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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 r1 n% A" g N( Q' pGONADOTROPIN
# }4 W( @* s" [( iRICHARD C. KLUGO* AND JOSEPH C. CERNY
! z% n" m1 W- j5 T# i% W7 h1 [1 ~' iFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 a1 f' n X$ c! }* O AABSTRACT. o( w8 ^/ C7 ]5 u0 z& Q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 A+ N% Q5 }. @6 Hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-8 t' ^/ \! c$ Z! _* {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 W T: o7 _9 O0 Lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent1 I: N/ } Q! f) B- q; t- f' R
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 f2 z) u- C2 |6 r$ `5 cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% W8 [3 s5 X7 A% I$ e: vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 u4 }3 F2 [5 i m% Noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# L0 E* }; ?# j, { zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" u, s0 I$ I! b0 y$ F
growth. The response appears to be greater in younger children, which is consistent with previ-+ t0 u+ G. b; [& ]& R7 _
ously published studies of age-related 5 reductase activity.
2 B, g% i% t3 g/ b" c+ B6 BChildren with microphallus regardless of its etiology will
; J; b" F2 \$ P$ l9 orequire augmentation or consideration for alteration of exter-8 o$ Q p: x9 _+ L# X9 ?
nal genitalia. In many instances urethroplasty for hypo-
% G3 o2 g, k" m8 J1 ]4 [spadias is easier with previous stimulation of phallic growth.6 [" I+ r5 ^3 ~1 e
The use of testosterone administered parenterally or topically$ p' v' r) t# g9 I- e0 Y
has produced effective phallic growth. 1- 3 The mechanism of0 `/ G8 e) `- }1 C( Z1 @4 Q
response has been considered as local or systemic. With this
: a& n. D" J6 F7 _! `in mind we studied 5 children with microphallus for response
+ \8 v$ C, I, g8 t Mto gonadotropin and to topical testosterone independently.
9 {4 S) Q' x3 K7 A+ _MATERIALS AND METHODS+ Q8 G8 {! f; P' o5 d" z- a! H
Five 46 XY male subjects between 3 and 17 years old were
" w H1 C" M4 Q/ t4 sevaluated for serum testosterone levels and hypothalamic9 M8 a5 T+ M9 H2 f+ ?
function. Of these 5 boys 2 were considered to have Kallmann's
" s- T: a& a9 y" p3 Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 S8 t1 K% u& I/ g4 zlamic deficiency. After evaluation of response to luteinizing
! h* }- V. A9 j; G' h+ O- g9 _& O6 n& {hormone-releasing hormone these patients were treated with7 c" J- p# C) \$ p- Z8 x
1,000 units of gonadotropin weekly for 3 weeks. Six weeks* j5 R3 Z# L% g- L ^6 t
after completion of gonadotropin therapy 10 per cent topical0 `6 F$ k7 M! |$ @ \
testosterone was applied to the phallus twice daily for 3 weeks.; g; H! `/ l+ r1 Z
Serum testosterone, luteinizing hormone and follicle-stimulat-
8 L# v$ F2 H; ]9 [( C1 `# jing hormone were monitored before, during and after comple-
5 ~8 ?, Q" j( t3 }6 s) M! ation of each phase of therapy. Penile stretch length was
( R5 R* j: p5 U s w$ `: G iobtained by measuring from the symphysis pubis to the tip of
7 e; W5 v3 p0 d1 w+ |the glans. Penile circumferential (girth) measurements were
* _# N9 |" y7 H6 L% b8 M/ K' vobtained using an orthopedic digital measuring device (see" U% T3 M( K) O ~3 | \
figure).
# b, E3 f- f) c3 w: j/ C1 B& u, JRESULTS' G+ [* r/ d# x+ V; y+ Z
Serum testosterone increased moderately to levels between! C2 v$ Q) K J I
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 ?/ l5 m2 d9 b% E1 d e) b; K) D- x
terone levels with topical testosterone remained near pre-
. V: E! |* ]' m! D1 M& M+ Ctreatment levels (35 ng./dl.) or were elevated to similar levels1 z. f' q0 B8 d) [
developed after gonadotropin therapy (96 ng./dl.). Higher# ]2 W( G5 V+ M% o0 E+ W" J
serum levels were noted in older patients (12 and 17 years old),8 A0 n3 F( X& q2 b, S% r
while lower levels persisted in younger patients (4, 8, and 10
/ n7 U+ W3 v7 K) u. Jyears old) (see table). Despite absence of profound alterations2 V6 T( s; c+ D% o& K
of serum testosterone the topical therapy provided a greater
8 q4 C/ d( b+ l' y/ w/ LAccepted for publication July 1, 1977. ·
v2 C1 H8 i3 NRead at annual meeting of American Urological Association,' P! N5 C A" R1 g
Chicago, Illinois, April 24-28, 1977.& Z9 F# O3 |) S: t' ~) {
* Requests for reprints: Division of Urology, Henry Ford Hospital," ^, S! p' L; l1 J. C
2799 W. Grand Blvd., Detroit, Michigan 48202.7 w( J: E( O$ h4 Z) Q
improvement in phallic growth compared to gonadotropin.
