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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: x$ O$ w+ u- [2 uGONADOTROPIN4 a+ g% X( z& n; n& l
RICHARD C. KLUGO* AND JOSEPH C. CERNY
/ I" H+ d1 l; wFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ B) P$ R" w0 C; H4 GABSTRACT
; e4 l7 s+ O- C; f7 c0 QFive patients were treated with gonadotropin and topical testosterone for micropenis associated, ~$ n: H1 s9 m
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 \- v- N1 T9 n( }: ~; u8 k. O
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% h" j4 Z# M& a1 _! K! Icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* Z2 y) A3 {4 r0 e9 ]
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( |/ b; W8 G( b
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 W: r! J0 a) _( M. ]4 v5 @$ \% sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 l$ H0 a3 P" `, i6 ~3 P! Ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( L, E" n. ^& G. _/ f$ A+ {8 F- s
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile( t5 o6 t6 L( S% B* p
growth. The response appears to be greater in younger children, which is consistent with previ-6 Z$ a5 Z5 I! A3 k
ously published studies of age-related 5 reductase activity.( }9 L3 @! Q% w1 }- p8 \6 {1 ^
Children with microphallus regardless of its etiology will7 M$ t. u8 e. Z& j% ~' w
require augmentation or consideration for alteration of exter-
$ r7 }, S( V8 n2 J: I/ enal genitalia. In many instances urethroplasty for hypo-+ }$ l1 X! z; A, L
spadias is easier with previous stimulation of phallic growth.% u7 P1 c& s. \. t, L' v
The use of testosterone administered parenterally or topically6 _9 \+ w9 }) L" F. ^
has produced effective phallic growth. 1- 3 The mechanism of' V; p1 H( o- V* s1 c- }
response has been considered as local or systemic. With this
& x0 Y# }5 ]6 D8 W# g a8 p: Y+ f, w+ ?in mind we studied 5 children with microphallus for response8 U2 L, `+ x9 F2 N* o' d* z9 S
to gonadotropin and to topical testosterone independently.& ?0 v3 h, J* G2 ~3 B, n# Q
MATERIALS AND METHODS9 Y/ h3 s. b5 S9 T, E5 p9 s
Five 46 XY male subjects between 3 and 17 years old were4 f) \$ {) ]. ?/ Z. r/ {6 }1 i
evaluated for serum testosterone levels and hypothalamic
1 J+ @2 t1 N# O$ J( ]1 S, ^function. Of these 5 boys 2 were considered to have Kallmann's, P) M. I8 G/ K, X
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( \8 [' E* c. zlamic deficiency. After evaluation of response to luteinizing
) o; O. O% T' l- a( qhormone-releasing hormone these patients were treated with
3 s% g. N/ d* j; `0 u5 i1,000 units of gonadotropin weekly for 3 weeks. Six weeks" j$ l- l- R( W- \5 j
after completion of gonadotropin therapy 10 per cent topical
1 A3 v0 c! c8 b+ [3 btestosterone was applied to the phallus twice daily for 3 weeks.$ o2 x- o/ i$ `$ }) d) s9 ~' ~
Serum testosterone, luteinizing hormone and follicle-stimulat-
# u; m1 h" J3 p& U/ G- ]9 U. ting hormone were monitored before, during and after comple-' r0 N* g: N4 A" {# n9 @6 ]
tion of each phase of therapy. Penile stretch length was
" t g- T. w2 @& `2 v+ y/ \1 q* }3 ]# {obtained by measuring from the symphysis pubis to the tip of0 a& d# m3 l# ^1 \8 [. j/ g
the glans. Penile circumferential (girth) measurements were
; ^* A: `* F2 ~* D/ ?$ Qobtained using an orthopedic digital measuring device (see% C9 K& }% n/ ~
figure).3 T$ @% z9 b y+ k
RESULTS
/ P; R1 q4 I, A) V; M; e2 Z$ c( aSerum testosterone increased moderately to levels between
! S" @/ I5 ^$ k: z1 d50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" Q; L) c' _+ v. [
terone levels with topical testosterone remained near pre-
j9 U h% Y; u; n5 xtreatment levels (35 ng./dl.) or were elevated to similar levels& r& U) U6 U* n: `2 X( k
developed after gonadotropin therapy (96 ng./dl.). Higher' Q: Q( q+ n- x' Y7 I
serum levels were noted in older patients (12 and 17 years old),
1 o3 k; |# j! C2 i, [, ?" kwhile lower levels persisted in younger patients (4, 8, and 10
( _2 X: F8 s- B' g. k" Kyears old) (see table). Despite absence of profound alterations
0 b& E' L5 M6 Q& w6 Iof serum testosterone the topical therapy provided a greater; V; b6 }3 K- Y, M
Accepted for publication July 1, 1977. ·
) D' ~0 L) Y; J# u. _Read at annual meeting of American Urological Association,
+ V% c8 b3 O' d. LChicago, Illinois, April 24-28, 1977.
