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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ f6 E) s1 c/ [5 Z
GONADOTROPIN6 [' S  Z7 N; U$ L
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 a7 w5 y) A" LFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 L3 p6 _, p! b3 F" A+ }( IABSTRACT; b2 a- L! s" G+ S/ a8 w
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
. ?: n% J2 S3 n+ [) o9 e& ewith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 e/ k7 D6 ~! U6 ?/ y; G# htropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* i& m0 u# }5 ]0 `' J8 N. v8 w3 A
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! W0 d& ]" l+ V/ C* vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* k+ R3 U# W% c; x! @increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 y7 q( k" M# @2 [" b, o# Q6 Wincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 T5 v1 v$ y. f) ^: Xoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ ~2 R; f: {' X; `0 g1 {$ s
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% c, O6 l& l# G: s% X& D; @/ d! |growth. The response appears to be greater in younger children, which is consistent with previ-
) M- L- |9 j5 a. Cously published studies of age-related 5 reductase activity.
0 [0 ^+ b3 N" C! ^8 FChildren with microphallus regardless of its etiology will
( t: r, y! O  E/ U, `require augmentation or consideration for alteration of exter-
8 L: J, `4 m9 A( \/ h* p$ b$ Unal genitalia. In many instances urethroplasty for hypo-1 R" v3 N8 D. [5 b2 }/ ?) V  j
spadias is easier with previous stimulation of phallic growth.
5 ~; @3 V6 d5 V" H- |3 OThe use of testosterone administered parenterally or topically2 [  Q1 ?2 K% s  e8 o$ d3 K
has produced effective phallic growth. 1- 3 The mechanism of2 O' X% U* M- w& `+ W
response has been considered as local or systemic. With this
7 |' |4 g( j5 W% b' Hin mind we studied 5 children with microphallus for response
* @. O1 A" @( ]4 Q9 bto gonadotropin and to topical testosterone independently.4 _+ p9 b% p, C( i
MATERIALS AND METHODS0 @# x! i  R, X2 q& Y
Five 46 XY male subjects between 3 and 17 years old were: `. v6 X5 Z+ ^# ^+ n- I
evaluated for serum testosterone levels and hypothalamic
: Q4 H% a' |9 R* Mfunction. Of these 5 boys 2 were considered to have Kallmann's+ Z! P2 i* x' q& u1 m7 m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 i7 P0 W' B8 Q( g: A! Wlamic deficiency. After evaluation of response to luteinizing  b9 S3 g  O- H) [$ p. H# Z0 M
hormone-releasing hormone these patients were treated with
" X/ \1 Q0 B3 e1,000 units of gonadotropin weekly for 3 weeks. Six weeks- ^$ {: \0 j2 T0 a2 v: @- h5 Q
after completion of gonadotropin therapy 10 per cent topical
% ^( O" j9 S+ ]3 s4 y1 b, T9 Q) B  Qtestosterone was applied to the phallus twice daily for 3 weeks.' k8 v0 c0 R0 V7 B% H
Serum testosterone, luteinizing hormone and follicle-stimulat-" o! b. I+ K: n$ A
ing hormone were monitored before, during and after comple-) a/ Q- d0 u- |
tion of each phase of therapy. Penile stretch length was
+ Q7 q0 O9 d; D! n: g2 V' Hobtained by measuring from the symphysis pubis to the tip of/ \& K( D' P; J0 `" Z$ I) {
the glans. Penile circumferential (girth) measurements were
' M- z) ]5 P  xobtained using an orthopedic digital measuring device (see. `. Z& s4 V* _" d$ B+ J& m# {( r1 I
figure).
5 ^. b; s" m# h4 y; }* ]8 m6 nRESULTS+ _& l. \( @7 d1 J+ @
Serum testosterone increased moderately to levels between
# Z9 U/ j% p+ X, _9 i; C' q; \50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ U% t5 P: F% _7 q: `2 Z3 ~7 ~, [terone levels with topical testosterone remained near pre-
6 [) I" L1 |3 \# atreatment levels (35 ng./dl.) or were elevated to similar levels
6 k1 t1 f; G* R; }' vdeveloped after gonadotropin therapy (96 ng./dl.). Higher
4 f3 a8 s* W5 Y& d5 ], W! wserum levels were noted in older patients (12 and 17 years old),/ r1 B8 O9 ?. L6 d8 p
while lower levels persisted in younger patients (4, 8, and 108 d$ A2 v5 [7 u4 I; S$ R3 N
years old) (see table). Despite absence of profound alterations4 Y  b5 m1 N! {8 c
of serum testosterone the topical therapy provided a greater
: O; h1 [; @! u8 l6 F' AAccepted for publication July 1, 1977. ·
9 ]$ t( E' [; j1 ]* Y; S$ X$ bRead at annual meeting of American Urological Association,
# I- `$ C8 o  h1 JChicago, Illinois, April 24-28, 1977.8 e- t; M8 R* B: _
* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 \- Y! T8 l. a, D$ O. l, B: p7 h2799 W. Grand Blvd., Detroit, Michigan 48202./ e& Y$ x9 \5 w* ~' B5 Y4 m
improvement in phallic growth compared to gonadotropin.
