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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, i- {+ l$ Q5 \; K4 {  ~' X6 `7 ?
GONADOTROPIN3 j* u) o. L0 C8 ~2 O: H* v- o
RICHARD C. KLUGO* AND JOSEPH C. CERNY( R; b6 |6 q2 _8 n4 b
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 _1 z3 f' [8 |8 a+ rABSTRACT1 l& e5 k3 V, T4 J/ o0 {) h
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
1 K( k3 Y. O, _+ B; q, w. o% ~: E0 n1 e$ Lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 ^5 u! i+ v9 n( O8 Q7 \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! m4 q  I6 R! U0 V2 Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 Y% f( t% X2 }% a- @3 ~$ Kfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ d$ H  p# @; }8 C6 W3 q( T( L# }$ Tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% z1 J1 P; v' g4 e. w+ W$ A! \$ G% ~increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response3 ]# e9 U/ F1 K! X- P# w
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
* G; H9 i% H$ z7 ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- {: H9 Y' G0 X! p7 u+ h
growth. The response appears to be greater in younger children, which is consistent with previ-8 A5 s$ r6 [! @( H. Q0 `+ B
ously published studies of age-related 5 reductase activity.& D  C8 c6 ^0 p/ z, l* a
Children with microphallus regardless of its etiology will, j% A) v# m" B4 L
require augmentation or consideration for alteration of exter-- Q  {. J# P7 a* N. z" M1 N
nal genitalia. In many instances urethroplasty for hypo-$ R' k8 M( t* Z6 v5 t
spadias is easier with previous stimulation of phallic growth.9 H; F: _" x: I
The use of testosterone administered parenterally or topically4 V5 A) _+ @  y% n( p: W& L" z
has produced effective phallic growth. 1- 3 The mechanism of- q' C1 p, W7 @5 O
response has been considered as local or systemic. With this* `6 y5 I$ Z1 z2 G1 O/ W
in mind we studied 5 children with microphallus for response
  G- |2 W% h! P8 Tto gonadotropin and to topical testosterone independently.
/ |, _. I, ^! q3 f( \MATERIALS AND METHODS, Y8 u5 J# a4 \
Five 46 XY male subjects between 3 and 17 years old were
5 F5 U) ]/ I& Y: w. mevaluated for serum testosterone levels and hypothalamic
& ^5 M& G" k3 D) ~5 W1 q- Ifunction. Of these 5 boys 2 were considered to have Kallmann's7 u8 R! I$ v5 M5 g9 O7 j3 o, E
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 i; V3 ?. |" J. w+ }3 n# G% nlamic deficiency. After evaluation of response to luteinizing
6 Y; O$ f$ l+ I4 l- Chormone-releasing hormone these patients were treated with( a' ^* e% Q* n; r+ F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks% E$ K& B" F& [5 Q) W+ V# c, I
after completion of gonadotropin therapy 10 per cent topical
0 ~6 G( q0 e. J2 mtestosterone was applied to the phallus twice daily for 3 weeks.% ]; I7 T+ n! S
Serum testosterone, luteinizing hormone and follicle-stimulat-
3 `1 i( ]0 S$ S$ fing hormone were monitored before, during and after comple-
# W" r. ~$ v5 u" V2 N6 q8 E/ r7 ztion of each phase of therapy. Penile stretch length was, U! C0 v9 r8 h! m
obtained by measuring from the symphysis pubis to the tip of: U' ^% U: C' S: g
the glans. Penile circumferential (girth) measurements were
% c  P' r, s2 w6 b, Y8 L3 vobtained using an orthopedic digital measuring device (see$ R4 y3 U* s& U( i; h: S
figure).$ M0 E* J# q7 v6 i" _4 d$ d8 s
RESULTS" h! d; Y$ V+ P0 I5 H3 ~' K2 M
Serum testosterone increased moderately to levels between  L4 O" ^5 a- }8 `) U
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 e/ T4 j$ k, y
terone levels with topical testosterone remained near pre-5 L% c0 d* h. j9 g& S- o$ f
treatment levels (35 ng./dl.) or were elevated to similar levels- P1 s0 ~& ?5 ?& m) u8 p
developed after gonadotropin therapy (96 ng./dl.). Higher7 H2 U2 e: U- [5 b' X, G" x
serum levels were noted in older patients (12 and 17 years old),- M- k5 b2 J+ m
while lower levels persisted in younger patients (4, 8, and 10
% d' _  u7 X8 K4 _years old) (see table). Despite absence of profound alterations) g, T: t4 u" W8 J* x6 C: J' ?2 a5 {
of serum testosterone the topical therapy provided a greater9 [3 ?- G" b, l. D" n4 p! Z* b
Accepted for publication July 1, 1977. ·
4 b$ k' P4 w9 M& U/ jRead at annual meeting of American Urological Association," J- r  i( L. M0 e9 k# R; k
Chicago, Illinois, April 24-28, 1977.
