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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 R7 Z3 |; p. V- q( b7 |
GONADOTROPIN
0 P% q6 S9 {! ^1 X) VRICHARD C. KLUGO* AND JOSEPH C. CERNY+ x* W7 `  [$ f9 Q, s7 C) U# [- i. `) H
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& K3 C9 S0 G" a5 l) Z, a
ABSTRACT; i* z4 _3 p) E) a3 G4 d$ c2 D& u
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 l! |. j/ z3 X, Z0 iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( f# K" u3 d- P; p/ Otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ q4 R2 }" B" l( G0 J. F( w
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% c* V8 c5 k3 ifor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 l: k; `: `. eincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
/ X; h7 M" O0 [4 h* H5 d8 A3 qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response9 Y% x- D5 x7 k
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ E8 R- `2 i, |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ }3 A* ?6 A6 g' E4 S* h0 W
growth. The response appears to be greater in younger children, which is consistent with previ-: z8 L; l. m' [% P7 `
ously published studies of age-related 5 reductase activity.3 B9 y2 i; R, _" \2 t$ K: r
Children with microphallus regardless of its etiology will
% N9 q2 l2 ~, t0 D8 `require augmentation or consideration for alteration of exter-* w& {" A7 v6 U, K3 p
nal genitalia. In many instances urethroplasty for hypo-
* `( H" ^5 Z4 O6 c) G6 Mspadias is easier with previous stimulation of phallic growth.
7 n0 S  W- T* TThe use of testosterone administered parenterally or topically
/ X( l/ |1 ]+ C9 u7 X; C  ^has produced effective phallic growth. 1- 3 The mechanism of
# A" d. z; L8 u4 N0 rresponse has been considered as local or systemic. With this
1 r" s3 a1 L: L0 g( f4 ^: T  Vin mind we studied 5 children with microphallus for response
4 [; e% E+ I$ p4 J0 C( }4 Jto gonadotropin and to topical testosterone independently.
) \: T- B* p& f! Z+ E& BMATERIALS AND METHODS# P8 _" F1 F3 d& ]5 Y- @7 J/ T
Five 46 XY male subjects between 3 and 17 years old were' H( E! n2 |1 B: @0 n! m5 \
evaluated for serum testosterone levels and hypothalamic* K2 @* Y# F; h; i: v% ]: D3 h
function. Of these 5 boys 2 were considered to have Kallmann's
: r; Z5 M! w3 U: L$ S* N+ n8 Fsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 G: Y. ?, `/ n, J+ M3 J8 Elamic deficiency. After evaluation of response to luteinizing
/ q  c: c8 _: @4 v1 l# M& Ahormone-releasing hormone these patients were treated with, t( j* o- E6 P2 |4 T. V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks& R" s, V( p8 `2 A' Z
after completion of gonadotropin therapy 10 per cent topical" c7 `4 i* s: H: X5 M- G
testosterone was applied to the phallus twice daily for 3 weeks.
! O9 j& T+ l7 ~* I; eSerum testosterone, luteinizing hormone and follicle-stimulat-
3 t. E- z. D" L6 z6 N+ |' J6 _4 `ing hormone were monitored before, during and after comple-
* k) ~& [$ ^8 d8 O: Ption of each phase of therapy. Penile stretch length was2 m. c/ i9 s& _# D' F' o
obtained by measuring from the symphysis pubis to the tip of( j: u6 W: q) E  k
the glans. Penile circumferential (girth) measurements were
8 o7 Q1 |- A4 s" J) Q8 ]obtained using an orthopedic digital measuring device (see
% a5 R4 L5 K2 Z  Pfigure).% {# D& ~- |9 U+ L6 i' E' A7 l
RESULTS3 C$ ~/ c& X1 U. o: x
Serum testosterone increased moderately to levels between
' F0 x, c. Q0 x- M0 {0 x, o( Q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) h7 r  e7 t' J5 ~, [
terone levels with topical testosterone remained near pre-# _( Y7 w. z: |2 f( s  A
treatment levels (35 ng./dl.) or were elevated to similar levels
2 k, O' v, r' b; |5 o9 h1 @developed after gonadotropin therapy (96 ng./dl.). Higher0 W8 q8 I( @4 V" F
serum levels were noted in older patients (12 and 17 years old),
7 l2 j' B4 o3 n* e: d3 m: ~( L3 cwhile lower levels persisted in younger patients (4, 8, and 10
% ]! F+ b) H/ D/ Z+ vyears old) (see table). Despite absence of profound alterations8 |; s: b" K* o. |
of serum testosterone the topical therapy provided a greater" a& v& W+ L3 D! K
Accepted for publication July 1, 1977. ·
% Z9 P3 I) m2 M- W* }+ I' E2 Y, ERead at annual meeting of American Urological Association,
/ g$ R: ]1 U  A" l5 ~  NChicago, Illinois, April 24-28, 1977.9 D7 R' Q+ w0 q; K1 T- [
* Requests for reprints: Division of Urology, Henry Ford Hospital,( i4 t5 s. X  i8 H) `9 J; v, f: V
