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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: S4 n. B2 E0 B G7 r* A* u: jGONADOTROPIN$ p1 M! f4 b+ C
RICHARD C. KLUGO* AND JOSEPH C. CERNY; s# d" B% W1 B* [; a c8 Z2 _
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ p6 z: b: \) a3 R7 S
ABSTRACT V4 F/ Q5 a9 V$ h- b* v% D! V6 L
Five patients were treated with gonadotropin and topical testosterone for micropenis associated u8 D1 I8 O3 K4 C
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 c6 V0 M! @ Q! ]; Btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ N+ c! Z- z% F4 w1 \& Gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 z+ h# O% q2 [ l" X0 Vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" ?) I. y# ]7 n, S
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- }) M# f" Q8 f0 D" H, ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ d# n) g6 Q! y5 T- f9 R- W
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, h- F. H9 `; U) o
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile. g2 f1 C7 f* R8 w5 X# Z9 Q
growth. The response appears to be greater in younger children, which is consistent with previ-, Q# t4 r! e6 ?/ p+ Y
ously published studies of age-related 5 reductase activity.9 f/ Z1 [* j* O6 ]9 L& q% ?; t. @4 N
Children with microphallus regardless of its etiology will! M3 _5 O# E& u/ Z6 _
require augmentation or consideration for alteration of exter-
% O3 Z$ D8 d7 u! Qnal genitalia. In many instances urethroplasty for hypo-+ @" c. j7 N+ i# `4 I3 J7 G4 _
spadias is easier with previous stimulation of phallic growth.5 E3 d- {" M- S$ B
The use of testosterone administered parenterally or topically, `0 S# e' W) g) I, ~2 a! @$ X5 a
has produced effective phallic growth. 1- 3 The mechanism of6 q+ ]9 ?. l. O0 o
response has been considered as local or systemic. With this
2 X+ x$ s' l+ y! @3 |in mind we studied 5 children with microphallus for response
+ q! T W+ J! _% W8 bto gonadotropin and to topical testosterone independently.6 D. N' l: q# x/ C; o" _9 Q
MATERIALS AND METHODS
v) C$ S }# G! s$ cFive 46 XY male subjects between 3 and 17 years old were
! K/ A: U& o# o, A' b' y nevaluated for serum testosterone levels and hypothalamic5 r9 R3 m. B, o: m$ V& S: N
function. Of these 5 boys 2 were considered to have Kallmann's( {" X; c+ l3 ]7 r; E t# b, X( [1 F2 ~% m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! _! \9 }+ N8 J$ }0 Plamic deficiency. After evaluation of response to luteinizing
6 N" c7 @6 E: u: xhormone-releasing hormone these patients were treated with
/ g- s: l' s% i' G: h1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 w" v& X& h" nafter completion of gonadotropin therapy 10 per cent topical0 C& F! f, v% |) U8 e8 k9 a
testosterone was applied to the phallus twice daily for 3 weeks.$ c7 \0 y2 K% L0 u/ Z N+ m
Serum testosterone, luteinizing hormone and follicle-stimulat-" o) C9 O- ~9 }: D+ U( @
ing hormone were monitored before, during and after comple-
. O. s1 m' \/ o+ y5 ^* Ation of each phase of therapy. Penile stretch length was$ y+ \3 l/ O( J/ v: ^1 T
obtained by measuring from the symphysis pubis to the tip of4 S! ?: _3 f5 U2 z7 x5 M5 _3 |# t
the glans. Penile circumferential (girth) measurements were( `( m* y) A, ~5 k4 F
obtained using an orthopedic digital measuring device (see' l7 z( w) S$ U' r# n5 @, w" c& {6 s( U
figure).
5 _+ X0 A# a4 oRESULTS. P7 Z3 n# q6 I' S6 T
Serum testosterone increased moderately to levels between' o2 \3 I; o2 T; h: Q5 a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% k$ s9 u! S, |1 hterone levels with topical testosterone remained near pre-
c( e7 d8 V+ ?# c! |treatment levels (35 ng./dl.) or were elevated to similar levels
4 P1 P2 }3 I5 v) S' @6 t2 edeveloped after gonadotropin therapy (96 ng./dl.). Higher7 r! J( X6 u2 z8 p4 S9 j- g/ ?: Q" T
serum levels were noted in older patients (12 and 17 years old),. w' B" c8 T3 o, E8 z& B
while lower levels persisted in younger patients (4, 8, and 10
) A" r- K z+ b* l) g1 I' hyears old) (see table). Despite absence of profound alterations
( }0 a D, p& K# d* Nof serum testosterone the topical therapy provided a greater" D6 \6 } _+ @7 ]5 @
Accepted for publication July 1, 1977. ·) a) _, C1 n& c- t
Read at annual meeting of American Urological Association,
: k: q" {3 s, Y" N" y0 _Chicago, Illinois, April 24-28, 1977.
