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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
' O1 t- m0 G+ \$ S2 k2 j8 pGONADOTROPIN$ o3 J$ Y( p( m' c: T! R6 m
RICHARD C. KLUGO* AND JOSEPH C. CERNY, t2 R( `; w2 j' B! o1 q; Z; {
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan( W+ w% H# |4 F4 p: V, O
ABSTRACT6 h4 G9 Q: k8 d  m
Five patients were treated with gonadotropin and topical testosterone for micropenis associated1 |. x' Q  W6 V5 P0 O; Y, a
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ N% j5 z9 ~! Q% Q8 m" q4 b4 Ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone8 g: |6 f2 j9 K- Z3 x' a
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. J8 T( e' j+ n, efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 n' K4 z' U5 c" B
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 }/ \, Q+ g4 z6 Rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; E8 c! S% c) S- I( l+ O- Poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This) E( q! a' N% w8 `$ `# S
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 M% e2 }5 c. \0 U, k' r2 ogrowth. The response appears to be greater in younger children, which is consistent with previ-
1 f# B' p2 ~) m6 yously published studies of age-related 5 reductase activity.0 A! m6 W3 u7 a0 A& j
Children with microphallus regardless of its etiology will3 Z3 o* `3 a/ o/ s
require augmentation or consideration for alteration of exter-- W) P8 j( G; O2 z5 T3 p( T
nal genitalia. In many instances urethroplasty for hypo-
/ l8 a) i0 M/ q/ X4 [( ]spadias is easier with previous stimulation of phallic growth.
* H! Y: @2 h! jThe use of testosterone administered parenterally or topically/ F' s9 `# p& \2 d$ \5 ]- z
has produced effective phallic growth. 1- 3 The mechanism of
8 s, @$ R1 V' Y3 Jresponse has been considered as local or systemic. With this
' ]/ P2 Y& `$ r; ~+ t; B1 ]in mind we studied 5 children with microphallus for response
  Y0 b# K/ ~- Z+ T* z2 xto gonadotropin and to topical testosterone independently.9 {, f* L- q1 i+ S9 j+ C' Z
MATERIALS AND METHODS( F) V, |5 ~- V
Five 46 XY male subjects between 3 and 17 years old were
/ r* _, ^' |' O3 _+ j4 wevaluated for serum testosterone levels and hypothalamic
+ ~  l& B; ?* x4 t# nfunction. Of these 5 boys 2 were considered to have Kallmann's6 @$ w( t9 e1 m: ^4 [7 T% f
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) z' O' C: V' B; Z; h5 ?
lamic deficiency. After evaluation of response to luteinizing
! L/ ?4 G/ A4 F5 f6 Chormone-releasing hormone these patients were treated with" }: k+ M/ k7 T/ K' s) K# M2 V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 t6 e; e7 ]# G0 N" H1 ^
after completion of gonadotropin therapy 10 per cent topical  `* A; A: p, h+ `$ T
testosterone was applied to the phallus twice daily for 3 weeks.6 \# r) H8 ~4 N( v; _' V
Serum testosterone, luteinizing hormone and follicle-stimulat-
3 z# B" T! m) G/ k* d- v5 u9 ping hormone were monitored before, during and after comple-# h& v& t8 G9 W
tion of each phase of therapy. Penile stretch length was8 p$ {8 Q! J8 ~* G
obtained by measuring from the symphysis pubis to the tip of
, c6 ]8 ~; |5 Z8 |the glans. Penile circumferential (girth) measurements were
4 V2 q# |' J1 Y2 J) D* C2 H  y& Kobtained using an orthopedic digital measuring device (see" ]; O' V3 o2 N% U: p
figure).
- ?' R5 f- \. l: Q% V, Y+ P3 CRESULTS  M8 [0 ~8 n: _, O, Z8 B4 |2 i
Serum testosterone increased moderately to levels between( `3 Z& l8 l5 H" ?8 ?
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 y# ~9 _8 v/ r2 j. Aterone levels with topical testosterone remained near pre-2 B: U  [2 H- m& K
treatment levels (35 ng./dl.) or were elevated to similar levels# E6 J% `/ B/ `; J5 _$ o) Q
developed after gonadotropin therapy (96 ng./dl.). Higher
- _8 s) ?4 _; mserum levels were noted in older patients (12 and 17 years old),
6 G& m& Y) V1 L1 E0 v: Dwhile lower levels persisted in younger patients (4, 8, and 10
+ h4 ~3 T+ c# k' `- e: ?9 s) O1 cyears old) (see table). Despite absence of profound alterations
: |; W' f! l6 o9 H# ~3 Mof serum testosterone the topical therapy provided a greater) j( T' \# Z  S0 v
Accepted for publication July 1, 1977. ·
; R- Q  U( h4 }! P3 |' }8 DRead at annual meeting of American Urological Association,% r7 a" H$ }' C; B! W7 h( {
Chicago, Illinois, April 24-28, 1977.# ^2 a5 C& V; ~2 B7 Q. D. H
* Requests for reprints: Division of Urology, Henry Ford Hospital,+ q" {+ _9 u; g) ~! J: ]9 o4 [