2799 W. Grand Blvd., Detroit, Michigan 48202.
4 w+ f8 n4 U9 J/ B; M# eimprovement in phallic growth compared to gonadotropin.6 _  v6 [' H) i* C$ B
Average phallic growth with gonadotropin was 14.3 per cent
; |% I* B& Z1 ?7 nincrease in length and 5.0 per cent increase of girth. Topical
+ |7 {) ^( y2 r& G) [1 f* ~/ X" vtestosterone produced a 60.0 per cent increase of phallic length  Z( O2 I  k% a; S) Y
and 52.9 per cent increase of girth (circumference). The
% p4 d' e$ I1 u* v5 ]0 i9 F+ M; bresponse to topical testosterone was greatest in children be-
0 C' I! o5 P3 Y7 Ftween 4 and 8 years old, with a gradual decrease to age 17
7 g1 u. f9 ]( o% Q. L2 @- Eyears (see table).9 r; G- I0 o7 g, [" n3 b7 t1 m: F% v
DISCUSSION" E: W/ n; q/ r0 q9 {
Topical testosterone has been used effectively by other% n1 I2 L) U) `. \4 u
clinicians but its mode of action remains controversial. Im-) n0 ~" D5 h$ U5 n/ u
mergut and associates reported an excellent growth response5 v! E2 F0 @4 f9 K
to topical testosterone with low levels of serum testosterone,; R# r, o  }" ^; c$ m4 u
suggesting a local effect.1 Others have obtained growth re-9 p& N3 f/ k: N  g7 E' f% `! C: I2 h
sponse with high. levels of serum testosterone after topical
- ?" R- ~$ Q" n8 s$ K- gadministration, suggesting a systemic response. 3 The use of4 i$ A: [: o0 A; @* v- g
gonadotropin to obtain levels of serum testosterone compara-
1 \1 e* g& A$ Mble to levels obtained with topical testosterone would seem to2 e- {. M9 n) E# g
provide a means to compare the relative effectiveness of
- m" q# l% I+ `, r: Ntopical testosterone to systemic testosterone effect. It cer-
/ P/ s3 A' B. K5 I5 utainly has been established that gonadotropin as well as par-
8 a9 }' Y+ B( D' E% h9 penteral testosterone administration will produce genital, z+ }  e6 G8 C" c& G( o
growth. Our report shows that the growth of the phallus was8 L! y' k% h& `
significantly greater with topical applications than with go-. H4 w: S: ^! l; y6 v0 q" a
nadotropin, particularly in children less than 10 years old.
) J) y- D% w0 q# t+ VThe levels of serum testosterone remained similar or lower& |4 [4 z) y& X/ C
than with gonadotropin during therapy, suggesting that topi-
7 d) p; P6 j" Q  z  C8 {cal application produces genital growth by its local effect as: s  X) k* |; s) m" W8 C
well as its systemic effect.