+ R0 Y6 v% X2 R- K, \' F  j8 oAverage phallic growth with gonadotropin was 14.3 per cent
4 O6 S' O; S$ k$ C7 sincrease in length and 5.0 per cent increase of girth. Topical. A6 J8 G& X  B9 o+ P7 Z
testosterone produced a 60.0 per cent increase of phallic length
* g0 d  ?! J4 a! J/ |* sand 52.9 per cent increase of girth (circumference). The% j% g, c: H+ W" N1 h6 S" D. d6 o
response to topical testosterone was greatest in children be-
0 y2 P; e# U; [9 N0 f0 Htween 4 and 8 years old, with a gradual decrease to age 174 l) j  ?% f9 n2 |" L
years (see table).
* z3 t# z0 c6 b( n" }7 W3 }DISCUSSION! M, ~- }% B2 V0 r- _; K' [
Topical testosterone has been used effectively by other% J4 [) J& |2 T2 Y6 C7 s. i
clinicians but its mode of action remains controversial. Im-0 H0 c; D9 d3 W# s) Y  L$ `
mergut and associates reported an excellent growth response
8 F/ E+ \7 M3 `6 W+ o0 dto topical testosterone with low levels of serum testosterone,
" b7 W: J& T2 nsuggesting a local effect.1 Others have obtained growth re-
: G0 x$ {4 Q  M* V' Gsponse with high. levels of serum testosterone after topical/ |2 T; ^' j+ |( n; V- C9 c: i
administration, suggesting a systemic response. 3 The use of) p' h! q! i; D  l; u6 q
gonadotropin to obtain levels of serum testosterone compara-
" |. R4 I+ w1 P3 V) J9 \) able to levels obtained with topical testosterone would seem to
" O% f' Q  ?. m" o9 X. Wprovide a means to compare the relative effectiveness of
- V4 O# \2 [' G4 ]2 Ptopical testosterone to systemic testosterone effect. It cer-
2 O7 x% F  ^6 `, e" ~% s. Ctainly has been established that gonadotropin as well as par-
* i- O' z; d! x/ ~8 Oenteral testosterone administration will produce genital
: c# I) V7 [) A: ~* D" vgrowth. Our report shows that the growth of the phallus was) \+ W5 h  m( _% a! N
significantly greater with topical applications than with go-
" F5 e0 L1 S- z4 d7 znadotropin, particularly in children less than 10 years old.
4 R5 E! s0 z) l3 ~The levels of serum testosterone remained similar or lower5 N0 X, G! g$ S( \! v1 ~  A, {/ ^$ D
than with gonadotropin during therapy, suggesting that topi-) x3 z  N6 U% g/ A% w8 S, P' m
cal application produces genital growth by its local effect as/ D& ]' A1 S  t3 k# D' d7 A7 h
well as its systemic effect.8 _4 S0 m$ _9 a8 m7 y2 c. n
Review of our patients and their growth response related to
0 S. K6 O: x" [4 K1 e# ]0 Uage shows a greater growth response at an earlier age. This is$ F3 ?& {+ L0 F3 p8 R+ R
consistent with the findings of Wilson and Walker, who
4 Z9 Q" q4 n0 ~5 Ereported an increased conversion of testosterone to dihydrotes-. E* p: P% h; a3 P! A! }8 X3 ?- J
tosterone in the foreskin of neonates and infants.4 This activ-
$ Q+ y) i. M& f& w3 Z- xity gradually decreases with age until puberty when it ap-
5 x( h  Z; U! w& m* G0 v: h1 Rproaches the same level of activity as peripheral skin. It may. |0 o9 g8 F/ O$ c5 y
well be that absorption of testosterone is less when applied at$ X; c9 q0 k; U0 e  t/ L. Q) z
an earlier age as suggested by lower serum levels in children
% F  k6 |3 o" k0 K$ B. _* W. h+ Vless than 10 years old. This fact may be explained by the
3 K5 N9 q' d7 [. b: P4 jgreater ability of phallic skin to convert testosterone to dihy-4 p- O1 K9 k% Q+ Q- `& l
drotestosterone at this age. Conversely, serum levels in older: V; _- F: @3 |8 p