2799 W. Grand Blvd., Detroit, Michigan 48202.
( u1 X. n  v; g/ \7 simprovement in phallic growth compared to gonadotropin.! F7 A# U6 O" D7 }( u, S
Average phallic growth with gonadotropin was 14.3 per cent
4 D6 c5 s( N) m7 f0 pincrease in length and 5.0 per cent increase of girth. Topical
0 I8 j3 r0 r: x" Z6 D/ ^testosterone produced a 60.0 per cent increase of phallic length; t, [, |2 g" F6 n
and 52.9 per cent increase of girth (circumference). The
# Z. _& l- d" m& i+ _2 Sresponse to topical testosterone was greatest in children be-
, G9 u) y. ?4 T7 @! G: ltween 4 and 8 years old, with a gradual decrease to age 17
% B; e6 B- G& A. j- F4 Q) [years (see table).
& _6 @4 A  K) T4 UDISCUSSION: J# ^) O' U. ?" r! T
Topical testosterone has been used effectively by other# y7 J& {* e" y
clinicians but its mode of action remains controversial. Im-2 d& A; ^+ S; ?: K6 ~: h
mergut and associates reported an excellent growth response
7 C1 O- ^- p' S0 A9 o4 Uto topical testosterone with low levels of serum testosterone,% ~, h9 E2 `; \# j
suggesting a local effect.1 Others have obtained growth re-: G8 G- h; d7 i$ r( f
sponse with high. levels of serum testosterone after topical
# k9 S' N. y9 V% B/ n# |administration, suggesting a systemic response. 3 The use of
6 |* }/ U" J8 k" m+ {! Q& Hgonadotropin to obtain levels of serum testosterone compara-
# i! r2 X. I5 E; Bble to levels obtained with topical testosterone would seem to9 r0 @! P( V" q6 `  d* q5 o
provide a means to compare the relative effectiveness of1 X3 Z  ?- w( G; P# a
topical testosterone to systemic testosterone effect. It cer-3 {! u, E, |! V4 c' i8 g. |8 S
tainly has been established that gonadotropin as well as par-
4 {- u& V9 v4 m: jenteral testosterone administration will produce genital
7 P5 m# M# B7 f) ngrowth. Our report shows that the growth of the phallus was- ^; e' c; f3 }: q
significantly greater with topical applications than with go-' m5 X% E6 Z$ ~2 @8 B
nadotropin, particularly in children less than 10 years old.
* \7 t" `! R; y  j/ C9 b$ Y3 Z, ~The levels of serum testosterone remained similar or lower5 p3 z+ _- l: k
than with gonadotropin during therapy, suggesting that topi-
# _; f3 f5 |& }" n7 }. Vcal application produces genital growth by its local effect as
0 t. X7 [5 J: B: D! W, D4 @well as its systemic effect.+ g. y3 g! L* M: q
Review of our patients and their growth response related to, Y" N" j# i/ J0 G& j/ s/ a5 N/ z7 D
age shows a greater growth response at an earlier age. This is3 F. T& I! x) Z! N. w5 T" C6 h
consistent with the findings of Wilson and Walker, who
, g( S, n0 s9 Kreported an increased conversion of testosterone to dihydrotes-
4 I# l2 c8 S) K5 K& \# }tosterone in the foreskin of neonates and infants.4 This activ-. H% c6 n! t4 z$ e& _& a7 T
ity gradually decreases with age until puberty when it ap-
$ o" m" R, X# y$ d( [proaches the same level of activity as peripheral skin. It may0 |8 g7 m* E! `0 N
well be that absorption of testosterone is less when applied at
/ r' K/ C  E8 o, H* ^an earlier age as suggested by lower serum levels in children
: a$ r/ N7 \0 s* t% sless than 10 years old. This fact may be explained by the
. _5 w* H+ T0 n2 qgreater ability of phallic skin to convert testosterone to dihy-
: t8 N  v) b" G8 xdrotestosterone at this age. Conversely, serum levels in older
1 Z6 r; {# ~! ^% o) Epatients were higher, possibly because of decreased local8 a5 G! P/ [5 x) o' s6 ^& n  i
667: Z) \% L" N: P* S7 F- x3 x0 L
668 KLUGO AND CERNY
) N; a- P! @  m+ z4 o6 Z, l9 L5 D5 Z, xPt. Age3 w3 x& Y  x. j- ?5 O7 r
(yrs.)