0 s8 g8 @4 ~" _5 M- U2 |) p& S8 c9 kReview of our patients and their growth response related to2 F; |7 r" h" W6 ]
age shows a greater growth response at an earlier age. This is) ?# |8 k$ Z* [( N# M! I+ i" x0 X
consistent with the findings of Wilson and Walker, who
5 v2 A( D% d# Jreported an increased conversion of testosterone to dihydrotes-
( b' {4 O$ f% T' O8 i' Ptosterone in the foreskin of neonates and infants.4 This activ-5 [' j9 b; j5 J! I7 b- i# x( a- @
ity gradually decreases with age until puberty when it ap-
0 `/ S; b5 k, P) ?proaches the same level of activity as peripheral skin. It may( P' e! `/ K5 j. y; |8 r
well be that absorption of testosterone is less when applied at
. I/ Z  `! M4 e5 r* @! u! fan earlier age as suggested by lower serum levels in children( a& A# U( C% u8 b. R1 y( U, `' r0 ?: E
less than 10 years old. This fact may be explained by the
2 `' ?, K5 [" D7 Bgreater ability of phallic skin to convert testosterone to dihy-2 j1 d" x( P/ b* O( Y6 t4 P- M- Z: Y$ ]
drotestosterone at this age. Conversely, serum levels in older
9 ^' |  k7 b$ x% g4 Ypatients were higher, possibly because of decreased local
( _1 p5 `4 q7 Z( V667/ V9 ~) H: }% V7 N. F$ I, y$ c
668 KLUGO AND CERNY
9 Z; w2 q( t) O7 ?Pt. Age6 K1 X3 p+ b) n1 z5 w5 Q6 f$ s
(yrs.)5 p4 t5 G& Q" ~  o% }# q
Serum Testosterone Phallus (cm.) Change Length
: K- b* w6 u7 h' Y6 R(ng./dl.) Girth x Length (%)
& U* D! a3 a4 B4- B: Z2 t' W/ l; {
8
; }1 U2 @5 m" Z) }/ [& U+ I5 D8 Y/ l( F10* |# [1 ~5 q* _, Z9 J; f  P: j
125 Q6 A9 b9 h: [7 Q( X% d
17+ f, ^- z6 n$ t3 b1 R# N- z
Gonadotropin2 _* ^3 Q8 ^8 f: [
71.6 2.0 X 3 16.6
& j! V2 ^* x' H" U50.4 4.0 X 5.0 20.0
- n6 T# i3 f* i3 A4 L22.0 4.5 X 4.0 25.0' I6 ]8 ^' D0 h, Y+ @
84.6 4.0 X 4.5 11.1
& P3 V) ~* d: ~/ |2 J2 Z85.9 4.5 X 5.5 9.0
% N5 a* r6 T  ]& q! X8 nAv. 14.3# S* r: H. y& `6 f
4
7 j! i; n* B* t( [* i/ c8
& ?' K/ k5 I3 a5 p; u/ l& ~10
+ J# s8 `% t: L; p2 b12
) E% d9 ?) t) L" e" e17" V/ ]- b5 }9 Q+ w( f( {7 B: o
Topical testosterone7 m; x) {: M) o& E
34.6 4.5 X 6.5 85
. y* _7 U  H4 v6 N38.8 6.0 X 8.5 70
5 R- m$ p( X$ c3 D3 ?3 y40.0 6.0 X 6.5 62.5$ l( R* y2 F. Z
93.6 6.0 X 7.0 55.5
5 ^4 L& `. L1 E, z95.0 6.5 X 7.0 27.2
1 z) m! y5 o8 s0 BAv. 60.0, i( P$ B( [+ G/ V
available testosterone. Again, emphasis should be placed on
- P9 u$ X5 R/ i/ |early therapy when lower levels of testosterone appear to3 ^- G8 X) \! u
provide the best responses. The earlier therapy is instituted
; p" k9 O8 B" n4 ^the more likely there will be an excellent response with low0 ?: k2 T$ [" h' [4 N/ j* L1 O
serum levels. Response occurs throughout adolescence as
: f( e5 J: d" R/ @noted in nomograms of phallic growth. 7 The actual response! x8 r8 b. ~! i1 U
to a given serum level of testosterone is much greater at birth* f) C5 J; V9 q& C
and gradually decreases as boys reach puberty. This is most
* R, z+ ^1 n# `5 W+ O* ^; rlikely related to the conversion of testosterone to dihydrotes-4 I4 n$ a" t1 c) D
tosterone and correlates well with the studies of testosterone
- P. z5 e4 r! k* X0 Sconversion in foreskin at various ages.
6 Y7 p3 T, ~/ _" zThe question arises regarding early treatment as to whether6 n1 W: G  r  n# j
one might sacrifice ultimate potential growth as with acceler-. W: O! C: T( \+ c: W
ated bone growth. The situation appears quite the reverse/ f. ~8 z! Q7 y" m8 y! \
with phallic response. If the early growth period is not used
8 B; v* x+ w! G* q# U( M2 dwhen 5a reductase activity is greatest then potential growth! i) d! h# B- `/ i9 a, [7 l
may be lost. We have not observed any regression of growth
2 V6 `( ~% F0 {" [1 g# j, J* V9 aattained with topical or gonadotropin therapy. It may well% I1 a& ?0 d$ L2 i
be that some patients will show little or no response to any: [! c! s2 u- @! Z
form of therapy. This would suggest a defect in the ability to
3 p. \3 i8 s, F- }0 T4 ~/ Vconvert testosterone to dihydrotestosterone and indicate that
) i" Q$ I" i' [5 ~8 e( [% ^8 |phallic and peripheral skin, and subcutaneous tissue should
6 q6 U4 l+ B, F# w: P% m$ w" dbe compared for 5a reductase activity.
