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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
* \2 d/ Y; q* l* g7 Q, oGONADOTROPIN
% F* T- x1 v; qRICHARD C. KLUGO* AND JOSEPH C. CERNY/ B4 {4 }% A6 Q4 X: v1 ?
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
) p1 c# R: e6 n1 l- nABSTRACT
0 K: P! I" l( m1 G1 n/ o% W! qFive patients were treated with gonadotropin and topical testosterone for micropenis associated
6 f' ~. h, W% F1 j8 x2 Z& Swith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( G: j7 f% V5 A* H8 D+ Z1 Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) j. | v; ~% E" y: R1 Y$ X- R
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 p# f1 f) o$ B2 W; n& S
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 e8 D; j$ V2 _: `3 _increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
/ `1 \! y& P) zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response" b3 j8 H( D) W ~8 Z2 I7 a" {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
8 l) `- _ y/ z6 I Bstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ u+ t' i W% N" [% @
growth. The response appears to be greater in younger children, which is consistent with previ-
, |+ M! M0 s4 p9 A; I/ vously published studies of age-related 5 reductase activity.
: Y/ q+ b1 R1 i% J pChildren with microphallus regardless of its etiology will
3 J. _ I# ~" g$ z2 E9 drequire augmentation or consideration for alteration of exter-
- U: l6 v* q3 b5 J' @# Onal genitalia. In many instances urethroplasty for hypo-
$ D+ Z5 J+ t4 p q: Espadias is easier with previous stimulation of phallic growth.
: h6 E7 X7 p% TThe use of testosterone administered parenterally or topically% L0 `- w, e, ] i% `! S* ?+ f
has produced effective phallic growth. 1- 3 The mechanism of
0 y% R1 ~+ c. d4 J. D" sresponse has been considered as local or systemic. With this3 V; |- d% F' h( |. Z
in mind we studied 5 children with microphallus for response M$ f2 a# R, k1 W
to gonadotropin and to topical testosterone independently.& l7 c( j. K* ^6 Q7 a
MATERIALS AND METHODS
2 T C3 O# S# g) Y3 p; b7 N1 IFive 46 XY male subjects between 3 and 17 years old were5 E# D5 F. i/ [
evaluated for serum testosterone levels and hypothalamic
/ w6 r( y2 s, ^' y! N7 Nfunction. Of these 5 boys 2 were considered to have Kallmann's
6 m8 G" Q- V- O4 [7 ^syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-$ W3 h( P$ i% u) [4 f; _# _6 K
lamic deficiency. After evaluation of response to luteinizing( o3 i# {* Z/ Y+ i, T2 X
hormone-releasing hormone these patients were treated with6 u5 |2 b8 T4 f) h# C! G
1,000 units of gonadotropin weekly for 3 weeks. Six weeks: p; i5 I6 f: {8 d
after completion of gonadotropin therapy 10 per cent topical
4 b: a Y8 r3 F- }+ Q" y. ptestosterone was applied to the phallus twice daily for 3 weeks.
" O4 A5 C* S, v; ?) aSerum testosterone, luteinizing hormone and follicle-stimulat- z8 e- ~. b0 N! U. g( k
ing hormone were monitored before, during and after comple-
* q/ E' u. d- A* Ution of each phase of therapy. Penile stretch length was
2 E. f9 B$ M+ N0 F% g! |: `! i5 _' f1 jobtained by measuring from the symphysis pubis to the tip of
0 b+ {. a# {* G' uthe glans. Penile circumferential (girth) measurements were) o" b' K5 G3 W- @% k
obtained using an orthopedic digital measuring device (see
/ h1 j0 K: E& y% S6 B8 J0 hfigure)., N" j5 k, d3 X- m" C
RESULTS4 e# H* h6 x( g, F2 @. Z4 u
Serum testosterone increased moderately to levels between! B) K" j& m! y4 x. _4 M
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 a+ Q/ L3 L3 R$ m+ x" A% ~
terone levels with topical testosterone remained near pre-
( B& w! f9 @9 P; [treatment levels (35 ng./dl.) or were elevated to similar levels" g- l8 X) @2 |
developed after gonadotropin therapy (96 ng./dl.). Higher f9 `0 K L" }" e5 e1 W8 m
serum levels were noted in older patients (12 and 17 years old),8 g! C$ _5 x+ b* J( Y \" _0 }2 B
while lower levels persisted in younger patients (4, 8, and 10
6 k, Y. o. ~) J, eyears old) (see table). Despite absence of profound alterations
- d! B) c- c, w7 p* [of serum testosterone the topical therapy provided a greater
% R9 e) q" O, P9 w. P. }# K/ E% b' Y+ JAccepted for publication July 1, 1977. ·
* [* Y4 V' |& I( PRead at annual meeting of American Urological Association,$ b' ], _( d3 f$ _/ X6 o0 N
Chicago, Illinois, April 24-28, 1977.1 G$ X/ q! `# i7 Q6 T( L* v
* Requests for reprints: Division of Urology, Henry Ford Hospital,: C% i. K5 b. l0 w1 F+ g6 }+ S. h
2799 W. Grand Blvd., Detroit, Michigan 48202.
+ ?7 o% Z" W$ bimprovement in phallic growth compared to gonadotropin.