# g4 x& |5 B8 Z b( R* Requests for reprints: Division of Urology, Henry Ford Hospital,
! w3 E' h$ Z- `4 n8 @$ N( q2 A2799 W. Grand Blvd., Detroit, Michigan 48202.
7 [; Q' Z! \- C5 dimprovement in phallic growth compared to gonadotropin.
# b$ K0 v6 R7 A3 z! I5 ^5 o0 jAverage phallic growth with gonadotropin was 14.3 per cent
; J" p; d" z; Q; D" J" vincrease in length and 5.0 per cent increase of girth. Topical+ \) B! d9 k0 M
testosterone produced a 60.0 per cent increase of phallic length/ @/ }* ^1 N. Q. h* |
and 52.9 per cent increase of girth (circumference). The7 y" x: i- |0 `: c
response to topical testosterone was greatest in children be-0 N& z' _6 P% }$ ?, l$ L3 ]
tween 4 and 8 years old, with a gradual decrease to age 17" a! b, i9 x1 C( g2 u
years (see table).+ g7 \" c& R1 {" T8 ^! @
DISCUSSION0 w# y( w' L: W& z+ @
Topical testosterone has been used effectively by other7 w+ R b0 Q0 {" k; |1 B+ v
clinicians but its mode of action remains controversial. Im-
2 Y+ w% q% T. H8 q. e3 m u2 bmergut and associates reported an excellent growth response, B; M+ [# Z# k- Z- N6 W( }- t
to topical testosterone with low levels of serum testosterone,
, g+ N# L4 ?% vsuggesting a local effect.1 Others have obtained growth re-3 U* b& j" s) t
sponse with high. levels of serum testosterone after topical( n. |6 ?) q& p; F# r9 ]# u% n
administration, suggesting a systemic response. 3 The use of) }* @6 n# x# h H, |+ R0 E6 o
gonadotropin to obtain levels of serum testosterone compara-
1 W$ f/ f& H1 N" O4 u2 }ble to levels obtained with topical testosterone would seem to5 q! l( j: f8 h6 w/ T5 o8 F @0 p7 C7 x/ o
provide a means to compare the relative effectiveness of! j. }/ B6 ~. N% S
topical testosterone to systemic testosterone effect. It cer-# b, D G8 B$ }8 [5 B+ t4 z
tainly has been established that gonadotropin as well as par-
+ x" G6 S7 O" q+ Jenteral testosterone administration will produce genital
x2 F) i! t; Sgrowth. Our report shows that the growth of the phallus was
* t/ h# F/ Q2 D6 u% gsignificantly greater with topical applications than with go-2 ] }, I( r/ V& h! A( o j& \' Q- P$ B
nadotropin, particularly in children less than 10 years old.! z* K. Z% I7 z5 N3 X" f
The levels of serum testosterone remained similar or lower. m7 d. i8 c2 u5 U, l
than with gonadotropin during therapy, suggesting that topi-
: e- O8 \8 b4 Y1 Qcal application produces genital growth by its local effect as0 x, S% b6 V1 z0 H% N
well as its systemic effect.
" F$ Y+ ?8 d CReview of our patients and their growth response related to
/ {6 f+ V- d( Z. p) ]3 ~6 e1 Sage shows a greater growth response at an earlier age. This is
3 \5 J0 J4 O3 ~+ h! Jconsistent with the findings of Wilson and Walker, who; [4 {/ n: q% ~$ x! K& }2 t
reported an increased conversion of testosterone to dihydrotes-. R: g* x0 B0 i8 F2 |
tosterone in the foreskin of neonates and infants.4 This activ-
7 V& m. H& b" C2 U6 w2 y m# v/ Fity gradually decreases with age until puberty when it ap-
2 E1 F/ Y" i- E+ sproaches the same level of activity as peripheral skin. It may: M7 ]4 }6 y' e+ x4 `! ?! c' `
well be that absorption of testosterone is less when applied at
8 m/ B' ^, @4 e2 ^an earlier age as suggested by lower serum levels in children
. H- p/ q" E, V ^1 @less than 10 years old. This fact may be explained by the
$ K% Z/ T# X; `9 X7 ?. ^6 m' Y2 }! A8 zgreater ability of phallic skin to convert testosterone to dihy-0 \: s8 I5 ~8 B& e
drotestosterone at this age. Conversely, serum levels in older, N% w% o) X1 Y# D4 L0 Q$ j
patients were higher, possibly because of decreased local) P# Y" M) r+ ^) L
667
6 V& O+ ^. }8 i2 S5 e7 ^. o' v668 KLUGO AND CERNY
8 A' }) E0 l5 `9 | v) dPt. Age
* J6 ^1 u) B* P, r( ]2 o1 o(yrs.)