5 w) ^: h9 u/ T( H* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 p' [  [! ]% B% _6 A2799 W. Grand Blvd., Detroit, Michigan 48202.& a, a  D9 I/ p/ X/ |
improvement in phallic growth compared to gonadotropin.: t$ Y; n/ H" L& R1 r3 Z4 T
Average phallic growth with gonadotropin was 14.3 per cent$ N2 D& [. D" _8 X; E( z
increase in length and 5.0 per cent increase of girth. Topical
( ]. K- f/ D& v; f2 L( g$ stestosterone produced a 60.0 per cent increase of phallic length
$ _" K& Q& B) g  Z6 Sand 52.9 per cent increase of girth (circumference). The
! V7 n% L# q& o6 O6 {! Eresponse to topical testosterone was greatest in children be-6 t1 q7 E2 Q7 x
tween 4 and 8 years old, with a gradual decrease to age 17
- M& Y0 f; [+ }4 \years (see table).
% r0 i+ V, F) S5 fDISCUSSION8 z" t' h+ r& ^) o. k% e7 {
Topical testosterone has been used effectively by other0 v$ M! D6 B0 i: `
clinicians but its mode of action remains controversial. Im-
2 n$ _2 p$ I- A* lmergut and associates reported an excellent growth response7 N) @! R5 B. Y( w. |; Z4 R3 m
to topical testosterone with low levels of serum testosterone,7 L) C3 P% v' D& J# Z% p
suggesting a local effect.1 Others have obtained growth re-
8 E2 p% O  E* u* V  ?sponse with high. levels of serum testosterone after topical
' o9 ^- o$ r! H( e7 c0 Qadministration, suggesting a systemic response. 3 The use of- l( c) k- z0 V3 T6 p; g
gonadotropin to obtain levels of serum testosterone compara-
; b! W3 k3 ]# l4 fble to levels obtained with topical testosterone would seem to2 M) V7 D+ [" q6 i; `; ~* e( k
provide a means to compare the relative effectiveness of
( g0 B# L9 }! j' O8 f5 T% J( ptopical testosterone to systemic testosterone effect. It cer-# i* A- ?% S/ L/ J$ p
tainly has been established that gonadotropin as well as par-
( A* `. J2 \9 ^, yenteral testosterone administration will produce genital
0 g0 |2 ^9 b) |7 @+ P, F6 E2 u9 c( Hgrowth. Our report shows that the growth of the phallus was9 q. `- A0 k; p7 F0 k* v: D  v
significantly greater with topical applications than with go-3 k' q4 M6 J# [" x
nadotropin, particularly in children less than 10 years old.8 r+ v* }' R8 G' ?
The levels of serum testosterone remained similar or lower( y' W7 @  i- d$ K6 K. i6 i! }6 F
than with gonadotropin during therapy, suggesting that topi-
, z& u5 w: Q# f7 Y* Ucal application produces genital growth by its local effect as% f8 B( S# I- y' w* m( B6 e
well as its systemic effect.. ^  \8 `% e1 F, m6 v( j* |% V
Review of our patients and their growth response related to* N3 J. e' y2 P
age shows a greater growth response at an earlier age. This is
! I& j# }9 n) Z2 Yconsistent with the findings of Wilson and Walker, who
+ y0 c( V* l" @9 L& @reported an increased conversion of testosterone to dihydrotes-
) N4 Q% ~: I# q5 U: W( ~/ ptosterone in the foreskin of neonates and infants.4 This activ-- b  g6 A# e  M5 }8 P* e
ity gradually decreases with age until puberty when it ap-
, d2 o( u# F  Y9 w2 Cproaches the same level of activity as peripheral skin. It may4 q6 |. v2 L6 W0 T6 `9 l0 K
well be that absorption of testosterone is less when applied at
, [1 A% X- v9 ]0 F$ u0 Kan earlier age as suggested by lower serum levels in children
# z7 a( Y4 N6 nless than 10 years old. This fact may be explained by the
6 H" B' n& f& vgreater ability of phallic skin to convert testosterone to dihy-
+ b$ X# _" D7 T6 C' N) Kdrotestosterone at this age. Conversely, serum levels in older2 G5 O: {/ K4 _7 K" V2 ~( b
patients were higher, possibly because of decreased local
. \4 K& `/ k1 H7 q% F667
% z; x/ T; y6 x+ Y$ d0 ^9 J) i1 [668 KLUGO AND CERNY' t; M9 C4 v2 U. D6 ]
Pt. Age
9 r: P. [' |* `, O% ^(yrs.)