* s& i- o4 \' B% E# V4 L/ {Average phallic growth with gonadotropin was 14.3 per cent
\, K: G5 h! f5 l( Pincrease in length and 5.0 per cent increase of girth. Topical
/ K% y7 X8 e0 R6 A$ L* ttestosterone produced a 60.0 per cent increase of phallic length) x! ?' \4 j; q! I" `# T" i+ }
and 52.9 per cent increase of girth (circumference). The
$ l' A3 J' G( K5 ]response to topical testosterone was greatest in children be-
1 C3 x- D) T& }1 [3 t( _+ ztween 4 and 8 years old, with a gradual decrease to age 17 M) U/ Z ~! ]+ a+ i
years (see table).
; }8 I; j- I: Z$ |" X; NDISCUSSION
6 @ x% _: o: }; o& \ k( A tTopical testosterone has been used effectively by other
M; {7 c& i) x5 c( fclinicians but its mode of action remains controversial. Im-
6 l' c( }5 V. l. Z s! W, e: L/ v+ fmergut and associates reported an excellent growth response( o1 o) [9 m7 |8 |0 m/ C
to topical testosterone with low levels of serum testosterone,
2 O5 f+ v, h. k$ e/ H9 Xsuggesting a local effect.1 Others have obtained growth re-$ q: @; J4 h5 C3 w4 ~* C& O- c4 u
sponse with high. levels of serum testosterone after topical
; e- e2 W; }; r: _0 G2 |- w/ M$ u' ladministration, suggesting a systemic response. 3 The use of5 f6 @1 e3 S8 V6 p8 J4 S
gonadotropin to obtain levels of serum testosterone compara-
! U0 W$ \$ G8 y' v" r& Jble to levels obtained with topical testosterone would seem to0 L! v# x- z* f. ^9 D
provide a means to compare the relative effectiveness of6 d$ p# S: C0 o G! A9 P- E. N
topical testosterone to systemic testosterone effect. It cer-/ t! u6 ^! C, z7 N
tainly has been established that gonadotropin as well as par-, Q$ E4 i8 R* m: A; P
enteral testosterone administration will produce genital
' `- b+ M3 y& v1 E) b1 }/ Zgrowth. Our report shows that the growth of the phallus was4 p9 I- U( ~# k% l
significantly greater with topical applications than with go-
/ z: X1 h; g; E. C! rnadotropin, particularly in children less than 10 years old.9 V8 r' }0 ^" g% Y% `6 `0 H
The levels of serum testosterone remained similar or lower+ i8 G( u& x8 S5 \6 V$ ~2 Y* S
than with gonadotropin during therapy, suggesting that topi-) I5 p2 _; g0 A7 K# S9 N7 E
cal application produces genital growth by its local effect as" E) ?" v0 a: `$ e. U o, V3 \ w
well as its systemic effect.
* K! L ?% d+ R$ J$ UReview of our patients and their growth response related to
4 t5 w' _ g$ I1 z7 K6 Uage shows a greater growth response at an earlier age. This is* ~5 n/ s9 w# H
consistent with the findings of Wilson and Walker, who3 U/ T: R A, M: [2 h3 ]
reported an increased conversion of testosterone to dihydrotes-; C" |6 a/ X" n3 ~' ~0 g( }
tosterone in the foreskin of neonates and infants.4 This activ-
+ `7 v) d* O) dity gradually decreases with age until puberty when it ap-: p/ ?8 u( y( j6 p1 p$ C1 g e
proaches the same level of activity as peripheral skin. It may0 `, D# l r) B; r
well be that absorption of testosterone is less when applied at
1 M2 h5 O6 n9 Y. @" n% m" b: r. y' Zan earlier age as suggested by lower serum levels in children
5 a4 L7 Y4 h, zless than 10 years old. This fact may be explained by the$ u) g4 d2 j, d w5 b E I: T
greater ability of phallic skin to convert testosterone to dihy-' S7 t! d& V3 i, M
drotestosterone at this age. Conversely, serum levels in older
0 a# ^+ x" C$ A- {. J! opatients were higher, possibly because of decreased local3 k% @% I# [! L/ ?+ G7 {* D7 ]5 |
667/ l \: O- _! c$ y1 z1 W
668 KLUGO AND CERNY# t% ]8 z! O# R8 W8 d
Pt. Age) i3 I! \1 i1 T5 t& ?! |
(yrs.)