+ X0 Z% X; B; Y. B6 oSerum Testosterone Phallus (cm.) Change Length5 G( S6 j2 Q/ ?( k: s$ i& V9 I
(ng./dl.) Girth x Length (%)
. ?2 b( {; [0 z0 r, m4) X A* T$ I% m2 D( b/ R: [1 E
8
2 ]) y) @8 ?2 K* ~* @. {3 I' X/ L10
5 z/ C1 T1 Z- _! Q# a! a12
+ _1 w% r' C; Y174 R! C: |* K# I. t
Gonadotropin
+ q+ ?$ c7 Y0 h4 o" s4 R! J71.6 2.0 X 3 16.6
; N( ?( C6 j+ S9 I O$ k50.4 4.0 X 5.0 20.0! a* y7 u, e# D( q+ J% U& L. \
22.0 4.5 X 4.0 25.0) L8 C3 r; a( `8 \. y$ S3 X
84.6 4.0 X 4.5 11.1
4 d" x, v( a: I! O85.9 4.5 X 5.5 9.0
( T% C. _5 m/ m3 vAv. 14.31 t1 h; L- O+ f$ c
4
4 q: d* T$ S+ J) h3 e" ~8- |4 _$ h" W+ R
10+ L! }/ {' D( o2 I( T/ j
12
; X& r8 i; R& P' Z17
9 d) A3 b- v1 STopical testosterone
/ J4 c9 L5 a/ k. N2 [34.6 4.5 X 6.5 85# P& T5 ]$ H7 ^, e9 s" V$ u m
38.8 6.0 X 8.5 70
+ g/ Z5 K# ?( i+ R8 j40.0 6.0 X 6.5 62.5
% ~: R! Q n. \9 p8 d7 v93.6 6.0 X 7.0 55.5
! M- Q6 e V+ K5 g* n- k95.0 6.5 X 7.0 27.2
H, ~' L$ G( n* i: c; }Av. 60.0
4 M0 E' q( g/ y9 ?/ F2 Y/ B Wavailable testosterone. Again, emphasis should be placed on
* }- ], B3 O3 }early therapy when lower levels of testosterone appear to! `" f9 ~1 b) ?' s# h
provide the best responses. The earlier therapy is instituted
2 K4 A) z4 }4 h+ o" b; R0 ?the more likely there will be an excellent response with low5 z& L q6 p) ?, c8 `4 E K" _& w
serum levels. Response occurs throughout adolescence as" V/ j$ q3 ~# I R( Z4 A
noted in nomograms of phallic growth. 7 The actual response
6 ~6 U# P1 Y! F3 E# d/ A7 {to a given serum level of testosterone is much greater at birth+ a0 }2 @% h w" R
and gradually decreases as boys reach puberty. This is most- V V( i0 J \3 I" p
likely related to the conversion of testosterone to dihydrotes-
4 w% f' ~' n2 p; i. L" itosterone and correlates well with the studies of testosterone( s* B0 p" g) h8 T8 {. N
conversion in foreskin at various ages.+ |- A! A. s1 l! l) X3 M, v
The question arises regarding early treatment as to whether% N; ?5 f' q) r8 w
one might sacrifice ultimate potential growth as with acceler-8 _& a/ l/ ]* U* P
ated bone growth. The situation appears quite the reverse- `+ B2 p3 Z! E& E% I O2 W, W
with phallic response. If the early growth period is not used
; z$ g( W8 H* _when 5a reductase activity is greatest then potential growth
* }: d8 F8 D' \8 C" Z B* W) [may be lost. We have not observed any regression of growth
. q) a$ m- q" C+ A; Yattained with topical or gonadotropin therapy. It may well' u: k% E; p1 C# q; ~
be that some patients will show little or no response to any- r7 ~+ b% R; W# R3 J- F, L
form of therapy. This would suggest a defect in the ability to
" t, x4 R- n- G; Hconvert testosterone to dihydrotestosterone and indicate that
2 d. S/ e1 i# d) s2 cphallic and peripheral skin, and subcutaneous tissue should; J7 T) D' v: p0 x9 _' e) W
be compared for 5a reductase activity.
