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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
3 @" e0 J; x+ v7 s ]9 B" ^' VGONADOTROPIN R! ~+ U. p7 y% m
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 C1 C" Z O: X- O* Z7 TFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& j/ t& `; w7 E K; {ABSTRACT
, O1 N* o# j( f: n; b9 xFive patients were treated with gonadotropin and topical testosterone for micropenis associated7 t- U# ]6 F) i6 h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, z9 G- m/ O' g8 i" P& j! z7 m& stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) W( O. ~7 i1 [2 v) ~cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent w% g4 W; t k3 i0 ?" F- |, Z
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* H2 ~) g& Y( q2 L9 a
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! `% I+ h3 V; D3 V
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ j6 K# T1 g5 ^- I/ z$ @2 R; roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& L& Q4 n# i8 _& U" ]
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 A1 i* R$ J1 _1 |1 I6 R' E/ S
growth. The response appears to be greater in younger children, which is consistent with previ-# m1 x3 ^; T" \7 h+ M7 o
ously published studies of age-related 5 reductase activity.. R; x( a: r# w& M
Children with microphallus regardless of its etiology will
2 J% f# c0 ^7 S1 Xrequire augmentation or consideration for alteration of exter-
* H0 F. F) S5 _( z+ ?9 o P$ Vnal genitalia. In many instances urethroplasty for hypo-
% B2 R8 ~1 o! C! gspadias is easier with previous stimulation of phallic growth.! {* i. j) O! |- g. m
The use of testosterone administered parenterally or topically
7 k* u7 @$ F5 Thas produced effective phallic growth. 1- 3 The mechanism of
. l p2 _$ z& ^& h @response has been considered as local or systemic. With this
, x1 O5 J. t0 `5 t# zin mind we studied 5 children with microphallus for response: S: g2 i& L9 a4 n: m$ ?6 l
to gonadotropin and to topical testosterone independently.
3 ? a# `2 h% T- `MATERIALS AND METHODS5 }* R4 f: w* X6 ~
Five 46 XY male subjects between 3 and 17 years old were& U- B4 V |2 k/ z
evaluated for serum testosterone levels and hypothalamic+ O/ ?) \5 P( L; A$ u
function. Of these 5 boys 2 were considered to have Kallmann's
$ ? H- J! @2 g* o3 H8 isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' x& `- n" v- slamic deficiency. After evaluation of response to luteinizing
- S2 j: @' L; d ?( h7 Ehormone-releasing hormone these patients were treated with: x/ t: L/ M; v! V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 n: _0 c. k# h0 ?2 C' p6 }' lafter completion of gonadotropin therapy 10 per cent topical/ s. V) p8 |3 c4 ~' d Y8 T! R1 i
testosterone was applied to the phallus twice daily for 3 weeks.' l! i, k$ X6 @/ c, y
Serum testosterone, luteinizing hormone and follicle-stimulat-
: M7 _; x" d, n9 Eing hormone were monitored before, during and after comple-) s3 n9 I( R' s' a9 d2 H) c
tion of each phase of therapy. Penile stretch length was
3 i8 Q* {5 r6 B/ X1 J( jobtained by measuring from the symphysis pubis to the tip of
% `2 R3 }5 c; i5 ?% Q0 @( xthe glans. Penile circumferential (girth) measurements were' E& Q9 w: |# ^9 c
obtained using an orthopedic digital measuring device (see+ |1 J3 M/ ]( L, u# ~3 @5 S/ ?$ q, h
figure).
4 v: n7 T# f0 a. o2 L4 s& qRESULTS
6 J$ j9 B' C& I6 N. D1 A0 q: ZSerum testosterone increased moderately to levels between
1 A) j- s3 d: G50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
2 q; D8 g+ ]0 y) p# [' {; zterone levels with topical testosterone remained near pre-9 l- R j2 x0 A8 x k. D
treatment levels (35 ng./dl.) or were elevated to similar levels
& Q1 F( ?( E Q2 [: Ndeveloped after gonadotropin therapy (96 ng./dl.). Higher* l. a- y: W$ w. s6 G
serum levels were noted in older patients (12 and 17 years old), {2 v- U7 R; G$ {" h
while lower levels persisted in younger patients (4, 8, and 10# L% D1 Y2 C* u! G9 v2 ^
years old) (see table). Despite absence of profound alterations* i' j8 T3 f1 J* y% g
of serum testosterone the topical therapy provided a greater& q9 o1 C% z2 Y# j5 ?0 e! b
Accepted for publication July 1, 1977. ·) `. Q2 G. ^0 T. b
Read at annual meeting of American Urological Association,
8 X, ~ K1 p" B& `! z' E; ?Chicago, Illinois, April 24-28, 1977.& G# f# E8 b4 T4 g# |2 D7 K
* Requests for reprints: Division of Urology, Henry Ford Hospital,6 S, j7 K1 t$ {* {
