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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: l2 F, w7 b: D0 d1 o6 ^
GONADOTROPIN# w" N+ Q% ~- i0 R
RICHARD C. KLUGO* AND JOSEPH C. CERNY; q8 ]; o$ k; b4 _
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& b, |; J& d2 h' T
ABSTRACT: g, Z& E- R! Z4 a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
G" O2 [! {( F% V, Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-% w; S" H' o# M/ `+ Y
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 K; r: {1 }2 W' f3 y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
& ~ m; T4 b; Q' s; X. p2 Afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 K+ u: O$ l) g. G8 Y& U: j
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average" N( o. u# d# Z" N8 Z/ T+ H ]/ a; j. F
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ j" o u4 a: b4 [; E0 Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 g) C! X$ G$ j) zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: z1 w7 O4 C% d3 V( ~2 zgrowth. The response appears to be greater in younger children, which is consistent with previ-
8 f' m4 E8 P- g P$ L; Cously published studies of age-related 5 reductase activity.& ?% W( D% D+ M! H+ F
Children with microphallus regardless of its etiology will
+ _( T+ G A2 p* W u& |require augmentation or consideration for alteration of exter-
$ X4 @3 f) Q; [% y! dnal genitalia. In many instances urethroplasty for hypo-9 R9 }- N3 C: G/ M* G L9 Q: M
spadias is easier with previous stimulation of phallic growth.& D5 e4 v; M- \/ m) D3 _, b) V
The use of testosterone administered parenterally or topically
3 @# h! U# g2 g3 }has produced effective phallic growth. 1- 3 The mechanism of
, y: U. W$ [7 jresponse has been considered as local or systemic. With this9 Y/ |# }; |4 |2 s; b, }: b t
in mind we studied 5 children with microphallus for response" N1 h) `9 b6 D5 X6 Z
to gonadotropin and to topical testosterone independently.
7 _ U- O! H( J& t* [MATERIALS AND METHODS
1 R* T( r' T$ B+ y% \3 R9 {8 {3 r2 HFive 46 XY male subjects between 3 and 17 years old were6 t' }* y( H* _3 i/ r, g
evaluated for serum testosterone levels and hypothalamic
2 \6 O4 v- i/ \5 I& K, W0 r6 ]function. Of these 5 boys 2 were considered to have Kallmann's1 r& M2 L1 E0 Y: N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
4 z# m, Q: W6 c/ `2 Vlamic deficiency. After evaluation of response to luteinizing' p# t- T, p5 v2 N0 @
hormone-releasing hormone these patients were treated with' o& ~+ E$ [* B8 _$ ?
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
; U% V( j, R6 @after completion of gonadotropin therapy 10 per cent topical, X; z4 z4 L! ~) P" O7 ?
testosterone was applied to the phallus twice daily for 3 weeks.4 m3 {+ b3 I& _
Serum testosterone, luteinizing hormone and follicle-stimulat-# b. L0 o' W- w4 e3 \( S. y
ing hormone were monitored before, during and after comple-
& [' o6 L6 i4 l. r4 }4 ution of each phase of therapy. Penile stretch length was
6 B/ ^+ \$ E yobtained by measuring from the symphysis pubis to the tip of' T9 z I6 [) {4 S& v
the glans. Penile circumferential (girth) measurements were9 u! Q/ L& n( s+ y
obtained using an orthopedic digital measuring device (see
2 Y% T6 Q E$ c$ X5 Kfigure).5 J& Z4 {5 ?- P$ B& c) l- V7 [
RESULTS
3 [ q, w5 E' d9 P! s4 p4 lSerum testosterone increased moderately to levels between
, z1 ^3 `3 R+ a0 k3 x" r50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-% B, c7 _6 O7 \% p: _
terone levels with topical testosterone remained near pre-
2 |$ `! K' R+ w5 u; g! ]+ @* btreatment levels (35 ng./dl.) or were elevated to similar levels! z4 v8 }) v( \. t ^4 v- D- ^' @7 ]
developed after gonadotropin therapy (96 ng./dl.). Higher7 m% p1 v# _0 p2 q5 q# j
serum levels were noted in older patients (12 and 17 years old),
' T' o) o/ ~& u2 a1 \" h0 Pwhile lower levels persisted in younger patients (4, 8, and 10
5 u5 {( z6 x4 F# C h' Fyears old) (see table). Despite absence of profound alterations0 Q+ t, L7 c; Z' m3 ^0 E, E$ u; G
of serum testosterone the topical therapy provided a greater
- n+ Q. a9 l) l3 B5 X, {Accepted for publication July 1, 1977. ·6 t2 y. T& l3 E* l; F* j
Read at annual meeting of American Urological Association,
' [, a+ O( e1 i1 H5 E0 v/ g& A/ I0 _Chicago, Illinois, April 24-28, 1977.) L( V" M: v& b" b8 k, W" h
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 E) Z3 Y% j) _: U2799 W. Grand Blvd., Detroit, Michigan 48202.
