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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 ?$ P A, w0 h; f; c
GONADOTROPIN2 }2 \2 o4 Q8 f ~5 f9 v) f$ u
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 i8 O/ V5 C9 MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' d1 s: u: V* M) K, W6 z6 B. M8 y
ABSTRACT8 M3 D- \2 C- i. @6 t) l9 m
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 ?$ i9 X8 [' cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& M/ d, m+ D4 c* i/ G1 g) Ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# ]9 @, L& c: j, W, ~0 v E4 Ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 S+ d) N8 f# E' v2 s* r1 `( N
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* [4 n% U% k5 m9 J: xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 K9 \, ~6 i) W G4 `
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
9 y& T2 x# T0 K9 a7 b; G0 ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 C# _0 w! \% I+ wstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- v" p+ h Z, ygrowth. The response appears to be greater in younger children, which is consistent with previ-1 d9 b4 O5 `/ O8 D- Y# `) m
ously published studies of age-related 5 reductase activity.
7 u# o, }6 v1 R! JChildren with microphallus regardless of its etiology will
# b$ {2 K& a- @$ @5 j4 f" e0 @require augmentation or consideration for alteration of exter-# N* m: v2 D4 U
nal genitalia. In many instances urethroplasty for hypo-
$ N1 z9 _5 ?8 s O4 v' s+ b8 Kspadias is easier with previous stimulation of phallic growth.8 Z6 w# m; v) }3 h# J R
The use of testosterone administered parenterally or topically' z4 W/ F7 g$ Y* V/ Q; Q( u
has produced effective phallic growth. 1- 3 The mechanism of9 c7 C& M% ^! n0 E# T8 d
response has been considered as local or systemic. With this4 a8 |; p! Y. J) y/ ]' w, W% Z3 k5 c, k
in mind we studied 5 children with microphallus for response
# q! K3 N ^! f2 ?4 o3 ato gonadotropin and to topical testosterone independently.
* `* |; c8 r: `: S' ]MATERIALS AND METHODS
5 c1 J. r- I- J# F* R( WFive 46 XY male subjects between 3 and 17 years old were
0 u# ]& V- _. {. S2 levaluated for serum testosterone levels and hypothalamic0 l8 M. h, O5 X i. V) u, @
function. Of these 5 boys 2 were considered to have Kallmann's
# V5 G7 E6 l$ C2 ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 g2 ^; O( s- w' B+ ]7 N( q L9 Xlamic deficiency. After evaluation of response to luteinizing3 b, M# W @" C( k9 ]
hormone-releasing hormone these patients were treated with
1 b, {5 P* D# y7 o. `1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 r. W1 M- ?1 b8 a) g) S2 F& o
after completion of gonadotropin therapy 10 per cent topical, l$ B ] s: V7 ~
testosterone was applied to the phallus twice daily for 3 weeks. P* P) s# _; k5 ?" ]
Serum testosterone, luteinizing hormone and follicle-stimulat-- t' n9 R4 W# e$ q) H2 V0 I
ing hormone were monitored before, during and after comple-# j! F# j: D6 z( F) [
tion of each phase of therapy. Penile stretch length was
d. O* {4 V: U. R' Nobtained by measuring from the symphysis pubis to the tip of; p# g3 ^; x/ W% c4 ~6 X+ G& U
the glans. Penile circumferential (girth) measurements were
" ?0 h* H. r9 @ U' s0 Hobtained using an orthopedic digital measuring device (see
; f* q3 }- m5 w: u: E: ufigure).
2 W3 q. C+ M* NRESULTS
5 K& P5 o- h' [/ FSerum testosterone increased moderately to levels between
' \# Y9 ~/ m* D50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 o3 e0 _ e; ^1 c4 Y5 X; J7 n
terone levels with topical testosterone remained near pre-( t& r1 N/ ^3 a! W5 _9 H( c s/ E
treatment levels (35 ng./dl.) or were elevated to similar levels
8 K0 C0 q- p* f3 Bdeveloped after gonadotropin therapy (96 ng./dl.). Higher$ y9 M# Y2 ]/ y9 ^* v$ X. R
serum levels were noted in older patients (12 and 17 years old),
" K+ I |6 B- \, H4 _while lower levels persisted in younger patients (4, 8, and 10
7 {& s6 y3 w; D" vyears old) (see table). Despite absence of profound alterations
2 [: ]6 M7 v! y9 U1 J4 @' S8 Z; h) Cof serum testosterone the topical therapy provided a greater
( K* y* R2 g; J5 J R0 S4 A zAccepted for publication July 1, 1977. ·8 C( R# X- P3 N+ Q1 B, s
Read at annual meeting of American Urological Association,
: d. |( F) B# z$ K/ qChicago, Illinois, April 24-28, 1977.