2799 W. Grand Blvd., Detroit, Michigan 48202.
3 f, r: e3 |+ t4 ?4 Wimprovement in phallic growth compared to gonadotropin.% d' }- o) f! _
Average phallic growth with gonadotropin was 14.3 per cent* A! I1 R$ \8 D* p1 W; I, e
increase in length and 5.0 per cent increase of girth. Topical2 S5 g& F' e" w, b! @
testosterone produced a 60.0 per cent increase of phallic length7 N* ^4 ^$ l3 B
and 52.9 per cent increase of girth (circumference). The
% V8 i0 `+ X! {& q6 g1 Rresponse to topical testosterone was greatest in children be-" F: d6 o) P1 E( `$ ?
tween 4 and 8 years old, with a gradual decrease to age 17
6 ^ W& A3 L# P6 P' u- yyears (see table).
3 }% e1 e3 x# L% cDISCUSSION& F# Y! e2 ]! n' L! w( S
Topical testosterone has been used effectively by other, B" s: r. E) `6 A
clinicians but its mode of action remains controversial. Im-- g$ c; ^, N9 I/ u
mergut and associates reported an excellent growth response0 P8 N+ j8 f/ c+ v- r
to topical testosterone with low levels of serum testosterone, W$ r& v7 z+ u4 ~
suggesting a local effect.1 Others have obtained growth re-4 a- N; e% w8 `* Y" L
sponse with high. levels of serum testosterone after topical1 j L$ a0 F- l1 H
administration, suggesting a systemic response. 3 The use of$ J+ b% q4 n. k0 j" [
gonadotropin to obtain levels of serum testosterone compara-5 _- @# i: u' i" G( m. X) B- y
ble to levels obtained with topical testosterone would seem to
0 y! N( {* b! }/ Zprovide a means to compare the relative effectiveness of; \9 [1 W2 x, O
topical testosterone to systemic testosterone effect. It cer-, W* H/ m5 `1 v0 _: Y+ ~7 q1 ~; M! [1 x
tainly has been established that gonadotropin as well as par-7 N8 J9 J# Q+ e$ D
enteral testosterone administration will produce genital
/ G2 k9 {8 [/ H$ Ngrowth. Our report shows that the growth of the phallus was
2 s3 w- V% ~2 X. t) T) p( jsignificantly greater with topical applications than with go-
K: p4 t$ m0 `* Unadotropin, particularly in children less than 10 years old. m1 V# }7 h$ k) \
The levels of serum testosterone remained similar or lower3 E- Q9 J! t2 s' V6 h
than with gonadotropin during therapy, suggesting that topi-
5 v( `, Y% |/ v6 C- m" b+ r; kcal application produces genital growth by its local effect as! [- m8 Q; n6 M8 h/ c" X
well as its systemic effect.0 s+ Z; h7 Z) f" {# f
Review of our patients and their growth response related to
7 V0 o( G4 V) L- qage shows a greater growth response at an earlier age. This is) v7 ^3 ?' d) j; X( i
consistent with the findings of Wilson and Walker, who+ q0 [ p( N1 x2 D; }, P' a- ]
reported an increased conversion of testosterone to dihydrotes-& Q" r. r7 ]8 \( s. J; H. x/ ?