+ ]$ C+ F( u( q% Q; }/ n; d* Requests for reprints: Division of Urology, Henry Ford Hospital,
3 k* p- \, [- Q' S/ L* O2799 W. Grand Blvd., Detroit, Michigan 48202.3 e' q7 j5 l- F8 U3 c0 S+ U- C. j
improvement in phallic growth compared to gonadotropin.
" k/ v( j2 {0 Y0 M& W- s8 iAverage phallic growth with gonadotropin was 14.3 per cent1 F$ S( Q; [" X( W3 E. M
increase in length and 5.0 per cent increase of girth. Topical
# J" v9 p# j% Y, w* m5 jtestosterone produced a 60.0 per cent increase of phallic length: {1 |! o+ O" h
and 52.9 per cent increase of girth (circumference). The
( B8 N# ^/ @- o% b' Y2 tresponse to topical testosterone was greatest in children be-- a! V: D0 x2 ?$ Z! z- X8 [' i
tween 4 and 8 years old, with a gradual decrease to age 17
V6 @+ |& |( Q4 byears (see table).
9 y4 D) v" ]$ }' d4 D) c( u- rDISCUSSION
- |4 C/ B, V, ~0 m0 Y0 v: ETopical testosterone has been used effectively by other- D% z! [8 G3 D# b. Y. ]0 c
clinicians but its mode of action remains controversial. Im-
* @, R% y# c/ Cmergut and associates reported an excellent growth response
' {' g" v% r0 E- ^) Hto topical testosterone with low levels of serum testosterone,
4 V3 ^- g8 N7 Y; i" Tsuggesting a local effect.1 Others have obtained growth re-
. O6 o. V- F' V8 {. E7 V1 |1 W$ Asponse with high. levels of serum testosterone after topical
4 V0 }& f6 O3 X; J& g$ L- \administration, suggesting a systemic response. 3 The use of8 k$ a8 p2 y2 d# k# y% k
gonadotropin to obtain levels of serum testosterone compara-$ J) x3 H3 C* ~9 Q f* P; U8 W
ble to levels obtained with topical testosterone would seem to
+ c5 t9 r; ^* s3 G5 q5 P4 Bprovide a means to compare the relative effectiveness of
# K m, V. T; O6 R' Ytopical testosterone to systemic testosterone effect. It cer-
/ k' O4 x& t, x9 ~& o7 E: q7 [/ ?tainly has been established that gonadotropin as well as par-; p0 S C/ L" W& K+ @. o
enteral testosterone administration will produce genital
( a! v! x( u+ B6 B" ]. A( p# Ygrowth. Our report shows that the growth of the phallus was
! S* u, Y; O/ B1 jsignificantly greater with topical applications than with go-
. z. p/ b c/ onadotropin, particularly in children less than 10 years old.' r% A2 p7 I. J/ V7 y, x
The levels of serum testosterone remained similar or lower$ y5 s& I, v# L& ?% v' d" M