( L+ s6 V6 t0 `9 [0 oA, loop enlarges to measure penile girth in millimeters. B,' W1 H; L% t( s1 j% R9 a6 h0 j
example of penile girth computed easily and accurately.
Z4 a$ z0 w3 y$ f# R$ ?conversion of testosterone to dihydrotestosterone. It is in this
& A+ g/ A4 n* a" P' t/ Qolder group that others have noted high levels of serum
% r7 T/ `; c5 E( O5 `testosterone with topical application. It would also appear4 M! l5 r+ x5 c
that phallic response during puberty is related directly to the3 C( ~& J) _' M4 _% J$ J& j
serum testosterone level. There also is other evidence of local# C" r3 K0 ~, ?: u
response to testosterone with hair growth and with spermato-8 G% o2 g, B7 g# a+ W x( M6 z
genesis. 5• 6
5 F; y+ p' k) C6 W& |Administration of larger doses of gonadotropin or systemic
' U! \% X" s9 k+ btestosterone, as well as topical applications that produce
0 x% f/ b& \% @/ {1 Uhigher levels of serum testosterone (150 to 900 ng./dl.), will8 @% [9 P) X" o$ L, z; w. Z
also produce phallic growth but risks accelerated skeletal2 x) \( Z: T9 m9 M& [
maturation even after stopping treatment. It would appear# u- _7 x- F" U. I3 j
that this may be avoided by topical applications of testosterone
# W, b& ]' k+ E4 e0 Mand monitoring of serum testosterone. Even with this control
# _: i b0 z* }1 d1 Nthe duration of our therapy did not exceed 3 weeks at any# T1 E% o6 G, z' {
time. It is apparent that the prepuberal male subject may
* ^# \ X1 U( _; T: \suffer accelerated bone growth with testosterone levels near
) S4 p# d& ^$ Z! g0 z @200 ng./dl. When skeletal maturation is complete the level of* F& T& q4 X2 [; p5 L
serum testosterone can be maintained in the 700 to 1,300 ng./6 O7 I. [0 ^# p. |7 Q
dl. range to stimulate phallic growth and secondary sexual4 Q5 X& i8 y2 G2 `$ Y2 L0 g" C
changes. Therefore, after skeletal maturation parenteral tes-
+ k; W& `( U9 T$ X- Z: ]* y7 M# itosterone may be used to advantage. Before skeletal matura-& Q3 U& A( Q+ w. H& p
tion care must be taken to avoid maintaining levels of serum' m& l4 U) b$ K0 c' b) F
testosterone more than 100 ng./dl. Low-dose gonadotropin
- K8 Z! h7 _, p) odepends upon intrinsic testicular activity and may require" \1 J" L1 V- R5 P: N$ c& ^
prolonged administration for any response.
' [1 H* D% j6 c! d, l4 eAlternately, topical testosterone does not depend upon tes-8 S, |" E7 ?3 y2 l' }! f
ticular function and may provide a more constant level of
: T8 [: r- q0 P! y' ZREFERENCES
$ s4 k6 M2 i8 i8 u$ E( p7 w! E1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 `6 _ T. \6 b) ?, b! ^- OR.: The local application of testosterone cream to the prepub-4 r) l* M" g1 T- J
ertal phallus. J. Urol., 105: 905, 1971.5 O' W) W/ H7 ~) W
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
3 k! X; V4 T0 Y p( l h9 t5 Streatment for micropenis during early childhood. J. Pediat.,
5 H8 q) j+ D- ]- q: l83: 247, 1973.$ y$ N+ P: @1 q& c2 }( e& T3 Z
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, P1 t x3 H; F& \2 h( o
one therapy for penile growth. Urology, 6: 708, 1975. G7 d" W7 D* l
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, ~# f( T0 `1 q6 dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 ^/ J& x3 w6 s; D
skin slices of man. J. Clin. Invest., 48: 371, 1969.
q$ @; j9 f4 |* ] N0 U" c5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) C. n8 t, r9 h7 oby topical application of androgens. J.A.M.A., 191: 521, 1965." ?$ B7 k% P1 O) Y7 |! @" N3 T
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; O; j1 I$ g- g# G' Dandrogenic effect of interstitial cell tumor of the testis. J.* O/ ~3 u" _, n) m) o
Urol., 104: 774, 1970.7 b9 V: Q0 b7 ~ Z9 [
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' X4 I2 M# ?; m( Qtion in the male genitalia from birth to maturity. J. Urol., 48: |
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