patients were higher, possibly because of decreased local9 T7 E7 ~, f" _1 |
667
7 _4 n+ t* [7 [! L668 KLUGO AND CERNY
: E( r0 w' ^. X3 zPt. Age9 _  Y5 {0 ^5 U9 a
(yrs.)  g( Q4 [) B0 V4 A% \7 F
Serum Testosterone Phallus (cm.) Change Length
7 V0 G; N5 [1 A2 w(ng./dl.) Girth x Length (%)
0 K( ?/ A7 B8 e$ R$ R8 q% l  r' |4
$ d: {6 q( E7 {" i& B3 t8+ P; `# B7 G4 u4 `# e4 m- h( x0 x
103 F0 X8 X* h- m/ V* O
127 j! B+ K' u8 X' M6 Q5 P; p2 i3 N) E0 x
175 G( K: ?; f# i* b/ l0 c2 w1 i  h; c
Gonadotropin" Z. [; Z  A  k2 |2 V+ Y
71.6 2.0 X 3 16.6
$ b+ `0 y$ z6 T) o3 G+ K50.4 4.0 X 5.0 20.04 i# G' L( r0 S/ a/ @1 Q% i5 n* O' d
22.0 4.5 X 4.0 25.0
. i" x8 |& G: j. q84.6 4.0 X 4.5 11.1
$ f3 H9 m3 E# t' F85.9 4.5 X 5.5 9.0
1 Z; c5 L) |8 XAv. 14.3
8 E9 H( `: A- Q2 v0 Q4) I& R8 f' d5 B
8
4 P7 t6 d1 A+ R: A# x$ w. f% o1 w7 E10
* F# v0 N# D3 @" Y( E12
& f; a; I  h4 a. t) k6 Y2 }) T) u17
) T# ]+ |" `1 P5 VTopical testosterone
( l# ~* b& G: Y" n( Y3 I34.6 4.5 X 6.5 85
7 ]8 \8 Z( \* [% c( ?& [! b! C38.8 6.0 X 8.5 70
( F/ V9 i9 ^5 {5 L$ F: M% M! m- \40.0 6.0 X 6.5 62.5
1 X8 ]' i" M' M( @+ `93.6 6.0 X 7.0 55.5" ?# n( f% l% U; W
95.0 6.5 X 7.0 27.2
& Y( ]9 K- r/ w3 l( e9 p, i; n; pAv. 60.05 N5 Z9 l6 s( m% y2 `: i/ m
available testosterone. Again, emphasis should be placed on: Q& m5 Y( p& H6 N3 m/ `( P( j
early therapy when lower levels of testosterone appear to
3 c, m7 p' Q7 X6 J. cprovide the best responses. The earlier therapy is instituted
* [6 T8 i' Y3 L, q# S0 H3 f" mthe more likely there will be an excellent response with low
1 @" O) Q8 K9 X& r5 mserum levels. Response occurs throughout adolescence as  R  L2 {1 k  D/ t; c  D1 B$ Q9 v
noted in nomograms of phallic growth. 7 The actual response
0 ?5 b: t0 u/ M; b% p; pto a given serum level of testosterone is much greater at birth4 d4 W( P- K$ {
and gradually decreases as boys reach puberty. This is most& k: k* a2 L' A$ c8 O+ J4 b- S7 q
likely related to the conversion of testosterone to dihydrotes-* N, x7 C5 t, m
tosterone and correlates well with the studies of testosterone
, }4 V6 ^7 u; ~4 J1 yconversion in foreskin at various ages.  d, l' s+ x+ D2 Z; t6 I' ]
The question arises regarding early treatment as to whether9 k" d. h% w. [. D# D/ w; e
one might sacrifice ultimate potential growth as with acceler-
9 @: _8 c% F2 p3 ^* c4 r9 U7 iated bone growth. The situation appears quite the reverse- U6 B4 f" ?0 E+ I3 O/ [
with phallic response. If the early growth period is not used; K8 N0 N8 w7 _
when 5a reductase activity is greatest then potential growth
- O3 |  W6 d" ?2 b' _may be lost. We have not observed any regression of growth
# T+ L! \; M* C$ s6 T2 s* v$ R! jattained with topical or gonadotropin therapy. It may well% Z  E$ m9 |: B* x
be that some patients will show little or no response to any/ W' L# {. E3 ^7 c0 W. h* C" p
form of therapy. This would suggest a defect in the ability to
; `3 \& G+ v( ~  O& B0 I4 Z* |convert testosterone to dihydrotestosterone and indicate that% M! W7 b! @+ Z+ o
phallic and peripheral skin, and subcutaneous tissue should. q2 ]" [6 X1 H# a1 Z7 P
be compared for 5a reductase activity.- c- ~( V/ E/ D/ l, A9 X/ ]! Z& t
A, loop enlarges to measure penile girth in millimeters. B,
. g5 W* D9 ^* f: ]6 cexample of penile girth computed easily and accurately.
