% Plikely related to the conversion of testosterone to dihydrotes-
* C8 P* ^+ c7 o# Q7 a, K D+ ftosterone and correlates well with the studies of testosterone
9 ~! g% `" A& d* b' j- k) n9 Rconversion in foreskin at various ages.
+ q5 w9 l4 D+ l! K/ s& UThe question arises regarding early treatment as to whether
/ ]6 O" x- W* H8 v& }; w2 z( Oone might sacrifice ultimate potential growth as with acceler-- p$ \ I8 [& `9 C$ U; W
ated bone growth. The situation appears quite the reverse, d/ x; j8 l% f( g) e; J! t) K
with phallic response. If the early growth period is not used
- g7 c( M; G5 q! d2 @when 5a reductase activity is greatest then potential growth
7 v; n1 n1 M* @/ [, _" |2 E( pmay be lost. We have not observed any regression of growth# d+ |& N! I- M( \! v7 H6 Z3 C
attained with topical or gonadotropin therapy. It may well
( T; D. ], d" R0 Fbe that some patients will show little or no response to any
3 l* l. ~: s, hform of therapy. This would suggest a defect in the ability to& O& p+ s) A# e5 c; w
convert testosterone to dihydrotestosterone and indicate that- \$ e. J; r7 x
phallic and peripheral skin, and subcutaneous tissue should. }2 J# X/ Z2 q2 B6 |$ p
be compared for 5a reductase activity.' @4 {% t( [! ^) h" X1 v& v, \: @5 G
A, loop enlarges to measure penile girth in millimeters. B,5 n5 \ ^2 G/ S( ^$ i' L. U
example of penile girth computed easily and accurately.
4 D# T" ~8 ~2 a- P2 bconversion of testosterone to dihydrotestosterone. It is in this# B' u: ?, C$ f7 P" q" s/ \
older group that others have noted high levels of serum
7 N& f6 @1 a) C n$ itestosterone with topical application. It would also appear6 Y& W" \4 E4 m3 E. e
that phallic response during puberty is related directly to the
# V' y d3 R5 s' Cserum testosterone level. There also is other evidence of local
2 H, h3 w8 s! g, I9 T- hresponse to testosterone with hair growth and with spermato-( d3 X) Q% \# I
genesis. 5• 6
0 H; y5 `" w0 h( Z/ `# {( TAdministration of larger doses of gonadotropin or systemic
, v+ y4 m" y; w+ V, {: otestosterone, as well as topical applications that produce
1 S: C* Y* _' w, q6 {6 phigher levels of serum testosterone (150 to 900 ng./dl.), will
% u4 ?1 O' j2 ~, a% J, calso produce phallic growth but risks accelerated skeletal
2 c, }+ D8 ]- `, ^8 A) J% xmaturation even after stopping treatment. It would appear
* |- o& p. h/ y& Lthat this may be avoided by topical applications of testosterone. ]. h1 I0 s, Y# R' _) Z
and monitoring of serum testosterone. Even with this control5 @/ n/ b; X: z, F# t) p
the duration of our therapy did not exceed 3 weeks at any
k: D; G8 |, v7 Xtime. It is apparent that the prepuberal male subject may
1 t% v# f& S" {, q5 rsuffer accelerated bone growth with testosterone levels near
6 e8 ]" ~- D4 M1 g8 T9 m, ^7 w200 ng./dl. When skeletal maturation is complete the level of+ o5 }0 ?8 w6 _* N: z* L; b7 P7 S
serum testosterone can be maintained in the 700 to 1,300 ng./& l4 _& T* U4 e! A
dl. range to stimulate phallic growth and secondary sexual0 D: d; I; p- n2 [
changes. Therefore, after skeletal maturation parenteral tes-
+ b/ K2 h+ I9 a) Y) A Ltosterone may be used to advantage. Before skeletal matura-& \1 c: i* _& C% f, k$ q. W/ R
tion care must be taken to avoid maintaining levels of serum
! B; p- D) `; utestosterone more than 100 ng./dl. Low-dose gonadotropin1 ?' v' m$ z: X4 a
depends upon intrinsic testicular activity and may require
# G |2 e8 f, K/ p ]/ ~$ R sprolonged administration for any response.
9 I! V, f' F) n7 H( ]4 kAlternately, topical testosterone does not depend upon tes-+ l' |, D( \6 i- q
ticular function and may provide a more constant level of4 c" W. P; Q z& t1 [, A9 D( h# r1 A* f
REFERENCES
& \3 C4 ]3 Q3 S2 T. ^# X$ D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ @/ A! q; ~# R D
R.: The local application of testosterone cream to the prepub-
) _ ~$ [+ r9 ?, Wertal phallus. J. Urol., 105: 905, 1971.4 M R! b$ h- j, @( X
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% G1 r6 ~) o7 }& `7 }) @" P, }treatment for micropenis during early childhood. J. Pediat.,3 {/ q: K J2 @0 R' O
83: 247, 1973.
* _& |9 V- N. t! o, T+ b0 b2 x3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& l) i& }# n z& U+ g1 } M
one therapy for penile growth. Urology, 6: 708, 1975.
5 k% }* V! |$ y( @; |7 F1 y6 Y# |# i4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 N' L0 ~6 V0 g6 f% z) _% M
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
$ |1 g* t, O3 j, `9 u; iskin slices of man. J. Clin. Invest., 48: 371, 1969.
, C4 v5 r* i( Q5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth" R$ u2 i8 @9 n: e Y3 l5 {( t) h! R
by topical application of androgens. J.A.M.A., 191: 521, 1965.! f7 ?0 W" J/ G) ?0 ~8 K V- N+ U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, n, F* x. A5 E- U
androgenic effect of interstitial cell tumor of the testis. J.
. `! A& {% @1 Z) \- h \Urol., 104: 774, 1970.
) ]1 ?8 ?; R( |0 `5 l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ t" w; I2 r) a i) z6 Ition in the male genitalia from birth to maturity. J. Urol., 48: |
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