1 }! d1 Y6 B* Y" \( H# O5 ASerum Testosterone Phallus (cm.) Change Length
0 r& p* R- [) L(ng./dl.) Girth x Length (%)8 d7 L$ d/ c" O& I3 `; ^
4: b3 W# W. ~5 C$ ~
8
" |+ E9 u' H* [8 H' t0 ?10
7 b5 B9 {0 C9 z# }, D12: T5 b5 o2 |) u5 }6 k8 M' Q% T
170 u" w, i4 z' ?  z( v
Gonadotropin
* x  {1 Q- L" k/ d" c71.6 2.0 X 3 16.6
9 G' w2 W' D" q' S* f# k+ Q50.4 4.0 X 5.0 20.05 e0 S; G1 F% {' v# F7 B" k
22.0 4.5 X 4.0 25.05 o- t6 ]$ n7 Y  _( f
84.6 4.0 X 4.5 11.1
: B2 Q. V) ?+ r& A85.9 4.5 X 5.5 9.0% \1 M5 q9 _& _. _& w( x, x
Av. 14.3
0 m2 k* J2 t; l, \4
6 ~* }% M7 i# W: a8# Z! C, U3 s; T1 F! B/ [
10' H1 I3 f& f4 m) R+ Q" D
127 B/ O; j# }2 t" {+ q) B
17
  H9 X  C- P4 N# E. vTopical testosterone( D8 i6 t( o3 j8 ~! g
34.6 4.5 X 6.5 85
( _2 z% @. f7 c3 x# T& h38.8 6.0 X 8.5 705 i3 |6 r& |7 X! ?0 a( L1 E: M6 g3 M0 C5 O
40.0 6.0 X 6.5 62.5+ M! W; k* c; i: Z9 b0 i5 `
93.6 6.0 X 7.0 55.53 w% @* ?3 X9 z+ E
95.0 6.5 X 7.0 27.2
% t- X( k1 V6 j( c9 y: }Av. 60.0: t( h# E2 k, M) w( n; ]
available testosterone. Again, emphasis should be placed on
) q% f7 s% F, T: F8 Q3 Zearly therapy when lower levels of testosterone appear to( m8 `  `! p' n% \9 h( G5 c
provide the best responses. The earlier therapy is instituted
9 |8 K( R4 e$ {the more likely there will be an excellent response with low# X" B. z5 {0 R9 f' I: l
serum levels. Response occurs throughout adolescence as
6 i- ?- C5 v2 D. Enoted in nomograms of phallic growth. 7 The actual response* T8 P: {" [/ e0 N; I5 p) H3 L1 L2 G
to a given serum level of testosterone is much greater at birth3 |, `8 L1 V7 c7 F
and gradually decreases as boys reach puberty. This is most
+ S9 |) d' w  v8 x) Y5 rlikely related to the conversion of testosterone to dihydrotes-
! V5 y" z$ H* T: C9 rtosterone and correlates well with the studies of testosterone
- I; z" ]3 p7 x2 l# ^9 @& w+ Oconversion in foreskin at various ages.& ^2 M8 l6 j, o7 {* w* J
The question arises regarding early treatment as to whether+ S$ L: {' r4 W1 l
one might sacrifice ultimate potential growth as with acceler-) V2 F4 ]9 M" f/ M! t
ated bone growth. The situation appears quite the reverse
2 Q, y2 k) A! {& r6 J: K* {* ^with phallic response. If the early growth period is not used
5 {& u. t" U+ u4 f1 z3 Gwhen 5a reductase activity is greatest then potential growth
! |0 S& d; w9 ^$ @! s! w7 V. cmay be lost. We have not observed any regression of growth
4 r, g2 ], x6 jattained with topical or gonadotropin therapy. It may well
: N+ K3 ~  N7 n, _be that some patients will show little or no response to any" O- h1 w- E1 L: _+ f: I
form of therapy. This would suggest a defect in the ability to
; P4 d) ?+ J# M4 vconvert testosterone to dihydrotestosterone and indicate that
4 ]" E7 g" E: D: n9 pphallic and peripheral skin, and subcutaneous tissue should1 W/ N$ O* g- Y; B! c9 h( Y
