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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 d9 S) A8 {; ~( L$ S6 \
GONADOTROPIN* c7 K" n: K6 P6 t
RICHARD C. KLUGO* AND JOSEPH C. CERNY$ ?+ b" l( ]1 i$ `/ k, f
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 z- R9 J0 ?6 A5 U2 S% L" dABSTRACT/ @: O) r2 u9 k% N& G! y
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
; E( ?' {0 u* h) S+ j) j- iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ E. e1 k7 `! K0 Y9 t
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ F( m% Y5 f9 ?& @3 q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
& V* E) K, r4 d$ W$ y& B* sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# k) L' ~9 L# C4 ~
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average* { X' C/ t- c+ R2 @
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 C6 z& N* k$ ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 v1 j7 l1 N+ b0 ]
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile g; y q* L1 U1 j1 N1 w$ i* h
growth. The response appears to be greater in younger children, which is consistent with previ-4 M8 W% ^( p. z1 L
ously published studies of age-related 5 reductase activity.
$ f! q7 I' ]+ b+ ^6 v) DChildren with microphallus regardless of its etiology will
, { E3 ]$ }% {$ nrequire augmentation or consideration for alteration of exter-; B" w+ T2 |0 `. N! ]: o
nal genitalia. In many instances urethroplasty for hypo-
' O% G8 }% P" z" Fspadias is easier with previous stimulation of phallic growth.( Q7 g [ D3 w! f+ J2 j
The use of testosterone administered parenterally or topically/ L$ W1 h6 q% W1 q+ Y4 K- L5 u* C9 G
has produced effective phallic growth. 1- 3 The mechanism of2 q! e0 g# d5 }0 w) q- p8 [+ C6 Z
response has been considered as local or systemic. With this
. Z! ?4 D" h! \& Q2 A& P7 ain mind we studied 5 children with microphallus for response
?! h5 x1 F% O& K6 J, V+ I1 w6 b& |, [8 Qto gonadotropin and to topical testosterone independently.
f7 I+ E! @0 G& h9 nMATERIALS AND METHODS1 W; q3 {8 }9 d
Five 46 XY male subjects between 3 and 17 years old were5 W q7 G7 u8 b( A
evaluated for serum testosterone levels and hypothalamic( T! X2 X2 R9 K) y& Y* C# ?
function. Of these 5 boys 2 were considered to have Kallmann's5 n' k) A' D8 x- a
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ z! V7 }! R" J9 ~lamic deficiency. After evaluation of response to luteinizing
# X9 F/ } ]5 p4 Q2 W5 chormone-releasing hormone these patients were treated with
: T* l+ {9 w; y8 ]0 M( p1,000 units of gonadotropin weekly for 3 weeks. Six weeks% Z: s7 ]) a W$ h1 s
after completion of gonadotropin therapy 10 per cent topical6 l- A& i* [- X* m: \* N( Z0 U
testosterone was applied to the phallus twice daily for 3 weeks.$ S+ Z% `/ g& H: x& F2 U7 W4 a" _
Serum testosterone, luteinizing hormone and follicle-stimulat-- q& {5 x2 }* t4 D- O! E
ing hormone were monitored before, during and after comple-
' e, Q ]( [% k- o- C7 i/ Ltion of each phase of therapy. Penile stretch length was5 @6 n. x5 z8 N3 v1 @2 V
obtained by measuring from the symphysis pubis to the tip of" O: v% \- H, n$ O8 M- P1 q* b8 _7 T, ]
the glans. Penile circumferential (girth) measurements were
! U) r; z% Y$ s5 S4 |9 a" K9 cobtained using an orthopedic digital measuring device (see
& {" q+ y: m! Xfigure).
( O: M T8 {& ~+ F& i& m* g# S2 v+ fRESULTS& ?5 h, o( {- d, B" P) U& q
Serum testosterone increased moderately to levels between( \- B- u9 E# A' M( ~, X: q8 P
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# J. i0 e' B# gterone levels with topical testosterone remained near pre-
2 Y2 @' [7 Y6 o ]& A F4 Btreatment levels (35 ng./dl.) or were elevated to similar levels3 T! v( e y3 p. [
developed after gonadotropin therapy (96 ng./dl.). Higher' O; `1 z. u1 t0 G! o
serum levels were noted in older patients (12 and 17 years old),0 t% v4 w/ ~2 \- N6 c) x
while lower levels persisted in younger patients (4, 8, and 10
! e. X2 n/ B/ X3 hyears old) (see table). Despite absence of profound alterations5 V+ j- Q1 K# f' `2 T
of serum testosterone the topical therapy provided a greater- l6 H" f% ~0 p2 P* t
Accepted for publication July 1, 1977. ·
+ `' a% ]) X) R* }) t# w& w" BRead at annual meeting of American Urological Association,* q. n# j4 v) M/ \% }7 N: z- p6 }
Chicago, Illinois, April 24-28, 1977.