4 m. Q {% t# Q6 z+ OSerum Testosterone Phallus (cm.) Change Length
/ V3 Y& n0 R- z( h8 A/ S(ng./dl.) Girth x Length (%)
8 E. t* D8 B# e' s& y. q/ |4
# s) f; Z9 G0 J d2 h4 Y! ?87 E. ^0 M4 ]4 f- g
105 e& n! O# |* M" P1 ~$ e! S2 y5 _
12
$ ~2 d/ q' V9 X17
x3 a! C8 v1 {Gonadotropin, `5 M9 A7 S5 w7 V
71.6 2.0 X 3 16.6
& p, B3 t I# k2 k50.4 4.0 X 5.0 20.0- E3 Y0 T6 C" x/ E
22.0 4.5 X 4.0 25.0* H% @3 O# m4 l" Z
84.6 4.0 X 4.5 11.1
, H( X) t, g& _: _4 b" i- `85.9 4.5 X 5.5 9.0: h" H) ?3 a1 X0 T- ^. l
Av. 14.3
% x6 a0 o1 Q" D. c4
- ^: f/ M. f: y+ q: O3 a82 C+ o; ~; c. ^! ]0 b# W
10# Q6 c! I( h0 c
12
. q' n2 O& S* O2 ]/ k17: X* ?) b( r* o$ R
Topical testosterone
/ A1 T! `+ ^. B; d: a3 z34.6 4.5 X 6.5 85
5 G$ W! r' s. F- E# |6 U( {38.8 6.0 X 8.5 703 c3 q# z) _) Q2 a5 g" t1 }8 R& n* v2 R
40.0 6.0 X 6.5 62.5 j" j, R( z+ K9 h
93.6 6.0 X 7.0 55.5- I5 |# `/ L1 i8 f' T
95.0 6.5 X 7.0 27.25 v- l7 n. Q% g* w" X
Av. 60.03 { Z& s$ i/ n0 t4 H& \2 E# i
available testosterone. Again, emphasis should be placed on
1 `1 @; }* l* [* Rearly therapy when lower levels of testosterone appear to
3 A: h: _, x) h* @9 r" ^2 I( hprovide the best responses. The earlier therapy is instituted
4 n! P! E% n1 @) ?% F8 R- Tthe more likely there will be an excellent response with low
. q& D2 @. z: E% {serum levels. Response occurs throughout adolescence as
8 M+ K, d2 X# t0 b0 p4 @$ `# i7 o: J3 Wnoted in nomograms of phallic growth. 7 The actual response8 p) Y/ p {3 k( @0 r+ a
to a given serum level of testosterone is much greater at birth
$ ]2 m4 M' u9 n/ J- q$ G+ Pand gradually decreases as boys reach puberty. This is most1 |2 X: s) p0 q c# a6 H x% N# z
likely related to the conversion of testosterone to dihydrotes-
+ N" X0 X6 Y, U9 X7 f' Ptosterone and correlates well with the studies of testosterone$ Z' T% h/ F2 Q' X1 `3 @. {
conversion in foreskin at various ages.
! |) f+ u5 F! x% ~; oThe question arises regarding early treatment as to whether
* {9 r; r/ w. Q9 H! Gone might sacrifice ultimate potential growth as with acceler-2 J( P* D2 y) H9 P
ated bone growth. The situation appears quite the reverse2 l( R, g$ w7 G$ W
with phallic response. If the early growth period is not used
' w9 G# f. _1 s7 Vwhen 5a reductase activity is greatest then potential growth1 P' Q+ [4 L* D$ w- u4 Q
may be lost. We have not observed any regression of growth6 x* `, m( _8 N9 W& ]5 Y4 R' \) f" y
attained with topical or gonadotropin therapy. It may well/ t/ M* }0 v1 t
be that some patients will show little or no response to any
9 e3 R4 ~9 D* f6 D2 f0 M0 L5 _3 Bform of therapy. This would suggest a defect in the ability to( e9 t$ w0 ~. I+ L3 N" H) l
convert testosterone to dihydrotestosterone and indicate that
4 h, ?- K* @. H9 f! @phallic and peripheral skin, and subcutaneous tissue should
9 y4 \2 ~, S/ x* u2 r$ ]# k: s Ebe compared for 5a reductase activity.