than with gonadotropin during therapy, suggesting that topi-" a* Q d& N: i# Y
cal application produces genital growth by its local effect as
# y9 f/ \! Q4 D) k4 e7 [" s1 Cwell as its systemic effect.
' x4 j L' |' D2 Q, z# b/ kReview of our patients and their growth response related to
- b* ]& `" ]1 R% F% _6 V% d; ~7 Dage shows a greater growth response at an earlier age. This is
2 `1 e- O- ]0 @# n& k- \. {consistent with the findings of Wilson and Walker, who
, K8 q: |! ]% p/ D& n1 Ireported an increased conversion of testosterone to dihydrotes-/ c3 V4 ?5 x0 l7 O/ K5 T. ^1 }
tosterone in the foreskin of neonates and infants.4 This activ-0 [2 [5 Z' H9 [0 o
ity gradually decreases with age until puberty when it ap-- \& N8 h- w- X8 Y; y& Y
proaches the same level of activity as peripheral skin. It may
5 p1 k8 e$ U8 U% b" ^! }6 {well be that absorption of testosterone is less when applied at
* l! m, V& K3 ^5 k) oan earlier age as suggested by lower serum levels in children
! ?- e/ e% \/ M" p* V% d, K6 Xless than 10 years old. This fact may be explained by the
5 O8 Z1 _" L7 M- F) R# T$ F- Mgreater ability of phallic skin to convert testosterone to dihy-
% }+ R6 p! S( R. i: ]drotestosterone at this age. Conversely, serum levels in older- }9 I" I! u3 g7 Z8 b i J1 u* c
patients were higher, possibly because of decreased local+ L. i3 l' D' ^7 ]0 A+ O
6671 a, R1 g! Q7 U, |! t Q
668 KLUGO AND CERNY3 p$ S$ I; P1 h, l7 V
Pt. Age D" ?# W# h( q1 Z
(yrs.)+ k& n3 k0 [: `0 @7 X5 r; Y! Z/ N
Serum Testosterone Phallus (cm.) Change Length" T: I/ j2 X' Q6 G/ A" E
(ng./dl.) Girth x Length (%)3 X/ l/ R" Y- D" _2 w* g
4
, @, p$ S, O# z: K3 z% t8 F b8* B) g6 f( d, s7 H; x9 }, r
10' e( C( H: l& F, Z4 x
12
9 K# O( J; I3 y17
: Q- B( v9 j% {) Y& m5 WGonadotropin: c0 B- |5 C( y- a8 z. y: t
71.6 2.0 X 3 16.61 V) @/ F! p" E! u; j( t$ T1 {
50.4 4.0 X 5.0 20.0, D0 d1 R- }1 m; f8 p' W' o+ m* y
22.0 4.5 X 4.0 25.0
' G! i0 G) D$ }- N84.6 4.0 X 4.5 11.1# C: b8 I' I) V8 u1 e4 ~9 w% f
85.9 4.5 X 5.5 9.0
. J2 B6 L$ ?% I$ W! j) yAv. 14.3
4 O; d( \; z3 ?) ?8 X4! x* K: L3 l' [4 Q8 o" Y$ J
85 B6 Z) T9 J: [
106 V2 `1 V& w H4 B4 c
12
, G( Z a. W" ~. A& ?174 b( J$ B0 N# K R. E4 `* p
Topical testosterone; t: y" ?# s6 {7 W5 r' i7 ~5 W
34.6 4.5 X 6.5 853 S7 y8 g+ K! }- K# x
38.8 6.0 X 8.5 705 x- F# i A; @2 O1 k9 v; n) Q& W t
40.0 6.0 X 6.5 62.57 v+ a* V* g$ y# m/ q' i- A
93.6 6.0 X 7.0 55.5' q# [1 m3 z' B& e2 u
95.0 6.5 X 7.0 27.2
/ _8 l: [, s2 Z. yAv. 60.0; g- Z3 Y, [& }# m9 \. ?- O, y
available testosterone. Again, emphasis should be placed on
9 d) X4 \+ Q! J, E- g7 h7 qearly therapy when lower levels of testosterone appear to
9 N4 Y3 L& J3 U6 ^5 G M3 N+ nprovide the best responses. The earlier therapy is instituted
& F$ y) W" U; F0 Dthe more likely there will be an excellent response with low
1 f( [! b- e& i' m+ \serum levels. Response occurs throughout adolescence as
$ K! n7 T. Q- n: A* I& Z! t9 anoted in nomograms of phallic growth. 7 The actual response
( u# P$ Z& l2 W5 M1 v" f5 ~to a given serum level of testosterone is much greater at birth7 p4 j# ~+ ~ H/ l
and gradually decreases as boys reach puberty. This is most
2 u( Z9 e( A3 V% Zlikely related to the conversion of testosterone to dihydrotes-4 x f; ~4 t5 P- V
tosterone and correlates well with the studies of testosterone
6 N+ t% C7 O kconversion in foreskin at various ages.
0 Z1 S* k/ H3 q8 U5 iThe question arises regarding early treatment as to whether' X K, u# L0 s1 D8 ^; r1 F
one might sacrifice ultimate potential growth as with acceler-$ P% g" u, Z( W/ [2 n& e
ated bone growth. The situation appears quite the reverse
2 v1 R7 z, ~7 o4 g/ ~with phallic response. If the early growth period is not used
+ A R- r1 q0 iwhen 5a reductase activity is greatest then potential growth
% K `$ i% d1 Q) `1 t: Amay be lost. We have not observed any regression of growth' W ^( k, _; o! B
attained with topical or gonadotropin therapy. It may well
6 Z3 K5 o1 I1 e7 ^0 ]& Abe that some patients will show little or no response to any/ b3 \& T+ K2 X* J, q
form of therapy. This would suggest a defect in the ability to
) m4 W6 @2 @, l4 [0 c/ B( w% {convert testosterone to dihydrotestosterone and indicate that: }5 ^$ i6 B& X7 n