be compared for 5a reductase activity.: H) g+ R. W7 `1 W
A, loop enlarges to measure penile girth in millimeters. B,
9 U) @7 e5 x' dexample of penile girth computed easily and accurately.
6 k, X; g/ u( a! l! D% hconversion of testosterone to dihydrotestosterone. It is in this0 q! z; f/ t) f/ A+ Q* P
older group that others have noted high levels of serum
! J1 W0 s; q+ O) c7 X3 a2 atestosterone with topical application. It would also appear' X: w9 L+ w' _! V, ^
that phallic response during puberty is related directly to the
& X* M. b$ i  V$ C- y; J0 P" Lserum testosterone level. There also is other evidence of local
- R5 O: F1 j7 u/ M, `1 P, s: E! gresponse to testosterone with hair growth and with spermato-
; i3 W/ |' F% }1 Cgenesis. 5• 6
" q* {  ~2 Q( IAdministration of larger doses of gonadotropin or systemic9 C7 F5 \2 z1 E1 n4 `
testosterone, as well as topical applications that produce
1 {2 _" _2 j+ X. w) f$ nhigher levels of serum testosterone (150 to 900 ng./dl.), will# K, k, F: |) Y" c
also produce phallic growth but risks accelerated skeletal
/ q. G) }$ S  M( k) Y' Imaturation even after stopping treatment. It would appear
+ P: n) N9 \" @0 Kthat this may be avoided by topical applications of testosterone
4 i' ~8 r* |: q/ N% N5 p9 d; Zand monitoring of serum testosterone. Even with this control! L/ M+ s% N9 Y! P% C* v. L
the duration of our therapy did not exceed 3 weeks at any. {& r) u" y% q' T; W
time. It is apparent that the prepuberal male subject may
( x5 w' q# X, y: W0 o  c. Csuffer accelerated bone growth with testosterone levels near5 C# s. m; X7 K( R/ {
200 ng./dl. When skeletal maturation is complete the level of
# Z( T, s4 w  b9 Hserum testosterone can be maintained in the 700 to 1,300 ng./
+ I$ y. N! A. K$ j# y' `7 wdl. range to stimulate phallic growth and secondary sexual
' X# i% B" Q. e( h; Ychanges. Therefore, after skeletal maturation parenteral tes-
6 s+ J5 Y4 r. t4 i  E9 E- g- ytosterone may be used to advantage. Before skeletal matura-
3 x3 B, k& k4 M( k9 J' Btion care must be taken to avoid maintaining levels of serum7 w1 p% Y, C9 Y
testosterone more than 100 ng./dl. Low-dose gonadotropin
3 o' \$ o$ D' a, {depends upon intrinsic testicular activity and may require
( `( r7 e8 `/ dprolonged administration for any response.1 v; W6 v: T' j" r5 p
Alternately, topical testosterone does not depend upon tes-+ f8 P. @, |7 k- \. E
ticular function and may provide a more constant level of, V$ M. k: P$ \/ ^; s, f+ s
REFERENCES# b! z- g9 w. t" A( d: i! \
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
) a+ `1 w4 _3 V& e$ i  w6 T9 Y) z( z! YR.: The local application of testosterone cream to the prepub-
( |; E" Y2 i/ ~& ^0 hertal phallus. J. Urol., 105: 905, 1971.
0 g6 Y& ]* @/ Y7 ~8 `) M4 X( h5 N2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
* m; n  g' Z. b4 j: N+ G( vtreatment for micropenis during early childhood. J. Pediat.,
: e; v+ V  _( z83: 247, 1973.
! b7 a3 Y4 |0 a9 b+ l8 @3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, ]: X: s7 Q( W  Lone therapy for penile growth. Urology, 6: 708, 1975.
" T9 f4 |4 i' h3 T& L  s* f. b4 x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- `: G/ X" D) J% T9 v5 Y2 F
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; A# ^/ d* [* d$ _/ e
skin slices of man. J. Clin. Invest., 48: 371, 1969./ z% {1 L% ]$ {; z. p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth" p( j" J/ c: L
by topical application of androgens. J.A.M.A., 191: 521, 1965.5 ]2 U. B3 ~' n2 W6 I  \$ p. ]
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 v3 `# @, ?, \/ ]/ I& c
androgenic effect of interstitial cell tumor of the testis. J.( V; v: m7 C' x+ q
Urol., 104: 774, 1970.$ ?1 N$ K8 }8 s0 t5 l
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# a" q4 S! B3 z+ d' Q5 N- U, Qtion in the male genitalia from birth to maturity. J. Urol., 48:
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