1 ^- t- Z8 e" GAverage phallic growth with gonadotropin was 14.3 per cent
' s# b& Y0 v2 V' ^% c7 F: sincrease in length and 5.0 per cent increase of girth. Topical
2 p |0 J+ N% D+ G, qtestosterone produced a 60.0 per cent increase of phallic length: M" \; E. m: @8 O+ f
and 52.9 per cent increase of girth (circumference). The0 I; P+ w' |3 Z2 c- J+ \5 e
response to topical testosterone was greatest in children be-/ z" F" `/ p5 V
tween 4 and 8 years old, with a gradual decrease to age 17
) U/ T0 h$ Z* Z2 [8 Y0 r* T( s$ w7 e+ lyears (see table).
0 t* H$ _ Y% Y$ ZDISCUSSION
# ]* [( b% D+ }( x7 BTopical testosterone has been used effectively by other4 n* c9 P2 @) G6 p
clinicians but its mode of action remains controversial. Im-
6 d) M8 y1 `+ W0 Cmergut and associates reported an excellent growth response
0 i$ l5 p, C& J$ t1 |) t+ f6 a+ I& l9 }to topical testosterone with low levels of serum testosterone,9 h; {1 ^) O$ w& ]6 T+ K
suggesting a local effect.1 Others have obtained growth re-
* N" i5 H2 U- y( T4 @+ gsponse with high. levels of serum testosterone after topical
% X) J$ w" Y) @0 Z$ Dadministration, suggesting a systemic response. 3 The use of
( s2 o! c# e' n( `gonadotropin to obtain levels of serum testosterone compara-
$ Q' a: U7 s* Able to levels obtained with topical testosterone would seem to
1 k9 Q7 C0 d( j8 ?, \4 [provide a means to compare the relative effectiveness of
+ p" ]" ~2 K- W# c0 S# b: Z" wtopical testosterone to systemic testosterone effect. It cer-+ Q3 O* G" S7 T! D, B0 I9 W9 e1 d9 H
tainly has been established that gonadotropin as well as par-
2 W: H' k4 r+ x; h: Henteral testosterone administration will produce genital
* c& i% d7 h* L# @1 igrowth. Our report shows that the growth of the phallus was! ^+ a' o; V- z: A4 {1 d
significantly greater with topical applications than with go-
5 Y! Q. P6 L0 N0 i3 [0 Wnadotropin, particularly in children less than 10 years old.9 I0 S- n; m, s, j8 i+ l
The levels of serum testosterone remained similar or lower
% g. L9 g2 n* B7 othan with gonadotropin during therapy, suggesting that topi-
+ b8 z4 E) y, s1 C: X! Lcal application produces genital growth by its local effect as0 R8 U" a, w& [: w& L5 s' q7 Z) a
well as its systemic effect.1 m6 R) E1 ~: d( t3 Q1 \5 O
Review of our patients and their growth response related to
9 X! _8 K- j, M/ y( U& l p' l: {age shows a greater growth response at an earlier age. This is
6 U' l1 R c0 {3 F8 V- ^consistent with the findings of Wilson and Walker, who
& U. ]/ u6 ?7 S1 a8 f$ u0 i5 N" A5 vreported an increased conversion of testosterone to dihydrotes-
/ e/ `( q3 N4 p5 N& X4 Stosterone in the foreskin of neonates and infants.4 This activ-+ E0 m- U3 Y5 [& [8 @
ity gradually decreases with age until puberty when it ap-, y% y' s0 r* z
proaches the same level of activity as peripheral skin. It may
4 I9 k* l, M, _well be that absorption of testosterone is less when applied at
; D P# y I- Y- B6 w1 {an earlier age as suggested by lower serum levels in children, R9 Z5 ]# u( Z! f0 \
less than 10 years old. This fact may be explained by the1 |7 p7 V% j/ U3 X- i7 n/ j) n% I
greater ability of phallic skin to convert testosterone to dihy-
