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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
6 n+ p' ~9 N' OGONADOTROPIN
! p2 e) r' P& j5 [: L4 E$ KRICHARD C. KLUGO* AND JOSEPH C. CERNY
0 W0 [5 a! [* {8 m0 ~From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
" W8 K; c ?# B- JABSTRACT, C/ e! N8 y6 \' d% G8 c2 {, ?+ |
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
, g' c5 e! l, pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 g# P( M0 m' T6 {4 Z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
2 W) z& n: V3 x6 C3 Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( O) t1 {' l7 g- q+ ]* Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 h) D. p; u- Q) F, v3 D* a& Iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average9 G' b3 x9 d; x5 M# C
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response' u! _4 I, A2 u
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 i4 J1 D) P* g9 w# u& y; o0 a* C
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; Y0 o# S7 ?% G3 f+ ~
growth. The response appears to be greater in younger children, which is consistent with previ-
5 N4 Z2 u2 p+ W7 S( Wously published studies of age-related 5 reductase activity.3 A6 z; w' U% S* [& N1 ~4 O4 x- N( _
Children with microphallus regardless of its etiology will
@; g+ g, n0 grequire augmentation or consideration for alteration of exter-
6 R6 Z, i- W2 G' D% anal genitalia. In many instances urethroplasty for hypo-
5 U3 g/ R9 \ D' `9 Q1 J2 kspadias is easier with previous stimulation of phallic growth.
* C) }5 N2 j4 s+ a* LThe use of testosterone administered parenterally or topically. h0 z' l$ k O" C
has produced effective phallic growth. 1- 3 The mechanism of
6 m2 \2 x( _/ v4 `6 c! B/ }response has been considered as local or systemic. With this8 g( i' }& |+ ^% q9 w" i/ {! }$ K
in mind we studied 5 children with microphallus for response
1 P4 ^" O' M4 {# lto gonadotropin and to topical testosterone independently.0 K8 X' F3 h+ w9 u$ C4 }
MATERIALS AND METHODS; ^7 w6 N. P1 v9 v. y
Five 46 XY male subjects between 3 and 17 years old were' g" z( ^- d( R2 R! R
evaluated for serum testosterone levels and hypothalamic3 c! b& ?5 d# h" ]
function. Of these 5 boys 2 were considered to have Kallmann's S( L. I' f" c1 _7 }
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# Y/ ]5 w4 b. O' s6 C0 g- hlamic deficiency. After evaluation of response to luteinizing$ n1 n* B2 J1 l4 Y
hormone-releasing hormone these patients were treated with& a# P# U3 z* M. S+ M5 E B. G" `* _
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ y0 V. i# t5 E# K9 v% r/ h/ ?! K1 E$ Uafter completion of gonadotropin therapy 10 per cent topical
0 J8 F- i, l3 _& k" B& \, X C9 ctestosterone was applied to the phallus twice daily for 3 weeks.
; A6 Y/ u d" a8 U. w& H! [Serum testosterone, luteinizing hormone and follicle-stimulat-) ^+ b: K: X) Y( x
ing hormone were monitored before, during and after comple-
: _. z' I5 m$ X% o) t9 t$ B+ l0 ]tion of each phase of therapy. Penile stretch length was- B0 b9 A' _% ?$ G
obtained by measuring from the symphysis pubis to the tip of( P: K9 D' ?' k& f
the glans. Penile circumferential (girth) measurements were
9 }1 }; w# }3 O* G- G' |obtained using an orthopedic digital measuring device (see5 ~ o! d0 ~' ~# r% ]: j
figure).
6 T6 |2 h* p* j- S: eRESULTS
4 S$ m8 T0 Q* e7 uSerum testosterone increased moderately to levels between
! n* N4 F" q9 f) h* O* r* s50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 I) a' Y$ F0 v* X0 ]) T: i
terone levels with topical testosterone remained near pre-
9 W6 M. a2 z9 ctreatment levels (35 ng./dl.) or were elevated to similar levels% {1 e% D* }- e e
developed after gonadotropin therapy (96 ng./dl.). Higher
4 h2 P) f$ p& h+ iserum levels were noted in older patients (12 and 17 years old),5 D+ j3 H7 R5 M# A" t7 O- o
while lower levels persisted in younger patients (4, 8, and 10
2 _% @- P, P" v5 E+ M% _years old) (see table). Despite absence of profound alterations
" x4 Q0 H) U% a: Bof serum testosterone the topical therapy provided a greater" ?0 D6 o" J& i
Accepted for publication July 1, 1977. ·
, P' X6 E) U: d) F5 T K( P% HRead at annual meeting of American Urological Association,
, {5 A* E1 d% P- j2 O( _Chicago, Illinois, April 24-28, 1977.