7 z, [* m* p! I! b' _" C$ Cimprovement in phallic growth compared to gonadotropin.3 ]: ?; h+ q# c) J, W
Average phallic growth with gonadotropin was 14.3 per cent
6 I5 X8 o& m5 ^: p) tincrease in length and 5.0 per cent increase of girth. Topical
9 N& I8 }1 S3 x0 Y# h$ q3 \. Itestosterone produced a 60.0 per cent increase of phallic length
; o8 ^/ @3 W4 d6 C" Kand 52.9 per cent increase of girth (circumference). The
5 ^# p. t% ]( O) u2 n0 S1 {2 xresponse to topical testosterone was greatest in children be-: f) o8 _5 _4 Y2 J5 |" X f! Z
tween 4 and 8 years old, with a gradual decrease to age 17
" E* ^% ?9 V/ J3 u5 U3 uyears (see table).1 J% K( I& V7 F, p4 E
DISCUSSION
7 G7 S+ ^9 @5 Z" z. ?% LTopical testosterone has been used effectively by other1 n+ m T3 n4 {& a: |: K
clinicians but its mode of action remains controversial. Im-/ s ^4 e0 d1 j ?
mergut and associates reported an excellent growth response
1 [. W) K" Q8 c3 H. s& D2 O( oto topical testosterone with low levels of serum testosterone,
. T( R! A8 \) i; j* b- F6 osuggesting a local effect.1 Others have obtained growth re-9 p: Q4 t' s# k2 j4 T# A
sponse with high. levels of serum testosterone after topical; c' [1 s1 T O: D9 C
administration, suggesting a systemic response. 3 The use of4 d& m& r; a; r1 @+ S" M5 D8 v" Z |
gonadotropin to obtain levels of serum testosterone compara-4 \& f1 ~/ p" X* L4 l4 d: b
ble to levels obtained with topical testosterone would seem to
7 Y9 \# n1 i7 q6 Zprovide a means to compare the relative effectiveness of
, f2 h- I) ^. f4 m# s0 m; Y7 Ntopical testosterone to systemic testosterone effect. It cer-
& w: h$ m) h: T' B. |" ^. B# _" Etainly has been established that gonadotropin as well as par-+ l1 T% u0 Q; q- ~! s( i% F" P- S0 M1 E
enteral testosterone administration will produce genital5 c# |3 Q. j4 w; P7 q* w) \
growth. Our report shows that the growth of the phallus was
2 o7 _0 D$ E9 D. t+ a; [! Lsignificantly greater with topical applications than with go-4 U- q* u6 H# ^# X0 k
nadotropin, particularly in children less than 10 years old./ @( |9 A' @! f
The levels of serum testosterone remained similar or lower
/ O+ o3 ?5 C- }1 t( {( l) Fthan with gonadotropin during therapy, suggesting that topi-+ V* C* T1 Z' J* Y/ }, ~# W
cal application produces genital growth by its local effect as
) h) M% g- Y$ ywell as its systemic effect.% U) ]" z5 Q+ B. T: a0 r! M2 [
Review of our patients and their growth response related to
* }2 \9 O3 P: e& h% k5 }age shows a greater growth response at an earlier age. This is
* Z8 l5 H$ r3 u# Aconsistent with the findings of Wilson and Walker, who
+ A+ Y( R) C8 r: freported an increased conversion of testosterone to dihydrotes-
& {- d0 G' R( `9 S# f! `tosterone in the foreskin of neonates and infants.4 This activ-7 ^/ q; Y. e8 i8 P
ity gradually decreases with age until puberty when it ap-
9 a8 C6 M4 P, ?$ C" E! Z: Gproaches the same level of activity as peripheral skin. It may# N2 ]0 Z3 \- K7 K- D$ z
well be that absorption of testosterone is less when applied at
0 a; }& |- O [$ nan earlier age as suggested by lower serum levels in children
* e- y% K T) i, J5 Wless than 10 years old. This fact may be explained by the
: q6 G" J* W+ F1 n% vgreater ability of phallic skin to convert testosterone to dihy-
) b( f- L$ Y Odrotestosterone at this age. Conversely, serum levels in older