3 X& x$ j; M1 x2 Y) S+ i" ^* Requests for reprints: Division of Urology, Henry Ford Hospital,
% [6 Z: [, m- {; o5 ~2799 W. Grand Blvd., Detroit, Michigan 48202.# y2 o$ m! z% _/ @3 l: C
improvement in phallic growth compared to gonadotropin.
$ h" Z5 e+ R' a$ E3 A6 F$ yAverage phallic growth with gonadotropin was 14.3 per cent1 c7 R4 A7 Q. t
increase in length and 5.0 per cent increase of girth. Topical
9 B' |8 a8 {- ^testosterone produced a 60.0 per cent increase of phallic length8 R2 x; t: g7 d1 j
and 52.9 per cent increase of girth (circumference). The' B5 x" M6 T! A$ L% M* b
response to topical testosterone was greatest in children be-2 N3 w# S ]) F; {! ?0 @
tween 4 and 8 years old, with a gradual decrease to age 17# L w+ b$ X6 e, H3 B% G
years (see table).
/ @ V% N8 j7 WDISCUSSION1 f) U5 T; Z9 {) V
Topical testosterone has been used effectively by other p1 |, P3 ]# ^% G6 b5 L
clinicians but its mode of action remains controversial. Im-
+ |# R0 \8 b: F5 K8 \) l, y+ ~mergut and associates reported an excellent growth response1 v. P. @5 [) U) y* }* i
to topical testosterone with low levels of serum testosterone,
9 q( Y& ^2 d, |- wsuggesting a local effect.1 Others have obtained growth re-
8 O- y+ B% Z3 j# C9 ysponse with high. levels of serum testosterone after topical
+ r: W# n/ L/ `+ x. E, M+ _administration, suggesting a systemic response. 3 The use of
G/ K9 i9 R" [" }7 [' {gonadotropin to obtain levels of serum testosterone compara-
7 k& [* F! e" T6 T. a1 xble to levels obtained with topical testosterone would seem to
7 k; J) M# T! ]# b! Fprovide a means to compare the relative effectiveness of: \0 b+ y2 M3 i% m2 @$ Q9 f1 z$ G- N; q9 k
topical testosterone to systemic testosterone effect. It cer-! |! F/ l5 I6 I( M8 }! P
tainly has been established that gonadotropin as well as par-' y. U+ | ]' g) I: q
enteral testosterone administration will produce genital8 I% C, e2 ?1 t( f0 o S
growth. Our report shows that the growth of the phallus was7 U3 w6 L- H. {$ v
significantly greater with topical applications than with go-5 G$ y$ ]0 x8 o- q* _) p2 T
nadotropin, particularly in children less than 10 years old.2 E7 d2 x& K. H4 ` t; j
The levels of serum testosterone remained similar or lower- Y Z1 g. u) E$ u( N
than with gonadotropin during therapy, suggesting that topi-
; h2 E6 g4 L) F2 i- f8 P! ocal application produces genital growth by its local effect as1 {: a# c! Y( N
well as its systemic effect.( j2 S) C$ R7 W2 ^. Q# H: d/ A
Review of our patients and their growth response related to# d5 ]% ]/ f n/ q
age shows a greater growth response at an earlier age. This is4 }9 j7 ~: \4 Y$ ]' z# f/ ?) H
consistent with the findings of Wilson and Walker, who1 b% c1 P6 U% V# [ i$ \$ x# P1 J
reported an increased conversion of testosterone to dihydrotes- ^+ L9 J* f. G& n% k% g
tosterone in the foreskin of neonates and infants.4 This activ-8 m7 t# k4 |) G6 z# t, ?+ x. d S
ity gradually decreases with age until puberty when it ap- t" U" ~( K5 q0 U( d
proaches the same level of activity as peripheral skin. It may
& g9 [9 c) N7 C2 Gwell be that absorption of testosterone is less when applied at5 @4 h7 {" {. B2 e7 H
an earlier age as suggested by lower serum levels in children" h/ T4 A3 S) ~
less than 10 years old. This fact may be explained by the
$ { {+ L; e4 r! p6 L& rgreater ability of phallic skin to convert testosterone to dihy-
8 ?# _' P% i- w o8 Wdrotestosterone at this age. Conversely, serum levels in older% {& F& W2 Q- H1 Z4 v
patients were higher, possibly because of decreased local0 M; T. V* U( k& N, P
667! Q0 |+ j3 m7 g
668 KLUGO AND CERNY
( e3 U$ O* _. G9 j5 s/ ]- D; a! zPt. Age
' L1 Y: y5 R% T/ g4 C) F( X(yrs.)