tosterone in the foreskin of neonates and infants.4 This activ-; m7 B- N: b, m
ity gradually decreases with age until puberty when it ap-
" `+ x. j- |) R+ u& \0 G- s jproaches the same level of activity as peripheral skin. It may
0 W0 I( ]$ I2 W0 ewell be that absorption of testosterone is less when applied at. H) E1 B( ?1 a) o6 F4 V2 D
an earlier age as suggested by lower serum levels in children
' T! n; ]/ Q3 Aless than 10 years old. This fact may be explained by the
- Q: ~" O6 s$ F. Egreater ability of phallic skin to convert testosterone to dihy-
# `" z" s# i: K* ]! q, ?drotestosterone at this age. Conversely, serum levels in older
) I# O& o1 l9 U) _* t* V7 H# ~, lpatients were higher, possibly because of decreased local
- T6 U, k0 Q/ w& ?8 o667
1 A: I3 ]3 V, K/ ~! B+ D8 ? Y668 KLUGO AND CERNY6 `, \1 w+ y1 s4 w; A% s. j ~
Pt. Age. K4 ^) v; n2 J+ N: [$ p- _/ t
(yrs.); U _7 a' @2 O
Serum Testosterone Phallus (cm.) Change Length
' Q+ e, L1 A/ C/ Y) x(ng./dl.) Girth x Length (%)
- W0 w( [0 r3 d- o& L4
1 V# F* y6 _) L1 A% K% J3 r$ A5 }% X8$ S8 V" H+ _! G0 M) E
102 E% v5 b9 [& _- P9 x* b
125 _7 R8 }+ g% q) ^" ^1 G' w
17
4 p( O, f* l9 r6 v3 t# n$ r+ tGonadotropin
+ G2 m! t3 s! c* O* l* B" P2 H71.6 2.0 X 3 16.6
3 z/ h1 u; x$ p) J/ [1 w6 j50.4 4.0 X 5.0 20.0& p2 E6 v5 R3 d) n
22.0 4.5 X 4.0 25.02 _; f0 I- n8 G$ ]9 J7 Z
84.6 4.0 X 4.5 11.1
y2 j6 {9 _+ w* y$ K85.9 4.5 X 5.5 9.07 ]2 s# k% |: Y6 E
Av. 14.3
" S: r1 h) z5 D3 V, d7 Q6 I3 ]4
( i7 K0 |) j/ b8 {& Z# E8' h0 w0 T" |0 j) P8 }# v5 u6 D
10: \0 ^% }) j8 Z6 H
12
& M/ R( e* d/ G) h4 L k17
7 I! s1 w5 t) Z' ~Topical testosterone
. h; G7 J, C' E( M9 Y$ G# o. @34.6 4.5 X 6.5 85% n3 I2 f& M. Y `5 C3 _! L
38.8 6.0 X 8.5 70
, Z& g2 S+ ^0 W" N% L3 `8 I40.0 6.0 X 6.5 62.5. n' s6 p. b9 _( p" Q+ h7 h/ r Z
93.6 6.0 X 7.0 55.5
7 T& j" ^8 O5 {' ~# g# o# L95.0 6.5 X 7.0 27.2
$ S0 P) E3 A5 m2 H" v' ^; {4 hAv. 60.0
/ Z5 ~' ^7 ^" `. s! }available testosterone. Again, emphasis should be placed on: u. ], P: T6 f$ d/ ^7 S/ J$ z
early therapy when lower levels of testosterone appear to
6 L8 E! G' k* c& vprovide the best responses. The earlier therapy is instituted
8 S4 M- Z. ]! q/ r: Xthe more likely there will be an excellent response with low7 h6 Q! R0 E/ W4 A2 D8 F, z
serum levels. Response occurs throughout adolescence as, O& J9 Z6 A& y; R- S8 A" ]
noted in nomograms of phallic growth. 7 The actual response
' c; ^ X7 B1 W; K1 o- j9 L. B" X, Kto a given serum level of testosterone is much greater at birth
: F9 B) s- w% q) L1 Yand gradually decreases as boys reach puberty. This is most
, S+ b8 O, E! ?4 y; F0 j$ K* `$ flikely related to the conversion of testosterone to dihydrotes-, G, L% j* Z% O4 p1 ~
tosterone and correlates well with the studies of testosterone
7 T" b: b2 q5 U( oconversion in foreskin at various ages.; ]$ q+ @2 L( W' ]7 y" U/ z
The question arises regarding early treatment as to whether
' z$ [5 E* C1 done might sacrifice ultimate potential growth as with acceler-- C, A2 Z y* k2 @
ated bone growth. The situation appears quite the reverse
: W6 {5 ?! E7 Z5 Iwith phallic response. If the early growth period is not used
V! Z& L5 k- i+ G; y% Z* lwhen 5a reductase activity is greatest then potential growth
1 }; R5 l- Q& p' ^. omay be lost. We have not observed any regression of growth
( c0 f, W8 ], n9 I+ @attained with topical or gonadotropin therapy. It may well/ H( F. l& y: }/ \, w2 V: H2 Z1 Z$ S
be that some patients will show little or no response to any% x0 J% r2 V( r" S+ M
form of therapy. This would suggest a defect in the ability to9 i; k# K. @2 t! x0 u# z
convert testosterone to dihydrotestosterone and indicate that
! o0 \3 d, t% s6 Yphallic and peripheral skin, and subcutaneous tissue should
% H/ _4 u0 u$ \7 T- E% E/ qbe compared for 5a reductase activity.