- O h k/ D8 `8 [* Requests for reprints: Division of Urology, Henry Ford Hospital,
% T6 y+ p0 P0 {/ d+ K- H/ ?2799 W. Grand Blvd., Detroit, Michigan 48202.5 h: A" H% w* T7 l8 O# P+ t- ^
improvement in phallic growth compared to gonadotropin.; [0 C: o1 \( U7 u6 k+ `% C* o3 B4 f( m
Average phallic growth with gonadotropin was 14.3 per cent$ Z' m9 \: _$ _4 v3 B9 G' Z2 I& Z
increase in length and 5.0 per cent increase of girth. Topical
" S4 \( S( G8 S2 t" [! htestosterone produced a 60.0 per cent increase of phallic length; e$ A! q0 j( b y
and 52.9 per cent increase of girth (circumference). The4 c. y3 c" L# H$ O
response to topical testosterone was greatest in children be-4 D' i* _. C2 T/ v U- S& I
tween 4 and 8 years old, with a gradual decrease to age 17
6 {3 O% c3 t9 x3 T5 X+ Q2 @years (see table).
/ a8 y* ^; s" I; \" {0 j1 D1 JDISCUSSION& b9 d D/ L1 ^- p2 @( u) Z1 e1 T2 w
Topical testosterone has been used effectively by other
) D' Z' q+ g* c" R8 Wclinicians but its mode of action remains controversial. Im-
' v' s( C+ I. {, jmergut and associates reported an excellent growth response; \- }$ ]5 {" Z
to topical testosterone with low levels of serum testosterone,7 b t# i. u' ~8 D& i+ B( G+ I
suggesting a local effect.1 Others have obtained growth re-
) F% H% S# c3 _' W! W J( z2 ]& v& Wsponse with high. levels of serum testosterone after topical$ J. @7 s1 x; [( |3 _- U' _
administration, suggesting a systemic response. 3 The use of
/ o5 a w5 h6 s2 n- Sgonadotropin to obtain levels of serum testosterone compara-' z: o! [$ G! q# L) D& h+ d
ble to levels obtained with topical testosterone would seem to" m( C/ i, u. u: n, Z" K5 h
provide a means to compare the relative effectiveness of
3 s$ d& Z2 q' E. Otopical testosterone to systemic testosterone effect. It cer-
6 E; W8 R( Z, w1 C( E2 H8 t3 ^tainly has been established that gonadotropin as well as par-! o/ F; l4 f- |0 o0 Y
enteral testosterone administration will produce genital
. U" X5 m8 w) [% {8 k( }8 d$ e, y5 x6 \growth. Our report shows that the growth of the phallus was
6 k6 z5 |7 K' k/ O* T- Usignificantly greater with topical applications than with go-
B8 P6 u1 `6 @ S2 F! xnadotropin, particularly in children less than 10 years old.
) F# F4 J, h6 f; v6 N: B4 V6 h/ A0 TThe levels of serum testosterone remained similar or lower5 S" U+ O0 E) e& [
than with gonadotropin during therapy, suggesting that topi-# e7 h/ f- v$ J I+ V9 Y7 B
cal application produces genital growth by its local effect as8 j6 i. i8 [ Y- |2 N
well as its systemic effect.