; U( Q: F& j- \9 Z* f0 |Serum Testosterone Phallus (cm.) Change Length& R4 q9 d3 ~7 o' {% ^
(ng./dl.) Girth x Length (%)
4 k/ T5 E1 H4 u7 {: S4/ l& z! w) ^, B2 T* ]
8
% Y# \7 w4 h  I4 |& [+ o1 A* ~10
2 P+ ]6 {& H6 _2 C12  {3 U; O% ~3 \, T3 q/ n( X
17
0 b+ n7 F& ?3 \5 Q- {- R7 tGonadotropin2 g& p1 b9 E: p4 r+ e
71.6 2.0 X 3 16.6
. n; \8 X- ?0 d7 g  I50.4 4.0 X 5.0 20.0
/ Y- `  Y# Q  Z  |4 W22.0 4.5 X 4.0 25.02 d1 F" h" F/ s) l; z- l
84.6 4.0 X 4.5 11.10 F" V7 R9 u6 R" }1 P; S5 o4 K
85.9 4.5 X 5.5 9.0- Q, Y/ |! J( l7 f0 W' `
Av. 14.3
# w0 h* i7 P+ l( Z& U41 T. U, v0 d3 q( x0 r
8
: E) O$ q, r" ~9 T& J6 F* `) |+ z10, ]+ v, Z6 @1 c* r% K  z; v% X
12
4 Q, R4 _8 G0 B  G8 v- L17. Q7 I' ^4 L. S9 a8 s1 |
Topical testosterone( y- C% w5 U& G- }, a- h
34.6 4.5 X 6.5 854 x+ |" T9 U$ Q4 ^5 u
38.8 6.0 X 8.5 70) A4 U  y/ Z5 Y# x0 _+ B' M
40.0 6.0 X 6.5 62.5; j  S7 m1 d; B
93.6 6.0 X 7.0 55.5
3 e. F9 e/ X6 M( H; U, b5 R95.0 6.5 X 7.0 27.2- {6 h9 j( R9 s, U- N- w8 @
Av. 60.0
% J$ D7 o  g, ]) x+ D+ wavailable testosterone. Again, emphasis should be placed on; J4 x. t8 T4 [6 R
early therapy when lower levels of testosterone appear to
- l# t- K8 i+ B: cprovide the best responses. The earlier therapy is instituted
1 t2 X3 _3 h- ?2 q1 n( t) U+ k5 othe more likely there will be an excellent response with low/ R& c( W7 x, z9 Y& c
serum levels. Response occurs throughout adolescence as
, h6 }2 e9 K, v5 U4 F, B' ?noted in nomograms of phallic growth. 7 The actual response
; ?! l6 s' D# o  w1 ^) l, Oto a given serum level of testosterone is much greater at birth
- s8 e& w$ K- ~4 d3 b& M2 m6 N8 R% f& `and gradually decreases as boys reach puberty. This is most
( ^/ V7 l- h& u6 glikely related to the conversion of testosterone to dihydrotes-
* W; G) x1 g! {( rtosterone and correlates well with the studies of testosterone/ }; r7 `6 W1 B2 Y$ m
conversion in foreskin at various ages.2 i. ?- A9 H* O
The question arises regarding early treatment as to whether* s9 t1 H1 T4 \$ f
one might sacrifice ultimate potential growth as with acceler-
' e+ M: J/ y( z& f0 d4 mated bone growth. The situation appears quite the reverse* L8 ~) J6 s  h# N0 \# h
with phallic response. If the early growth period is not used( b! F! u% W+ I1 O4 u, C
when 5a reductase activity is greatest then potential growth  C/ B8 z4 M. E2 j. O; k
may be lost. We have not observed any regression of growth/ E3 l- ]2 b% ?& z
attained with topical or gonadotropin therapy. It may well
4 O! u9 v5 L: z' f. n2 M" Pbe that some patients will show little or no response to any- X1 G; F7 z# k, M- B
form of therapy. This would suggest a defect in the ability to; {; W5 p" G' y: b4 p& y: V
convert testosterone to dihydrotestosterone and indicate that- m# U$ d: y3 w6 _; e/ z: [1 q
phallic and peripheral skin, and subcutaneous tissue should
6 L7 H  s; ]+ T* }' j+ Y2 {3 _7 Vbe compared for 5a reductase activity.
# Z# u( Y, w. E% |4 f0 EA, loop enlarges to measure penile girth in millimeters. B,
  C8 j: U+ Q' Q+ s2 _$ ~$ Hexample of penile girth computed easily and accurately.