phallic and peripheral skin, and subcutaneous tissue should7 q) B; i- n5 B/ c7 I
be compared for 5a reductase activity.: l9 Y% g. U ?( ~; Y. I
A, loop enlarges to measure penile girth in millimeters. B,
1 W- J+ {. o, j% B4 l- ?; e* s* Hexample of penile girth computed easily and accurately.
" W7 O. K8 r2 m# \* K; mconversion of testosterone to dihydrotestosterone. It is in this2 N& {; `% T X8 }1 u5 q$ a& d
older group that others have noted high levels of serum" _- m' h3 C$ y! L+ r7 z
testosterone with topical application. It would also appear5 k$ {! g1 \$ P# I& }# e
that phallic response during puberty is related directly to the0 D6 W. t, }+ F. _! Q9 v( k
serum testosterone level. There also is other evidence of local6 f1 f# |) f8 x, Y/ H+ s/ T u
response to testosterone with hair growth and with spermato-9 S7 v7 l. p, h0 q0 Y
genesis. 5• 6
. _0 `7 H) u( Z& w4 x, IAdministration of larger doses of gonadotropin or systemic
8 s/ K# A) p: M; ^! x$ Ttestosterone, as well as topical applications that produce
; Q4 o2 q" T W) U3 A2 B/ [7 g3 Ghigher levels of serum testosterone (150 to 900 ng./dl.), will
# z) ?5 r2 u( p* Qalso produce phallic growth but risks accelerated skeletal
6 V( R- R9 v; s! k nmaturation even after stopping treatment. It would appear
! M# S/ ]# g, G8 C2 g+ X% U2 `that this may be avoided by topical applications of testosterone
! L, a& `: {8 O, l* F* W6 V% nand monitoring of serum testosterone. Even with this control
3 M! K( P0 y, I4 B) P6 G) a2 gthe duration of our therapy did not exceed 3 weeks at any
, [ m8 q8 X. ftime. It is apparent that the prepuberal male subject may4 f8 U; Q+ w- q3 k2 T2 Z8 Y
suffer accelerated bone growth with testosterone levels near
3 M4 `' Q/ Z5 K. w6 w200 ng./dl. When skeletal maturation is complete the level of
- [) U6 v [; p# b' Q3 B# N% jserum testosterone can be maintained in the 700 to 1,300 ng./
# |- g. Y/ u K, K! udl. range to stimulate phallic growth and secondary sexual# j5 `$ F. s, n6 j, [' \# w7 e* a
changes. Therefore, after skeletal maturation parenteral tes-
# ?! N6 X1 T6 r' J$ stosterone may be used to advantage. Before skeletal matura-+ ?& c, r' r: t2 r
tion care must be taken to avoid maintaining levels of serum+ J4 ]# N4 D6 D& A A. U# z
testosterone more than 100 ng./dl. Low-dose gonadotropin! F* `4 @/ r# g/ e" H3 h* ^
depends upon intrinsic testicular activity and may require
& W$ t7 x' j T# y7 Y# b6 Fprolonged administration for any response.- b; x7 y' D0 W6 m, L. `3 K
Alternately, topical testosterone does not depend upon tes-
; \- t2 ]4 w# M+ u6 C) g Iticular function and may provide a more constant level of g& v& d# _3 E3 t: O3 V
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9 Z. L$ I2 n/ t6 `* g# }$ B! i" J1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
- ^/ ]9 Z0 j' l5 eR.: The local application of testosterone cream to the prepub-
/ G9 n" }1 z% W% Nertal phallus. J. Urol., 105: 905, 1971./ a7 i. v/ T6 ?$ Y2 {2 O0 y. K
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone0 \. i+ S. X3 z( e: K( m
treatment for micropenis during early childhood. J. Pediat.,
$ M3 ?8 N$ H& H9 g- s- L+ n- y83: 247, 1973.
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one therapy for penile growth. Urology, 6: 708, 1975.0 }: e) n8 }: \8 O9 v4 @# D# R6 g
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 S1 K& z' i {+ B! u
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- x9 [- o1 O& Q7 u% eskin slices of man. J. Clin. Invest., 48: 371, 1969.# Q' v5 I- N* K7 R+ V9 f2 ~
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 {( y0 b/ J4 p0 r3 M4 y
by topical application of androgens. J.A.M.A., 191: 521, 1965.; R* m( O7 x. s6 ^1 q
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local# M- L9 l3 a; J( t
androgenic effect of interstitial cell tumor of the testis. J.
( t6 P4 Z- W; E" x+ {8 L; hUrol., 104: 774, 1970.
9 Z& |6 h5 {" P: @- D6 {7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 s6 y7 J& z8 v
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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