Z* Y. P& o) u& X1 G; o9 f& z1 p; FReview of our patients and their growth response related to
; j+ c2 f$ m7 o; page shows a greater growth response at an earlier age. This is8 j- ]1 j% [8 v n$ l0 f
consistent with the findings of Wilson and Walker, who
9 K( b4 `3 X) M; i* Hreported an increased conversion of testosterone to dihydrotes-
. _- e& o; B) j' S1 N/ D( ztosterone in the foreskin of neonates and infants.4 This activ-
v! y$ @3 w# f# }5 N3 wity gradually decreases with age until puberty when it ap-
$ ^' A$ Q% @ o6 ~" J% U8 ~! L- C$ mproaches the same level of activity as peripheral skin. It may
3 J6 f2 ]) ~9 c3 e8 ]' s' Uwell be that absorption of testosterone is less when applied at" }# K( ~$ `2 z. D$ ]6 |. D% m' P
an earlier age as suggested by lower serum levels in children
9 W1 g$ P' Z4 P( hless than 10 years old. This fact may be explained by the
& p6 B# I. b. {# Xgreater ability of phallic skin to convert testosterone to dihy-
5 }& j6 ^/ X3 s. tdrotestosterone at this age. Conversely, serum levels in older& v: Y0 m5 I5 d/ O" ^1 _
patients were higher, possibly because of decreased local1 L( V7 D2 o, v* w0 m0 P( Z
667
! `3 l1 {6 d% u/ ^ h: m. C7 L! Z668 KLUGO AND CERNY
+ V7 M+ t- R5 X3 f3 ePt. Age
4 ^4 m8 q7 [2 ~% B6 O9 c(yrs.)+ t- {3 L: b, A/ q" r- W9 N
Serum Testosterone Phallus (cm.) Change Length
4 m( D8 X& w5 \- n. s* p(ng./dl.) Girth x Length (%)
( K0 {7 M" y' E+ ~, Z4
) K1 ^6 }+ ~9 {) J: S8
- M* k( i: ]+ c$ @) j$ {10" A/ R8 m6 F i0 x
12- a7 A4 W2 {! }" q
17
* I+ D7 ^- N( B9 p8 i# aGonadotropin' n# D' J* K4 Q& K! f" u* R* P
71.6 2.0 X 3 16.6
$ _; |9 d: m o9 b. [% t# {! e50.4 4.0 X 5.0 20.0
$ A+ S9 x# p" z# Q( `1 j( Q22.0 4.5 X 4.0 25.0( C9 |9 ]* }9 t0 y8 a9 n" Y& I
84.6 4.0 X 4.5 11.1
) v8 Y$ q7 a b4 V85.9 4.5 X 5.5 9.0. N+ U3 G7 J% R+ s& [) _$ c) O
Av. 14.3) X3 e' e# w7 n; U4 a
4
D! O8 Y& g5 O/ h, g& H8
4 R- `4 b" L( n3 e10
# _4 K7 i- Q; ^* i" I" V% B125 o q5 z5 _8 o
17
i4 J2 Z6 K, V1 ~Topical testosterone7 a# o% O: t4 p3 c
34.6 4.5 X 6.5 85 ?/ o% w, e# ?+ e2 M3 l
38.8 6.0 X 8.5 70' H9 D! k# O z. ] T) l
40.0 6.0 X 6.5 62.5% L. p3 N# B/ f9 r1 l
93.6 6.0 X 7.0 55.5
1 W& Y, U9 H2 p; U95.0 6.5 X 7.0 27.22 j& g5 k# X) C! S% m
Av. 60.0* f' J0 s- ]" O& r: v9 `
available testosterone. Again, emphasis should be placed on
" S: J! y# I. T( {" oearly therapy when lower levels of testosterone appear to1 b2 Q ?( g9 @/ M+ l1 a
provide the best responses. The earlier therapy is instituted& I( q# j( r/ u1 ]* F. g
the more likely there will be an excellent response with low
. C) D0 j7 C6 B! g! Bserum levels. Response occurs throughout adolescence as
0 V2 P5 ?9 `3 tnoted in nomograms of phallic growth. 7 The actual response0 H7 b5 X( b' w5 l
to a given serum level of testosterone is much greater at birth% ^$ B& }3 B# c0 L
and gradually decreases as boys reach puberty. This is most
. b$ }* s& }! O) f* f$ D' }$ plikely related to the conversion of testosterone to dihydrotes-! L9 Q' V$ _3 O, }
tosterone and correlates well with the studies of testosterone
8 o6 q& n2 y4 O z+ Fconversion in foreskin at various ages.9 D z7 L, Z& n) p2 e" e/ Y
The question arises regarding early treatment as to whether9 F8 k( P7 ], ~0 O: I% @, r7 _
one might sacrifice ultimate potential growth as with acceler-
) u+ r/ a6 x4 ]' kated bone growth. The situation appears quite the reverse6 Y. P" T1 Q; W. _# @) F
with phallic response. If the early growth period is not used5 i; ^# o$ v" N- M- o* O
when 5a reductase activity is greatest then potential growth* J/ ^/ c/ o2 }
may be lost. We have not observed any regression of growth* E0 |+ I1 L, Z+ P" h
attained with topical or gonadotropin therapy. It may well2 ~6 D. L9 d" b4 Y: v
be that some patients will show little or no response to any( D% l: t/ M/ P* d* `( p3 Y5 H
form of therapy. This would suggest a defect in the ability to- ?$ i8 i# P$ [. L5 a- b6 n
convert testosterone to dihydrotestosterone and indicate that
: L8 H, L6 @ i, w, a: bphallic and peripheral skin, and subcutaneous tissue should
7 {; t/ p7 \5 Y2 `+ n4 O/ Z+ Hbe compared for 5a reductase activity." t, `' d9 s+ x/ Q
A, loop enlarges to measure penile girth in millimeters. B,. z1 Y% E; P ~4 f8 d
example of penile girth computed easily and accurately.