. l: k+ G! l' F* Requests for reprints: Division of Urology, Henry Ford Hospital,, I( c) L( C" L* W* l
2799 W. Grand Blvd., Detroit, Michigan 48202.7 C- g# _1 k r* g) a/ |
improvement in phallic growth compared to gonadotropin.
T% O& h/ G+ R9 A* b' bAverage phallic growth with gonadotropin was 14.3 per cent
/ @2 H" }/ W+ J* O( K# [increase in length and 5.0 per cent increase of girth. Topical
' p0 s v' e4 [testosterone produced a 60.0 per cent increase of phallic length" P% _2 }! q& P8 w( }$ t
and 52.9 per cent increase of girth (circumference). The! X, D# c$ Z8 C& x5 _5 C7 b
response to topical testosterone was greatest in children be-
' C# i- G& g" t1 M: [+ h7 ]tween 4 and 8 years old, with a gradual decrease to age 175 @5 D$ g: R; r, z
years (see table).& s C6 I X/ m" c% l8 p5 a
DISCUSSION# N/ I9 W4 X# x: y) M9 c
Topical testosterone has been used effectively by other
: ?. k7 J# {) V3 t; F- dclinicians but its mode of action remains controversial. Im-
, S& z; ], o6 h1 ?9 i& `& u" _& p4 Vmergut and associates reported an excellent growth response
6 G0 a& ?* m! V* @+ s& ato topical testosterone with low levels of serum testosterone,
" f! k6 Q+ G1 O3 Ysuggesting a local effect.1 Others have obtained growth re-
: [( u' t$ \- I; V- j& d6 X; r: Hsponse with high. levels of serum testosterone after topical
( D) G( E# b# E. x; o, F5 _6 e* eadministration, suggesting a systemic response. 3 The use of
! o2 m1 [5 d( M k& l" w: l4 {gonadotropin to obtain levels of serum testosterone compara- G' d6 B. M' j" W+ `5 n- J( ?
ble to levels obtained with topical testosterone would seem to
: ~0 c5 W+ K+ U) wprovide a means to compare the relative effectiveness of
3 G* F& x. b) }# C; \: r) P. wtopical testosterone to systemic testosterone effect. It cer-
) a2 P2 R0 `" f' Rtainly has been established that gonadotropin as well as par-+ a5 k7 ^* \3 a5 g7 Q5 v
enteral testosterone administration will produce genital
9 @, O- K. p) Qgrowth. Our report shows that the growth of the phallus was
& _" z, N% S3 Y5 ?# isignificantly greater with topical applications than with go- d2 B N! d# {/ `, f/ D P
nadotropin, particularly in children less than 10 years old.
. O$ x, x9 D: L# ]# N: v: oThe levels of serum testosterone remained similar or lower0 M+ \# C2 g& @" O1 L
than with gonadotropin during therapy, suggesting that topi-
3 m! [/ [8 x/ ?- r; Wcal application produces genital growth by its local effect as. v0 O) Q$ @+ x% a- X' s: j
well as its systemic effect. v; i" `0 d$ @% _3 |" I( C' w8 l
Review of our patients and their growth response related to2 U1 V/ q& _5 ^5 x$ A
age shows a greater growth response at an earlier age. This is
% C" R; ?4 m! H* t" cconsistent with the findings of Wilson and Walker, who
: Y6 N) n- c/ `2 U0 F; ^) Nreported an increased conversion of testosterone to dihydrotes-
( i7 o4 H. \, atosterone in the foreskin of neonates and infants.4 This activ-: ]7 o/ q. l3 R5 v4 B" \0 d
ity gradually decreases with age until puberty when it ap-
: q' T4 h8 V2 D6 k5 eproaches the same level of activity as peripheral skin. It may
+ P* G& l, A( q9 s; L7 ~$ Awell be that absorption of testosterone is less when applied at
& v1 X& ~2 G0 v: aan earlier age as suggested by lower serum levels in children8 m1 t+ l- ^0 n8 {
less than 10 years old. This fact may be explained by the) Z2 P4 Q4 ]1 q6 ?, X
greater ability of phallic skin to convert testosterone to dihy-( R" }- B2 I+ V# M r. S5 B1 g9 X
drotestosterone at this age. Conversely, serum levels in older2 l* D4 L4 O" o* l7 ^
patients were higher, possibly because of decreased local, W- A/ k$ q# M/ C
6670 j( u; W7 p) T0 p5 y$ t
668 KLUGO AND CERNY) X" ~ @* a& V* j4 G/ l
Pt. Age Z" m- X1 O6 F0 }8 @
(yrs.)