% w% @) g! e9 [/ j/ M! J, DA, loop enlarges to measure penile girth in millimeters. B,+ e2 N( y; ~: _5 Q# b: c
example of penile girth computed easily and accurately.
0 b" m/ }' S: v6 C, Lconversion of testosterone to dihydrotestosterone. It is in this. D- B! r' M1 @2 W& P
older group that others have noted high levels of serum
) s5 E' }/ Q! @* Ctestosterone with topical application. It would also appear
8 y( B7 i. t8 R0 D+ o' K; ethat phallic response during puberty is related directly to the) a" ~  W' x  M; B) ]# h  v
serum testosterone level. There also is other evidence of local5 O3 T/ t& H- i' \
response to testosterone with hair growth and with spermato-6 E( |  D$ y6 x# r0 c
genesis. 5• 6: @+ ?, d8 @' g) I4 b# s$ h7 M% g
Administration of larger doses of gonadotropin or systemic
5 E8 I, z; i% ?2 h2 Utestosterone, as well as topical applications that produce) k1 J0 {( {/ ^! `
higher levels of serum testosterone (150 to 900 ng./dl.), will3 A  T  D- r; x) M9 N$ Z7 n9 b5 ~$ |
also produce phallic growth but risks accelerated skeletal9 r, X* m6 i/ F0 [
maturation even after stopping treatment. It would appear
0 d) u0 G8 l6 m' }, _that this may be avoided by topical applications of testosterone- ]* L( [6 e/ |) a) H% t, I7 y8 Z7 T, m
and monitoring of serum testosterone. Even with this control
- i( x* x' t# T! x# Ethe duration of our therapy did not exceed 3 weeks at any
3 l0 p" K9 x2 A* dtime. It is apparent that the prepuberal male subject may4 {) i6 H0 n  E! ]6 P4 k8 N: x# c  R
suffer accelerated bone growth with testosterone levels near1 x/ X  _- S: R' q1 W
200 ng./dl. When skeletal maturation is complete the level of3 m8 _6 P4 R9 h" C% R4 d9 l. Z$ ?
serum testosterone can be maintained in the 700 to 1,300 ng./
. ?+ c- G& ?: b5 g$ a; R- Vdl. range to stimulate phallic growth and secondary sexual" f6 `) b' i0 a
changes. Therefore, after skeletal maturation parenteral tes-
9 e1 o  ^$ s  A/ s/ ?* k6 i: Y. U9 \tosterone may be used to advantage. Before skeletal matura-
/ _8 \2 z; C1 U( w) C; ~" Mtion care must be taken to avoid maintaining levels of serum
: D5 u- c# ^8 ntestosterone more than 100 ng./dl. Low-dose gonadotropin
5 ]# \5 V" C# v2 N/ M; Qdepends upon intrinsic testicular activity and may require
7 o: y5 a6 G# ?; D* b# l  w. |. T, Wprolonged administration for any response.% X$ _/ b' n$ I( a7 D
Alternately, topical testosterone does not depend upon tes-1 s' l% `  ~& @6 {, |
ticular function and may provide a more constant level of
9 ]$ r  c/ V+ U) O1 J6 sREFERENCES: l2 s8 k% _5 S- W1 i8 H
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 R* A9 F) A4 f6 P7 b* _
R.: The local application of testosterone cream to the prepub-! U* b, D$ M  A- X' K, @1 A' y
ertal phallus. J. Urol., 105: 905, 1971.
! ?5 W: e+ n$ I$ ~2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ N' E3 E; x- f: V' o1 ]" o( B* K! P
treatment for micropenis during early childhood. J. Pediat.,
# p0 a0 D) Z9 a4 p: {83: 247, 1973.
3 s* `% f3 V: L, j4 o3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 u% i5 p" l) z$ Z" ?one therapy for penile growth. Urology, 6: 708, 1975.3 }1 }+ i$ a' d& F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( H$ C9 D) r7 E# n+ kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ i. q- d; G1 Y  e+ D) g
skin slices of man. J. Clin. Invest., 48: 371, 1969.
- M; g: f% Z) x; `  d" b5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# u! U; Y9 W+ d/ q7 k# Y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: {; x& ]' y! G* J& b+ ^6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( `* v- D1 }4 s" b) `
androgenic effect of interstitial cell tumor of the testis. J.. L8 d7 A( n1 V1 H
Urol., 104: 774, 1970.
* Y6 L6 m* g! H9 d3 y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-" `( E3 d! \* W: q4 d- j
tion in the male genitalia from birth to maturity. J. Urol., 48:
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