. n7 N, l2 c2 q, g E' A: [Serum Testosterone Phallus (cm.) Change Length
9 c2 N( s* ?* K& |7 g(ng./dl.) Girth x Length (%)% P8 u" ? j& N# v |
4
5 U, A8 _7 W$ o1 I8
, f' F( v$ M3 b9 A10
; D8 U0 m6 F: \- a2 a* E6 ^120 u5 s4 E9 ~. W* E: W& s% B
17! V' i1 F8 d! B8 D6 J( e; o. Y
Gonadotropin# ?0 H( d: I* C7 ?
71.6 2.0 X 3 16.6
- q9 N" o- P; {+ a5 s50.4 4.0 X 5.0 20.0
% b8 q2 B5 c7 I; {0 N22.0 4.5 X 4.0 25.0
1 W5 U9 }/ C1 H' Z8 L# q" X0 X$ K4 w84.6 4.0 X 4.5 11.1/ u: S0 J3 n. x, i
85.9 4.5 X 5.5 9.04 p/ N# E4 x; l) B- B
Av. 14.3
2 ^3 Y* Z, U, g, i' x) v8 J0 H1 o+ H4
: z. x# v6 q7 T0 M88 I! h, Z9 }6 S! N
10
# m1 M; n. `2 X" ~; Q: p* x2 L122 e5 m4 J. P- q$ E" A0 W6 R
17" n X8 J/ z: s" F/ i: c7 l
Topical testosterone1 E* p& B6 @, J& a* Q1 y# n
34.6 4.5 X 6.5 855 c/ a* X! D, T: `7 }6 b
38.8 6.0 X 8.5 70; x9 T4 Z& [* i4 o7 w
40.0 6.0 X 6.5 62.54 O& r' ?# b8 z. w3 g# A
93.6 6.0 X 7.0 55.5
& u* B8 A3 U% I7 `5 ~/ }95.0 6.5 X 7.0 27.2
- p$ R0 V* {8 rAv. 60.0. K& s7 C8 N- a, W2 |: v
available testosterone. Again, emphasis should be placed on
- `# H5 y0 u, j4 `% h% E/ ?early therapy when lower levels of testosterone appear to
* C9 T% f+ N5 \4 d, S" X1 Aprovide the best responses. The earlier therapy is instituted
; }5 N9 N! n! d1 P) @the more likely there will be an excellent response with low! F; n* d# _0 t- o p
serum levels. Response occurs throughout adolescence as
0 _& J' P2 t$ ~& Dnoted in nomograms of phallic growth. 7 The actual response' K* A7 D* `8 W, b6 O% ]) _
to a given serum level of testosterone is much greater at birth/ z, ~& b% ^" o. l( ~+ Q# G) ?6 \0 G
and gradually decreases as boys reach puberty. This is most g% X+ `$ R! ^& Q
likely related to the conversion of testosterone to dihydrotes-8 E. ^& v% {5 \% l& x# [
tosterone and correlates well with the studies of testosterone
: d! F( a. |: h. `6 ^8 Kconversion in foreskin at various ages.