( U$ R4 L: t* d0 c0 M) R4 o$ k% N# t6 xSerum Testosterone Phallus (cm.) Change Length
m9 ^- V3 c }, F(ng./dl.) Girth x Length (%): s. J! w6 T2 E9 B8 e2 C
4% s% i9 {" D- A0 o, }
8' X; n, h( y# V$ W
10: }. n7 ^, u7 `
127 c* O8 s* g/ T
175 G. y& N3 U6 g, f
Gonadotropin
$ p( @! b; o7 a0 s1 B71.6 2.0 X 3 16.6. C8 r; c( {! R. F3 e% s. w' y
50.4 4.0 X 5.0 20.00 B0 B/ s" c0 D( b/ T5 h8 Y
22.0 4.5 X 4.0 25.01 O p- t& T( |* @5 \: |- Q; u
84.6 4.0 X 4.5 11.12 v. u, f' r+ J
85.9 4.5 X 5.5 9.0
2 I% \7 T/ R1 Z `0 Y# VAv. 14.33 K1 C8 s- h8 e
4" K3 A8 w& s: K
8
3 P$ u7 T- W. ~10
Z7 H* p; u" i6 K9 w4 u6 J$ G, h) e12
) t7 W R% D+ o2 K$ A/ O17
0 `/ |0 G0 Q3 o u* STopical testosterone7 N N8 j, w+ H% a6 c
34.6 4.5 X 6.5 856 E: v7 {8 [0 N+ ]; p
38.8 6.0 X 8.5 70
5 e( z U0 F& g% h6 K) J40.0 6.0 X 6.5 62.5
/ T; h {9 z. m- ~93.6 6.0 X 7.0 55.5
9 g9 B1 Z& E8 D2 Q5 |8 Y0 w95.0 6.5 X 7.0 27.26 x" f& Y c m
Av. 60.0
3 f+ g! t# i9 @/ \8 `) I- b0 javailable testosterone. Again, emphasis should be placed on
$ L- B: }6 Q# G0 F# ]7 _7 ~& nearly therapy when lower levels of testosterone appear to2 b/ E- R. j4 w' F8 M- ^3 D
provide the best responses. The earlier therapy is instituted
5 _2 {- t3 {5 D8 n# m- T; @6 K- Lthe more likely there will be an excellent response with low3 I8 a5 k; O% G, _0 Z
serum levels. Response occurs throughout adolescence as: X, X% c: {6 d" l: [* [( |/ S; G
noted in nomograms of phallic growth. 7 The actual response: o6 ~9 o* R: A2 j; y
to a given serum level of testosterone is much greater at birth: a$ I8 m, V3 ?; k# W: R) G- W% y
and gradually decreases as boys reach puberty. This is most& Y- B+ |1 s) h8 K4 {; ]8 [
likely related to the conversion of testosterone to dihydrotes-
" S1 [7 O$ P# u) w, U& ntosterone and correlates well with the studies of testosterone+ G8 W% Z4 C$ }5 T: K) T
conversion in foreskin at various ages.
$ `" Z4 k0 r6 A: ` TThe question arises regarding early treatment as to whether
' p! C8 C: k1 X F* fone might sacrifice ultimate potential growth as with acceler-
* G& ?5 A' T; I; I `! k1 j5 eated bone growth. The situation appears quite the reverse
" b. c" v& o; F. a2 f+ v. bwith phallic response. If the early growth period is not used
1 L+ ?- D7 n9 O6 x% n4 u. nwhen 5a reductase activity is greatest then potential growth
2 F+ j- o; k1 [2 L" M& tmay be lost. We have not observed any regression of growth7 a' p! H z3 m4 Q$ k5 a
attained with topical or gonadotropin therapy. It may well
* C3 l) u# i) Dbe that some patients will show little or no response to any: K ]) ~/ D4 r$ O* {
form of therapy. This would suggest a defect in the ability to
7 a% x" n* F8 Q4 h& }convert testosterone to dihydrotestosterone and indicate that
: |8 S: r' g5 L+ Uphallic and peripheral skin, and subcutaneous tissue should+ g h4 t! S0 _( |; S+ K: V( M
be compared for 5a reductase activity.