' Q) D8 b4 ?2 o7 M+ @8 f* ~8 Wconversion of testosterone to dihydrotestosterone. It is in this
4 W0 X; ^3 m2 n# s  K: Kolder group that others have noted high levels of serum
) C" S2 L  r& J: _& v/ d6 w5 utestosterone with topical application. It would also appear
* J' R+ R$ O! ^+ Mthat phallic response during puberty is related directly to the5 H* s$ o' B; A! H. A
serum testosterone level. There also is other evidence of local# p7 C) Z2 J4 [7 {8 n
response to testosterone with hair growth and with spermato-
( ^# O/ A; o1 U; }; w. b0 Cgenesis. 5• 6# J  V% Y, O0 v+ _# `0 R7 I( \9 v+ S9 Z
Administration of larger doses of gonadotropin or systemic: k# |# s3 Q2 u1 k
testosterone, as well as topical applications that produce% z" z# n+ [) u; |
higher levels of serum testosterone (150 to 900 ng./dl.), will3 M* H' C* M- O) [3 M; q
also produce phallic growth but risks accelerated skeletal
9 @, [1 l  J( U! E- x0 q" zmaturation even after stopping treatment. It would appear
" x6 }# D2 t' ~& j: n) v6 V2 k+ q- Gthat this may be avoided by topical applications of testosterone, |% c- z1 U4 a5 ]* y$ [" R) p2 q
and monitoring of serum testosterone. Even with this control8 z& ~- Z. C6 A  @5 k# N6 H
the duration of our therapy did not exceed 3 weeks at any
, `/ h( z/ S! m1 `time. It is apparent that the prepuberal male subject may: U/ C  k6 n  ~3 f& y! f- I1 [
suffer accelerated bone growth with testosterone levels near
7 f3 E( k* a3 W" R$ W+ |200 ng./dl. When skeletal maturation is complete the level of
. m7 `! K, W2 S% n9 F8 Yserum testosterone can be maintained in the 700 to 1,300 ng./' A" O  k+ A1 z; [. i) q0 d2 e
dl. range to stimulate phallic growth and secondary sexual
/ b% L3 |5 s+ z% t* `* Pchanges. Therefore, after skeletal maturation parenteral tes-
& t1 ~0 f0 O+ e& {tosterone may be used to advantage. Before skeletal matura-  P. w* o% O: x$ ?( O
tion care must be taken to avoid maintaining levels of serum5 m: z! K! ]; q/ V# A
testosterone more than 100 ng./dl. Low-dose gonadotropin
5 K4 p, W: Y$ X+ i, g+ idepends upon intrinsic testicular activity and may require
$ l8 M* W: }" _$ L4 wprolonged administration for any response.$ I: k6 h: T4 T7 G0 F
Alternately, topical testosterone does not depend upon tes-$ p% R, v" }3 A# r8 y$ ^$ w0 C
ticular function and may provide a more constant level of( C. e5 G( f5 n( w1 N
REFERENCES6 @& {4 I. b0 O; R4 o' l
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,  A* G  V! n. |) o* C8 w
R.: The local application of testosterone cream to the prepub-/ E( I5 W! X; D7 K% b' ?
ertal phallus. J. Urol., 105: 905, 1971.7 l& c. R2 t* z5 A" [
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 e4 o$ H) U$ q8 r+ r5 |
treatment for micropenis during early childhood. J. Pediat.,' m2 g9 c9 P! w( x
83: 247, 1973.
: A" O: k" h* H# g) C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& E8 s% X& Y) {, _' P
one therapy for penile growth. Urology, 6: 708, 1975.
2 {8 S: Y0 {3 |! a: G4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone2 t+ M+ \6 P8 Q0 @2 n  {
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* @9 l  N  X6 U; H* o* W1 L$ Xskin slices of man. J. Clin. Invest., 48: 371, 1969.$ F$ x. B+ \7 M% a
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( l  }3 P  E% A, dby topical application of androgens. J.A.M.A., 191: 521, 1965.
  S% l! H# N- w+ m1 k% t: `& T7 {6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: k+ M) {8 w8 j4 T$ I6 n- n
androgenic effect of interstitial cell tumor of the testis. J.
( D0 c% g5 P( T7 p, ~Urol., 104: 774, 1970.
" M+ c4 f- Q0 A. @$ A& j7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; ]  R2 a" y( B2 N, g3 S- {tion in the male genitalia from birth to maturity. J. Urol., 48:
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