$ J" @/ B9 m7 P" A4 Y+ |$ c, {The question arises regarding early treatment as to whether
7 |* ?" E1 W( R; _% R$ _4 Zone might sacrifice ultimate potential growth as with acceler-
; F9 s0 O4 p" Q. Q; R# ^ated bone growth. The situation appears quite the reverse
$ s3 |& U+ ~% p' \/ Nwith phallic response. If the early growth period is not used
8 ]3 ?: n% ~4 o9 F6 ^' Qwhen 5a reductase activity is greatest then potential growth
5 _/ ^ M, F7 \4 h) [8 O7 q! [may be lost. We have not observed any regression of growth
, M: x. B2 E4 Q Sattained with topical or gonadotropin therapy. It may well
0 a# n3 D. `# ?, h4 t/ ~1 M! S6 J4 qbe that some patients will show little or no response to any
/ c: |, S6 r; \0 q1 I, D4 Uform of therapy. This would suggest a defect in the ability to2 c, A0 G2 [/ h* i1 p- \( ^' _
convert testosterone to dihydrotestosterone and indicate that5 f! ~3 J/ O& p" K5 p8 r; A
phallic and peripheral skin, and subcutaneous tissue should1 o7 D+ e9 c" p! x9 _( a2 x4 m1 e
be compared for 5a reductase activity.; P4 g" A. V2 i2 d4 g) e/ O$ k
A, loop enlarges to measure penile girth in millimeters. B,$ |: ]& U7 \" ~% r% c% R7 |
example of penile girth computed easily and accurately./ S1 l; v' ~& m. t8 i) m5 s$ E
conversion of testosterone to dihydrotestosterone. It is in this4 p1 s7 ^# S+ q
older group that others have noted high levels of serum( y( Z$ G+ ~4 _- B- @3 s
testosterone with topical application. It would also appear8 n Q( ^- V5 ~
that phallic response during puberty is related directly to the, `6 r% Q1 g/ q5 I1 p
serum testosterone level. There also is other evidence of local0 W4 n/ m d3 \9 f4 K: a/ r- @
response to testosterone with hair growth and with spermato-
. a# ~9 N8 I" h$ c& }, f$ u1 e" {8 k9 T, {genesis. 5• 6
/ q) V" I9 I0 C# j! \Administration of larger doses of gonadotropin or systemic
% O2 \2 h v+ [* X4 J0 Btestosterone, as well as topical applications that produce* {. }6 z& |" u1 j) ?* s, s+ }3 i' E6 V
higher levels of serum testosterone (150 to 900 ng./dl.), will2 ^* f; k3 l( Q% q& a
also produce phallic growth but risks accelerated skeletal9 B4 D# m+ _/ j( o! o, s; o
maturation even after stopping treatment. It would appear$ L5 d2 c" j: \7 t9 x" ?& ]
that this may be avoided by topical applications of testosterone7 a7 F. a" e H6 T" G; T: a/ g
and monitoring of serum testosterone. Even with this control
! Y" H6 j+ b8 {6 Z& ]0 Othe duration of our therapy did not exceed 3 weeks at any* N9 M6 ?9 ~/ S* B7 v# T% @3 n
time. It is apparent that the prepuberal male subject may1 I- P* z3 v! p9 a$ m5 G5 Z) A
suffer accelerated bone growth with testosterone levels near
8 m9 m. @8 `* ]. \0 a+ `% i/ u200 ng./dl. When skeletal maturation is complete the level of
4 }8 n' h+ Z) b+ ]serum testosterone can be maintained in the 700 to 1,300 ng./
% d) Y# S- }& s7 B: y2 kdl. range to stimulate phallic growth and secondary sexual1 w2 t$ E) h3 L* @( r8 s
changes. Therefore, after skeletal maturation parenteral tes-
e/ q# z( L, o3 g' jtosterone may be used to advantage. Before skeletal matura-
+ r4 G# Q3 W) Ztion care must be taken to avoid maintaining levels of serum
- R" c( t) B a0 `# p2 D! Otestosterone more than 100 ng./dl. Low-dose gonadotropin
2 j9 f, A9 k% a- k/ }# O7 h5 s1 Jdepends upon intrinsic testicular activity and may require) a( f- }( x2 T) R/ w8 j
prolonged administration for any response.5 `& m$ v5 U1 T+ q
Alternately, topical testosterone does not depend upon tes-% J% p0 D) X1 l l
ticular function and may provide a more constant level of
4 ^& x' h7 B9 z' k; y9 DREFERENCES
" B* `6 X8 s# R% P+ o/ `1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, H+ Q) c8 t/ h4 D
R.: The local application of testosterone cream to the prepub-! v0 a: X% v" w4 E' s: [
ertal phallus. J. Urol., 105: 905, 1971.' Y+ H1 ~4 @" @- U
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% B+ n0 m7 n: ^treatment for micropenis during early childhood. J. Pediat.,2 K9 z; R; M9 P( z3 Y
83: 247, 1973.& g6 R6 K4 v2 U. T4 i( S
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 n5 }; f5 C! p$ [$ `2 ~) ^
one therapy for penile growth. Urology, 6: 708, 1975.
# C4 m3 _: q" t/ y/ D$ ^) `( ]4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
) A( r( k0 g- k8 i# a: ^to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, N' X# n7 k9 Gskin slices of man. J. Clin. Invest., 48: 371, 1969.* e; I7 c* M7 X1 D- e
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! L6 ], q; T% T, _# q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ _" {* J9 h: u9 F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ e' X& N7 ?0 T% C c" T, z0 {" Landrogenic effect of interstitial cell tumor of the testis. J.1 B) d h+ X2 L2 T3 r1 d
Urol., 104: 774, 1970.
/ D1 T, ]$ n8 Z, g$ `, z# [7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 d' k/ m5 C2 ition in the male genitalia from birth to maturity. J. Urol., 48: |
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