; o2 Q; }* q, T4 `6 Y8 \6 u! BA, loop enlarges to measure penile girth in millimeters. B,: Y0 ?3 B- U) ~& V( }% I
example of penile girth computed easily and accurately.% T: t. k" h' } w$ U9 i
conversion of testosterone to dihydrotestosterone. It is in this
. D, z0 D' P( X( dolder group that others have noted high levels of serum3 d4 |( N1 b: l/ q" v
testosterone with topical application. It would also appear
4 m! e9 h8 p8 c" gthat phallic response during puberty is related directly to the8 x2 Q# @" u. v3 _: w" V
serum testosterone level. There also is other evidence of local
# l9 T7 f6 g) K4 [- y4 q0 Q$ A* _/ Uresponse to testosterone with hair growth and with spermato-7 ?, _5 N- O7 O3 J& x& {
genesis. 5• 6
6 ^' h, S7 N3 ^Administration of larger doses of gonadotropin or systemic
6 {8 D# u$ K5 y5 T' p, f3 ]) N6 m! Qtestosterone, as well as topical applications that produce
5 v8 b6 |- X' j2 ]' i' g; }higher levels of serum testosterone (150 to 900 ng./dl.), will
# b# h$ |! U& K+ }# p9 ^; o1 {, Ealso produce phallic growth but risks accelerated skeletal/ Z7 P' x' t! E
maturation even after stopping treatment. It would appear" b' R4 T) |4 k: u# L) p
that this may be avoided by topical applications of testosterone
- F6 I, b( s6 f. t! }and monitoring of serum testosterone. Even with this control
2 ~1 U/ T1 L+ @) l/ R+ ]2 k; othe duration of our therapy did not exceed 3 weeks at any( E. x- E" p M0 y# \: U: D( B; N
time. It is apparent that the prepuberal male subject may
1 j; w7 O: r, l7 d/ X* C% |1 ~suffer accelerated bone growth with testosterone levels near( |- B, w" R4 s
200 ng./dl. When skeletal maturation is complete the level of
& }1 {% o* D5 y0 B e& [6 Dserum testosterone can be maintained in the 700 to 1,300 ng./
7 V% P( c( c' e* c- d2 t% }dl. range to stimulate phallic growth and secondary sexual
$ x7 `4 N$ ~ ~5 \/ D" gchanges. Therefore, after skeletal maturation parenteral tes-; j! f) b* W, h4 h w4 v' P5 w
tosterone may be used to advantage. Before skeletal matura-' f0 E+ H: ~0 N2 T
tion care must be taken to avoid maintaining levels of serum
0 \$ X1 C4 }: A" Q: P- b" Etestosterone more than 100 ng./dl. Low-dose gonadotropin
1 q( u3 V2 h) \: @. [8 ^depends upon intrinsic testicular activity and may require" d! t3 k y: h% Q3 E( k
prolonged administration for any response.
. |. `- E# K. Z) E/ JAlternately, topical testosterone does not depend upon tes-9 [' ]1 Q/ q* R8 ?3 ^+ ~
ticular function and may provide a more constant level of# V ~- `! L/ h" ?
REFERENCES" p+ V. n$ {; {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,4 y/ z. ]3 X8 z4 }
R.: The local application of testosterone cream to the prepub-
/ W, ]* E) ^6 t; n$ Jertal phallus. J. Urol., 105: 905, 1971.( b" p4 C/ f, p% N6 V# ]6 N
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 l4 y2 L8 ^8 x* ?6 ]9 Ztreatment for micropenis during early childhood. J. Pediat.,. L. F1 e! ^! Y0 @
83: 247, 1973.' c2 w d! f! n! b q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 P& z/ P9 c5 n; H" Qone therapy for penile growth. Urology, 6: 708, 1975.
& c+ h( r/ _# K; z& I0 d' g" p4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ h4 V8 `4 l7 ]* S' E. Vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" U$ v* p7 y1 P9 X% Oskin slices of man. J. Clin. Invest., 48: 371, 1969.
. `6 E' \1 Z: F( E( m4 W6 s5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 {/ Q8 f! _$ S4 a5 t! J* `
by topical application of androgens. J.A.M.A., 191: 521, 1965.
* L) ]0 a1 y3 g6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# w* \4 o3 A; `$ m Qandrogenic effect of interstitial cell tumor of the testis. J.
% \; }( s2 o Y9 W2 e% _0 Q; L- MUrol., 104: 774, 1970., p* Y$ _7 h% ~& z) F" Y) L
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-+ R' |& h* U/ I: w! _% c
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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