, G. U$ }0 |% Y g" ?. a& KA, loop enlarges to measure penile girth in millimeters. B,1 L/ q- E. T; F& p- L( B
example of penile girth computed easily and accurately.
4 P1 D/ Y, W% j2 D6 x' D3 rconversion of testosterone to dihydrotestosterone. It is in this
( o( `# ?7 }$ V& V& M+ U" Jolder group that others have noted high levels of serum; H9 c/ a, o n |. h
testosterone with topical application. It would also appear1 Y6 f$ d( z `$ K0 G, ]7 g
that phallic response during puberty is related directly to the
$ }0 U% {/ ^) S% i0 c, K3 Tserum testosterone level. There also is other evidence of local
& n. |- R W4 f8 N+ p* X% \response to testosterone with hair growth and with spermato-# l- Y4 x1 {$ ?- G) s* d/ ?9 x
genesis. 5• 6& Y1 C& }( D' }8 v
Administration of larger doses of gonadotropin or systemic
. C* I2 i& Q! itestosterone, as well as topical applications that produce, l0 {6 z0 `& N: h
higher levels of serum testosterone (150 to 900 ng./dl.), will
0 d( t& Y. v1 `also produce phallic growth but risks accelerated skeletal
2 R) g2 E# W' v" w5 Ematuration even after stopping treatment. It would appear( C4 s$ P% F+ ?7 h5 E
that this may be avoided by topical applications of testosterone. F8 o: E6 v9 G7 Y+ o; N
and monitoring of serum testosterone. Even with this control/ r, D5 H' S# z1 A: }" l
the duration of our therapy did not exceed 3 weeks at any _" z# ]# v/ x' Z& [
time. It is apparent that the prepuberal male subject may
( Y) |8 ] `6 ~suffer accelerated bone growth with testosterone levels near5 A# p6 {( s) |' U" D# h. J
200 ng./dl. When skeletal maturation is complete the level of! G5 |6 ^- d6 D& Q" I- j) n, t
serum testosterone can be maintained in the 700 to 1,300 ng./% c! @3 N6 Q+ A
dl. range to stimulate phallic growth and secondary sexual7 I% `( O$ G( N% A
changes. Therefore, after skeletal maturation parenteral tes-
1 j3 q& G+ T# S8 M( l; otosterone may be used to advantage. Before skeletal matura-
. Q$ u0 a2 p+ I/ m' W( {tion care must be taken to avoid maintaining levels of serum+ j! w5 B+ ]# I; x3 Z, R7 }
testosterone more than 100 ng./dl. Low-dose gonadotropin* Z% |/ a# K5 Q! v
depends upon intrinsic testicular activity and may require' |3 F/ E" ]& |$ j7 V1 ?7 Z$ a
prolonged administration for any response.
* C5 K8 T1 D, J2 O' _& W, ?& aAlternately, topical testosterone does not depend upon tes-4 c" `6 Q$ z& o% V' J$ l2 B4 O8 o
ticular function and may provide a more constant level of
$ P1 R1 N$ V7 p' N5 v( n# {' D9 zREFERENCES6 Q9 T$ b5 ^0 \8 n* M1 T
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- l+ B% A9 |: D6 q- c K+ ?
R.: The local application of testosterone cream to the prepub-
4 _. v) D: R. R3 t& a7 r1 |ertal phallus. J. Urol., 105: 905, 1971.
$ m7 p k: [# P* b2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! c$ V" I4 d5 U; a7 L5 D; btreatment for micropenis during early childhood. J. Pediat.,
' p3 d' r0 U; z3 I" y, O83: 247, 1973.
! B0 Q% v6 f) y9 c- u8 F! p3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 H" D8 M) U- p/ _3 bone therapy for penile growth. Urology, 6: 708, 1975.
0 a' H) b( Z8 q% C" ]4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. h9 t3 e6 ~ p/ Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ l, m$ {4 ^) _- f) A. [3 K1 i' S
skin slices of man. J. Clin. Invest., 48: 371, 1969.
2 z, b. |8 M8 {$ T; `- `2 C5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth0 g. s: g9 J' _' { U
by topical application of androgens. J.A.M.A., 191: 521, 1965.' \3 I1 q# [# m1 W
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ `$ R- r/ V9 P/ r; ?3 gandrogenic effect of interstitial cell tumor of the testis. J.
% t6 y3 u: N4 O( {3 f; eUrol., 104: 774, 1970.
9 d2 e* X( `& c% O' W: ]7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ c- k: h$ ?0 V/ C$ rtion in the male genitalia from birth to maturity. J. Urol., 48: |
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