/ H8 y" J$ J) n0 d$ ?drotestosterone at this age. Conversely, serum levels in older
5 e1 z( P/ n" f2 t+ x* v1 }' _- Xpatients were higher, possibly because of decreased local9 h3 L3 l- A0 |6 s8 O/ U! T- q, j
667 ~5 C/ q7 s4 M
668 KLUGO AND CERNY/ ]0 d' M- E; g
Pt. Age2 ^0 @4 S- _9 H; ^$ A% ]
(yrs.): A3 E$ L' W: p# E6 j
Serum Testosterone Phallus (cm.) Change Length1 U! u6 m' O0 e- I
(ng./dl.) Girth x Length (%)
1 G+ b2 }' W4 y2 ?% ]4
* {( G5 a3 F$ b( w, I2 {8! C9 ?# O0 G& \$ n
10
( U( i, k% p. q3 b: s5 O123 b H. A. g6 w7 G% W
17/ p q$ d, Z( {
Gonadotropin
0 _& m% C" M3 M% V/ @& l5 r, ~+ L71.6 2.0 X 3 16.6
5 r# Z3 M; o* p0 w50.4 4.0 X 5.0 20.0& i2 w. [ U m+ g. Y
22.0 4.5 X 4.0 25.0
- K2 j% w" M' Q4 a$ t84.6 4.0 X 4.5 11.1 `3 [ m$ v) V f& Z8 R, B
85.9 4.5 X 5.5 9.03 r" g1 ^% n3 P6 }% T
Av. 14.3
: W0 j0 X6 b- M/ a, `- [; e" {( W4& f' d& o8 T% {2 B
8/ T1 h: q% u9 ?+ F
10- }9 D: e7 b: b9 k( E
12% L" ^& O& E) y% K: v7 O. v1 A! W
171 ~; l- u, e' z1 b' B
Topical testosterone0 `: {' N+ U! t5 r, q& k D: a: |
34.6 4.5 X 6.5 85
3 y5 ^8 ?7 K3 G9 F38.8 6.0 X 8.5 707 P! T2 j2 n" }5 \. U- G) c
40.0 6.0 X 6.5 62.5
% I G9 W8 \* O/ e) X; T: x d93.6 6.0 X 7.0 55.52 k+ ]: x! r4 k% y i
95.0 6.5 X 7.0 27.2
/ ~+ X3 ?6 O. h: s' EAv. 60.06 k& t, q/ H h
available testosterone. Again, emphasis should be placed on
" D1 N/ F. m8 K. Y, aearly therapy when lower levels of testosterone appear to
5 r& ~* O9 Q h. N1 e1 Fprovide the best responses. The earlier therapy is instituted- D2 t% d6 R% g2 w
the more likely there will be an excellent response with low
4 v% {2 u* Q0 _+ zserum levels. Response occurs throughout adolescence as
; k, S+ R1 z2 R# ^- knoted in nomograms of phallic growth. 7 The actual response
' \( Q, R- Y! h$ P% J+ z9 mto a given serum level of testosterone is much greater at birth, A0 ?: G7 _! O7 @# i" V
and gradually decreases as boys reach puberty. This is most
s: s [& X- M$ m7 `likely related to the conversion of testosterone to dihydrotes-5 j$ j: J, t |4 J, }! O) K9 L
tosterone and correlates well with the studies of testosterone
6 S9 X7 [9 O, d y1 F6 T% fconversion in foreskin at various ages.
" ` v& F" k. [8 X, @2 rThe question arises regarding early treatment as to whether, ~) T) a9 X( d3 P
one might sacrifice ultimate potential growth as with acceler-- U" O' j2 n9 J. p) D/ p$ n
ated bone growth. The situation appears quite the reverse, n: n) T7 p3 A2 t3 G( ~
with phallic response. If the early growth period is not used
" h: X7 K+ [4 y2 }% \6 xwhen 5a reductase activity is greatest then potential growth0 L7 x7 ?; S* }. l( L/ x
may be lost. We have not observed any regression of growth
3 S! L0 b3 N& w* n! \' Pattained with topical or gonadotropin therapy. It may well, ~9 \7 l0 r0 s) h
be that some patients will show little or no response to any1 Q. A2 Y. }5 h2 t& a
form of therapy. This would suggest a defect in the ability to
5 q1 Q4 D0 E0 N- N) Tconvert testosterone to dihydrotestosterone and indicate that
' m* H6 [2 [$ H, ]phallic and peripheral skin, and subcutaneous tissue should, k- j+ i0 o$ K( @; g! B
be compared for 5a reductase activity.. o1 Q; F) X6 w& f( a
A, loop enlarges to measure penile girth in millimeters. B,6 k& J- |" |0 F; M
example of penile girth computed easily and accurately.