( D+ h& F9 O- `9 L: [. _- qpatients were higher, possibly because of decreased local$ b5 c# c( g/ U
6675 O7 ^" s: y/ P) r
668 KLUGO AND CERNY
( J. J; _- V/ G# m; p! pPt. Age
; A3 r' D* C) [( F8 e2 z(yrs.)/ [2 {& E" z- ]8 B4 x8 o |
Serum Testosterone Phallus (cm.) Change Length# ?6 V2 D1 s% z1 ]
(ng./dl.) Girth x Length (%)
* w( p5 P" w4 ]) t* t& f: Q44 u V1 {; g5 j2 s
8
! e% q; R* I' H1 b8 q4 c" y$ P0 c100 Q) ?7 |3 I# i$ p' E# L) i
12
- i( a! B Z; [ F7 x173 V7 Z3 i% ^1 [
Gonadotropin
' |/ p8 U/ |0 Y& d8 [71.6 2.0 X 3 16.6
d- p; j! t5 [& K- l50.4 4.0 X 5.0 20.01 B1 w1 g t8 n2 u3 l
22.0 4.5 X 4.0 25.0
! q/ H$ O( _. m84.6 4.0 X 4.5 11.1. L( f0 X; v, C6 W! C4 p' Q6 g; N
85.9 4.5 X 5.5 9.0$ A$ [4 |: T6 P; b# E0 D
Av. 14.3
! _1 ]" O5 O( @. F4 W3 O; t* W! U4 ^9 g8 O) D
8' \' l) N5 ^! @! l" o( j! d+ S
10+ j |1 g! U p' i# z% J" u5 m6 _. O2 I l6 G
12
9 }8 k- A2 u0 Q- k( \17 X8 ^# F+ J8 M
Topical testosterone
1 H5 V! D" y! {' U V) E34.6 4.5 X 6.5 85, {8 j5 W M' Q8 f( a: q0 A/ {% V
38.8 6.0 X 8.5 70
6 ~' K. m6 w: b+ k40.0 6.0 X 6.5 62.51 h7 d' J7 j0 V8 C
93.6 6.0 X 7.0 55.5* R% o- N$ G7 r V0 s4 d
95.0 6.5 X 7.0 27.2
$ K# y7 V" I lAv. 60.0
. u; ]6 t' y3 }available testosterone. Again, emphasis should be placed on
) `# l/ W6 R9 z+ ]9 K1 i' Iearly therapy when lower levels of testosterone appear to! ^" C' ?: W& o
provide the best responses. The earlier therapy is instituted m% \; d: |+ G# W; ?2 p& @
the more likely there will be an excellent response with low7 V% o* F4 @$ v/ W/ M( e: e: t- g5 ]
serum levels. Response occurs throughout adolescence as
+ E" k% f9 L; U% F* k3 unoted in nomograms of phallic growth. 7 The actual response
( l) x) w' P5 f4 V9 t3 c+ c. D0 O7 @to a given serum level of testosterone is much greater at birth
5 p% t' C9 a- r& G9 [; q$ m( ~6 tand gradually decreases as boys reach puberty. This is most
" u1 |, P* u5 y/ glikely related to the conversion of testosterone to dihydrotes-
% ]1 Q1 L: g7 j, F# E& |7 jtosterone and correlates well with the studies of testosterone% \! [- e( Q: e k. L, {7 K( Z
conversion in foreskin at various ages.$ L# }. Z$ T) c. f( d6 g
The question arises regarding early treatment as to whether/ g, g W; f% r d7 Z1 [
one might sacrifice ultimate potential growth as with acceler-
7 K _) x" N& H3 Dated bone growth. The situation appears quite the reverse
0 h, T) i) p& P3 ]" Z& ^$ rwith phallic response. If the early growth period is not used3 S5 T: ]: S* E- v+ ?' Q
when 5a reductase activity is greatest then potential growth
' q1 ?4 ?8 E/ H2 q) ?: nmay be lost. We have not observed any regression of growth# X+ x7 e/ t L$ l$ d6 M
attained with topical or gonadotropin therapy. It may well
, i; B! T! k( i! N% c" O ~be that some patients will show little or no response to any
1 w9 z6 H6 c2 n( hform of therapy. This would suggest a defect in the ability to/ t, n2 g) {& S
convert testosterone to dihydrotestosterone and indicate that# A) ^' S I8 Z5 Y' H
phallic and peripheral skin, and subcutaneous tissue should+ \) e% N$ t! U5 q" f3 m6 B+ E5 v
be compared for 5a reductase activity.1 \0 f; m8 D( u
A, loop enlarges to measure penile girth in millimeters. B,) t& D" u* n7 ?/ k/ Q: W3 @
example of penile girth computed easily and accurately.' Z# B+ _0 i+ {9 q- e* l
conversion of testosterone to dihydrotestosterone. It is in this) z% V" g/ d4 z$ O7 M, E1 ?