) n: o5 @# f6 `; `8 ?( Gconversion of testosterone to dihydrotestosterone. It is in this
7 A2 E; Q+ ?& H7 aolder group that others have noted high levels of serum
# b: X, n- n$ `: I* ]testosterone with topical application. It would also appear
8 l$ H( O9 N. R& ~. d- j! Y. ethat phallic response during puberty is related directly to the  r0 x5 r2 n2 |. r+ j& b! v* ]" o
serum testosterone level. There also is other evidence of local
( c2 {: X( L; E/ ^, b9 v' _& presponse to testosterone with hair growth and with spermato-  W! V  k3 ^- R5 M5 y
genesis. 5• 6
: I7 i% P; F! _$ F: C4 ]! B( EAdministration of larger doses of gonadotropin or systemic
1 {1 }. B, ]. \" q0 Itestosterone, as well as topical applications that produce5 u: h# O$ N7 z5 A& _
higher levels of serum testosterone (150 to 900 ng./dl.), will% F/ O7 K+ t2 r* J4 d. ]
also produce phallic growth but risks accelerated skeletal1 f1 e+ j) o: Y( g
maturation even after stopping treatment. It would appear
$ ]& q- U  d5 w1 ~; u# l& D) @' y/ [that this may be avoided by topical applications of testosterone
, `5 p( u' `# r8 \and monitoring of serum testosterone. Even with this control2 G2 b# ?* i9 _. p" F) j7 R: B
the duration of our therapy did not exceed 3 weeks at any4 X2 t3 i3 s( E
time. It is apparent that the prepuberal male subject may
8 x3 M+ \5 D, V( Nsuffer accelerated bone growth with testosterone levels near
. p* N, P4 c# L$ }200 ng./dl. When skeletal maturation is complete the level of' j1 }5 \4 X! b: W- }) Y, u3 H
serum testosterone can be maintained in the 700 to 1,300 ng./
/ w7 n% ?$ \9 ?; J, mdl. range to stimulate phallic growth and secondary sexual5 I, D' T! Y+ ^. u
changes. Therefore, after skeletal maturation parenteral tes-1 p' ~, C. ?9 ^
tosterone may be used to advantage. Before skeletal matura-
1 h. j% z% j( S: C3 N6 Ttion care must be taken to avoid maintaining levels of serum
, k! o; W5 i" R  D" gtestosterone more than 100 ng./dl. Low-dose gonadotropin
3 ~$ T% N+ E3 r; F, |depends upon intrinsic testicular activity and may require8 G: q4 m2 S1 A: a( m- j3 C4 Q
prolonged administration for any response.5 k/ \2 y# T! i" _
Alternately, topical testosterone does not depend upon tes-5 `7 g8 q" E: H/ [/ J3 }
ticular function and may provide a more constant level of
4 O0 y) R5 ~; s0 GREFERENCES5 t6 e0 o! y. p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
) j- I: I2 z3 I7 |R.: The local application of testosterone cream to the prepub-8 h- ?! H! t4 z! L! c5 w5 k- ~  Z3 t
ertal phallus. J. Urol., 105: 905, 1971., U6 V+ z4 S4 n0 ]% _1 l0 e0 z7 k' S
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 X1 b" _% W7 D  I# d* M; Q7 ?& g# o
treatment for micropenis during early childhood. J. Pediat.,+ J. o5 h" P* _, u. w  L6 {, [
83: 247, 1973.
4 j9 H8 Y: O5 l3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-- D4 [+ R1 T7 {' O8 _( C) z/ C
one therapy for penile growth. Urology, 6: 708, 1975./ l) f. f; D3 \
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ j, }! U# r, F7 {$ Yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( H6 m' b. i* m0 ?; B' G0 }' z
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 Y8 X4 S6 |  u! b, j
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 Y8 j' [# W2 e' ^& W9 {
by topical application of androgens. J.A.M.A., 191: 521, 1965.
/ |' b! {+ U, M6 Y1 F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. ], q- c* J( z1 B2 f1 B. T* yandrogenic effect of interstitial cell tumor of the testis. J.
8 h; v& j8 N. E4 {5 FUrol., 104: 774, 1970.
  t8 |; @* z% P' J. ~4 y( i6 q4 p7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 o' |7 {5 t% e) t5 \2 Htion in the male genitalia from birth to maturity. J. Urol., 48:
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