; r: Y8 J; X% C* l" oconversion of testosterone to dihydrotestosterone. It is in this$ U. v9 t0 C+ B# g1 B9 T; m& W
older group that others have noted high levels of serum
) j' D; @$ ]1 ~9 A" T5 wtestosterone with topical application. It would also appear+ z, e* k9 ] O" s8 S
that phallic response during puberty is related directly to the P1 d" Z4 e/ [( _3 Z5 B
serum testosterone level. There also is other evidence of local
+ x6 r- S! |4 |response to testosterone with hair growth and with spermato-
/ v6 u# c( V. a( g" Tgenesis. 5• 6" `5 y9 ]3 k+ A9 f
Administration of larger doses of gonadotropin or systemic
" C! d4 [1 R! b6 X5 m! A0 xtestosterone, as well as topical applications that produce
" P$ O- a' _% ?2 Nhigher levels of serum testosterone (150 to 900 ng./dl.), will+ N4 E+ r5 m/ s3 Q
also produce phallic growth but risks accelerated skeletal
! C4 n6 Y: o8 C7 ?3 s# }maturation even after stopping treatment. It would appear
! ^. e& ~$ G" q, h+ N' \* Hthat this may be avoided by topical applications of testosterone: c1 o5 n5 A1 v) F% L1 U) r' Y. }
and monitoring of serum testosterone. Even with this control9 k/ z. u% p5 F! w4 s
the duration of our therapy did not exceed 3 weeks at any3 Q8 S* a* l" R/ E6 \8 g* X
time. It is apparent that the prepuberal male subject may" p' s$ m- W1 H. F& T7 e
suffer accelerated bone growth with testosterone levels near6 H9 f, }& k# W) [# o, d
200 ng./dl. When skeletal maturation is complete the level of
$ D6 ^0 N$ A% }5 J0 f% E, Rserum testosterone can be maintained in the 700 to 1,300 ng./
& T* _* K, M t6 P* g6 ndl. range to stimulate phallic growth and secondary sexual
2 v3 ], W9 l0 M- W7 x' Q! D; e {* j7 x' jchanges. Therefore, after skeletal maturation parenteral tes-
* B* E3 q( E7 S4 O. Jtosterone may be used to advantage. Before skeletal matura-
3 d$ q* F5 G9 Z4 L+ k. z8 [tion care must be taken to avoid maintaining levels of serum
1 \2 L ]5 _5 w) u) f/ u8 ?, W8 Ltestosterone more than 100 ng./dl. Low-dose gonadotropin
1 t' z5 L: [: h; s" _depends upon intrinsic testicular activity and may require
$ M/ ~% x2 T9 [. Y/ J8 Nprolonged administration for any response.& }7 n# M+ e0 ?2 }, Y: [
Alternately, topical testosterone does not depend upon tes-9 P( l% Z6 T5 N% G# L
ticular function and may provide a more constant level of, }% j" a ]: M; [* p" B! N, O0 Q
REFERENCES) o! L$ b8 g; H! ]. k X5 l& |/ \
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ T/ {& z. g0 i6 M. U/ {- w* v+ N
R.: The local application of testosterone cream to the prepub-
2 R5 ^( l& b0 I Bertal phallus. J. Urol., 105: 905, 1971.1 m' P) i' v, e& s2 P X3 {
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
7 e8 q h' y3 Ttreatment for micropenis during early childhood. J. Pediat.,1 _( ~' k- d9 ~3 |
83: 247, 1973.
% Z, P) N. J- r$ ]* Y3 H3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' r3 O9 D3 b0 Q- Eone therapy for penile growth. Urology, 6: 708, 1975.
8 u5 c+ f i7 m, f4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% y$ [: V- k* x8 @" Q( Yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( @$ |! j" q% [) g/ P: W6 D3 f
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' C+ a3 ~, ^5 D' A, n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# s0 A+ n/ _+ E
by topical application of androgens. J.A.M.A., 191: 521, 1965.
2 M, `8 z6 }* X7 [; r: y3 m. x4 B9 n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 F+ e5 _" W, c/ b6 X$ ?androgenic effect of interstitial cell tumor of the testis. J.4 _; U1 k/ F8 U# M" \! M; i$ P
Urol., 104: 774, 1970." C* s$ P" `! P( T0 V) T
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-: V- ]3 k$ `5 ^% u, R2 K8 h( Z( {* d; a
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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