older group that others have noted high levels of serum3 M' H- M' m# B+ Q& M' h
testosterone with topical application. It would also appear$ g6 U# f+ k8 ?, [, T& L
that phallic response during puberty is related directly to the5 @0 Z% Q6 u! \9 \+ }& i K
serum testosterone level. There also is other evidence of local s% P4 `- Q3 Y8 `, ?1 _
response to testosterone with hair growth and with spermato-
( I+ w8 E* l& u% ggenesis. 5• 64 a4 ?7 p9 S2 m! o6 G' m
Administration of larger doses of gonadotropin or systemic+ H" g3 o. U; I6 Q2 s% X2 N/ U3 ~
testosterone, as well as topical applications that produce+ R3 d' ] s8 q' ^1 h
higher levels of serum testosterone (150 to 900 ng./dl.), will
! g4 a, y- f$ Balso produce phallic growth but risks accelerated skeletal# D# {* C. e: L# R6 W
maturation even after stopping treatment. It would appear
: F: `0 k$ H- M) [3 N9 `that this may be avoided by topical applications of testosterone7 ^6 A& t; l; P! \. ?
and monitoring of serum testosterone. Even with this control
/ S& P. ?+ s9 {the duration of our therapy did not exceed 3 weeks at any
- d5 O6 c( X7 J/ c+ Jtime. It is apparent that the prepuberal male subject may1 T$ G X9 y, g" z2 r
suffer accelerated bone growth with testosterone levels near
7 ^! t: m% K( r# L0 ^: ~200 ng./dl. When skeletal maturation is complete the level of% N; [' g0 L4 x# [8 T! N- }
serum testosterone can be maintained in the 700 to 1,300 ng./
- {$ H" ^! m+ ^9 _: G7 z$ Z; u6 \dl. range to stimulate phallic growth and secondary sexual
0 z& Y2 x, V& X' ?, ^* ichanges. Therefore, after skeletal maturation parenteral tes-. z/ ]; E- u- n
tosterone may be used to advantage. Before skeletal matura-
/ k" s9 }# {0 Q% S4 x6 f: G% S3 o* Ition care must be taken to avoid maintaining levels of serum
" A; e) g9 Z; C4 @4 qtestosterone more than 100 ng./dl. Low-dose gonadotropin3 `8 u; E" g2 y& o2 i
depends upon intrinsic testicular activity and may require
+ O' a, W# v; m& ^, P0 G+ s$ uprolonged administration for any response.
" z( ]! C- X, [5 \# J: G3 s6 QAlternately, topical testosterone does not depend upon tes-/ a1 C2 d9 C5 e$ I* f) @8 L
ticular function and may provide a more constant level of
* N9 [- R+ b; k7 @& K6 `9 @REFERENCES* k5 `$ m$ c8 W+ s+ T
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ y3 ^9 X" H( L6 L& o. h0 ?4 P
R.: The local application of testosterone cream to the prepub-/ ^4 w0 [$ @" Y* E+ f1 s8 w
ertal phallus. J. Urol., 105: 905, 1971.# |! K& M8 l$ g1 D E7 W, Z
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 i, F, {: R! otreatment for micropenis during early childhood. J. Pediat.,
& T' l$ o1 o' C83: 247, 1973.
& x+ r- W6 @ Z6 V" i2 [6 s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' F2 m6 W, K9 Q6 X6 wone therapy for penile growth. Urology, 6: 708, 1975.- l0 h( ]. v6 [3 H& P( _
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! t4 J, E& [: P" X+ Uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 n" f4 H4 q! A3 D1 z
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. p0 a- T% n8 {; ~2 g4 `- Q0 F5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 g" b) c* n8 j; M. c8 Cby topical application of androgens. J.A.M.A., 191: 521, 1965.
! V: c8 V8 t: i/ ~; |' e+ z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local* v( |+ F# ^$ Q* r1 L
androgenic effect of interstitial cell tumor of the testis. J.; |" P2 p8 x7 H. ~4 m
Urol., 104: 774, 1970.1 \; s! |5 r3 v. g" `1 |* m
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
' R X5 ] c5 ]' Z1 H0 G* g) @0 Ztion in the male genitalia from birth to maturity. J. Urol., 48: |
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