4 C/ S5 O$ [6 G3 ^+ J' `A, loop enlarges to measure penile girth in millimeters. B,' a9 E, e7 Q5 i% V4 O6 c
example of penile girth computed easily and accurately.
! y# a% K g( n& @! }2 Gconversion of testosterone to dihydrotestosterone. It is in this1 s0 z/ a6 r; `/ g
older group that others have noted high levels of serum& h" e6 s% t7 M/ w& u, l1 q4 V
testosterone with topical application. It would also appear
7 S% d# h' n- k5 ythat phallic response during puberty is related directly to the
1 b( J0 j( [ @. x& h. s) X6 X7 Oserum testosterone level. There also is other evidence of local
7 K( }8 R3 M0 a5 n- Fresponse to testosterone with hair growth and with spermato-3 I, t7 V1 ^3 Y' h0 `# [) N
genesis. 5• 6
8 J K" K3 u7 h! n% h8 ?Administration of larger doses of gonadotropin or systemic
' e9 u+ {' E$ W2 W+ w1 {) Vtestosterone, as well as topical applications that produce, H$ x1 y5 c) p9 f& H
higher levels of serum testosterone (150 to 900 ng./dl.), will$ |$ m; @* e% a1 X- Z
also produce phallic growth but risks accelerated skeletal4 d1 ^) z9 h$ U6 P6 Q3 w
maturation even after stopping treatment. It would appear
# l* O) W, x) P. H0 d! ]that this may be avoided by topical applications of testosterone/ u9 E6 Q$ O4 k7 x
and monitoring of serum testosterone. Even with this control
7 i- Q! Q J% k, x3 q2 J u' \ Cthe duration of our therapy did not exceed 3 weeks at any6 v# t* m4 |, ?: V
time. It is apparent that the prepuberal male subject may
# s0 b% x3 ^# o5 g/ ssuffer accelerated bone growth with testosterone levels near: N$ ?: F' ~0 q. Z1 `: d- Q6 z8 S
200 ng./dl. When skeletal maturation is complete the level of
$ {; d1 k9 z" A! y4 T2 x1 Xserum testosterone can be maintained in the 700 to 1,300 ng./% c% I A' \ L. q: d1 ?
dl. range to stimulate phallic growth and secondary sexual
9 {* l( n! p6 ?+ i c Lchanges. Therefore, after skeletal maturation parenteral tes-0 z) N( B% U# J
tosterone may be used to advantage. Before skeletal matura-
7 E0 C8 p2 N8 l: Q; a- Htion care must be taken to avoid maintaining levels of serum
. Q4 q$ Z% O% v* J- c ^testosterone more than 100 ng./dl. Low-dose gonadotropin/ m, V& b$ L$ J4 D
depends upon intrinsic testicular activity and may require d" u- \$ M2 f( i* O% n
prolonged administration for any response.4 {! T/ ^' M& z
Alternately, topical testosterone does not depend upon tes-
5 e6 |. d7 T) ]& p0 Q/ oticular function and may provide a more constant level of
5 n/ `' O6 i! Y! w5 DREFERENCES
9 |+ _) \- W% f0 r: ]! W1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks, _& f3 x6 H' ~; W
R.: The local application of testosterone cream to the prepub-% Y' t" |7 ^' n7 R
ertal phallus. J. Urol., 105: 905, 1971.7 `: W' S7 z6 ]: U( H O1 U4 x
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" i+ R" f: B1 q; R. E- u; C) X
treatment for micropenis during early childhood. J. Pediat.,
( Z. }7 T/ I! G: H+ F83: 247, 1973.+ H |! H J: q; H+ T( h
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, J) R, K O& G
one therapy for penile growth. Urology, 6: 708, 1975.2 l6 \1 T: w& P
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, |5 u9 s8 C4 yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 y; z n2 O/ F* Z: l4 k5 W
skin slices of man. J. Clin. Invest., 48: 371, 1969.- p3 T% Y! E5 l% H6 r7 V5 ^- p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ @4 w! c/ |" |by topical application of androgens. J.A.M.A., 191: 521, 1965.
$ K# H2 h5 G, `2 h6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 C4 h( S" s% @6 u2 X) H5 r* ?androgenic effect of interstitial cell tumor of the testis. J.
+ B2 R8 t$ S. ?& j8 Q! ]" y7 {0 FUrol., 104: 774, 1970." U- y& o6 h/ M3 }* y
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ p% }# \5 I# m
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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