r+ c( {8 \; z1 ?. ]5 sconversion of testosterone to dihydrotestosterone. It is in this6 Y" K. N# Z7 D d9 s9 W9 v1 V/ @
older group that others have noted high levels of serum# ?( q9 N' H4 @) [3 L
testosterone with topical application. It would also appear) S/ G7 L$ v# ]0 x Z
that phallic response during puberty is related directly to the
- v1 g1 S5 q4 l& S3 Oserum testosterone level. There also is other evidence of local
0 c# u9 @6 v( {* s4 Sresponse to testosterone with hair growth and with spermato-; K. {5 e" E9 A2 \
genesis. 5• 68 b4 c, C. N" F+ F* f3 r0 s& m
Administration of larger doses of gonadotropin or systemic. T2 G4 p% F5 ?0 {# @9 C
testosterone, as well as topical applications that produce
3 R ~7 a" d3 T. f9 w5 o t1 t$ { ~/ [higher levels of serum testosterone (150 to 900 ng./dl.), will1 ^8 `7 G# Y6 V
also produce phallic growth but risks accelerated skeletal% o( N: b7 C' N' i* ^% @1 Q
maturation even after stopping treatment. It would appear
6 A* k. }4 T4 m( P" b. Wthat this may be avoided by topical applications of testosterone
( G7 w# C1 e9 H+ xand monitoring of serum testosterone. Even with this control( A2 [* ?$ ^% E* [( q0 K8 V
the duration of our therapy did not exceed 3 weeks at any: [7 f. C' _0 {7 N
time. It is apparent that the prepuberal male subject may* K q( }6 q& a+ C' f
suffer accelerated bone growth with testosterone levels near" H3 e& ]) @/ G
200 ng./dl. When skeletal maturation is complete the level of
. _: ~; {, a# d/ e0 g/ ~serum testosterone can be maintained in the 700 to 1,300 ng./9 D+ p/ ]" E8 G5 \1 U* w8 {7 E6 b
dl. range to stimulate phallic growth and secondary sexual
; V1 F1 x) Y) qchanges. Therefore, after skeletal maturation parenteral tes-
2 @' Y- S y4 [4 ?5 Q4 V5 d Ytosterone may be used to advantage. Before skeletal matura-2 a( ]. ^3 S# T2 u8 m* h$ Y
tion care must be taken to avoid maintaining levels of serum$ |1 R7 ?% ?' e2 x9 V
testosterone more than 100 ng./dl. Low-dose gonadotropin
& x% d( D% w6 R7 P' O1 U3 ~: Ddepends upon intrinsic testicular activity and may require/ ?+ w" _/ u" L1 {" y' N! p
prolonged administration for any response.# [' z! V/ s/ E# i- x6 U. f
Alternately, topical testosterone does not depend upon tes-
/ z3 v3 S6 e6 {% ^( r5 l- ^ticular function and may provide a more constant level of
% F! p4 x, W4 U6 xREFERENCES
; u" ^5 S$ c1 c1 J# Y! \: U1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 f2 o( ~2 X1 O3 L iR.: The local application of testosterone cream to the prepub-4 N9 W: ?* t7 p, ~
ertal phallus. J. Urol., 105: 905, 1971.
; ?4 D( \ }; \8 a& w% b- Z/ L! a2 f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
0 Y9 Q. ] b/ E* u2 I+ g. Btreatment for micropenis during early childhood. J. Pediat.,
; z6 g7 F/ @4 Q; o9 w( q# X83: 247, 1973.( P! R! r6 @: B
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; j2 P1 [& s9 C- `, w* W
one therapy for penile growth. Urology, 6: 708, 1975.
, H# [! f* C# \! k4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone: s! O$ L+ B- d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
1 G/ O6 y8 d8 x9 T* h1 G1 D* rskin slices of man. J. Clin. Invest., 48: 371, 1969./ m, e# J) w2 D% }) i; s2 }
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. [. s3 [" |4 [! n* q! w2 h
by topical application of androgens. J.A.M.A., 191: 521, 1965.% ]' ]3 u& [. R# [5 u8 N g
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: }1 U: K' K4 J. b5 h* [" q5 q
androgenic effect of interstitial cell tumor of the testis. J.1 }1 q& b4 N/ L0 d3 C! [8 P( {
Urol., 104: 774, 1970.% h. {8 w2 r& C
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 ^! [1 v' F6 }
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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