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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 }5 C) p' S/ e; bGONADOTROPIN
& F' ^& g3 ~; Z. x/ [RICHARD C. KLUGO* AND JOSEPH C. CERNY7 p4 e! l7 l/ D& {
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! T2 }5 P4 F! Y, Q) AABSTRACT
" \( S4 O" W* X3 rFive patients were treated with gonadotropin and topical testosterone for micropenis associated2 ]' n( W8 P* E" ~6 H# B# J& K
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
  D6 b& @* t" g) jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone1 m; {" \. K" M- Y1 X0 a$ Z5 p
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. t3 H5 R8 ~5 F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 [) W% n7 i+ B1 i0 N
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, s" c' h' ~; P( P3 j: L" u( F% nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response4 m4 h4 ]/ i' J! v8 j& X  z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This! a+ H. _6 k9 l- @5 d1 d
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile) s8 j' P7 ~  w5 O' W# ?. K) T
growth. The response appears to be greater in younger children, which is consistent with previ-4 y) k+ G/ r" p. P
ously published studies of age-related 5 reductase activity.+ x* f; J2 n1 k  z! e8 L
Children with microphallus regardless of its etiology will
% G2 A# Y6 f7 Krequire augmentation or consideration for alteration of exter-
) p9 t6 U7 @" @0 x% gnal genitalia. In many instances urethroplasty for hypo-1 M( D( i5 F7 S3 Y/ k0 ?
spadias is easier with previous stimulation of phallic growth.
9 J: G* O6 n, @/ K* N2 [3 x" {The use of testosterone administered parenterally or topically) F7 D- V# [1 Y$ Q. a
has produced effective phallic growth. 1- 3 The mechanism of
- t% p7 m7 j" e7 G2 s5 w1 m1 B. }response has been considered as local or systemic. With this) T- P& T! b3 Q  O) `
in mind we studied 5 children with microphallus for response; w1 N: d7 a3 K. m( L
to gonadotropin and to topical testosterone independently.
; E1 ]: B2 _( E) w& [MATERIALS AND METHODS
, b2 ]! |; \8 Z% H- GFive 46 XY male subjects between 3 and 17 years old were& l9 p1 I& e, ^$ N
evaluated for serum testosterone levels and hypothalamic- E9 S  T3 s8 d' G# }( R) N
function. Of these 5 boys 2 were considered to have Kallmann's( r& i2 t" P# N8 {- u2 q* S+ @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( ?# D- B1 W7 m% f* Y3 E, alamic deficiency. After evaluation of response to luteinizing- t: Z8 ~7 z, c& Z
hormone-releasing hormone these patients were treated with& J. \3 e4 Y, s& u
1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 V1 a* {. W9 x
after completion of gonadotropin therapy 10 per cent topical
% v, b/ h4 _8 ^# s2 L  etestosterone was applied to the phallus twice daily for 3 weeks.
5 \: w" N. D4 j2 _* m4 y8 lSerum testosterone, luteinizing hormone and follicle-stimulat-
* [" J& x8 n% `! x  P5 Ping hormone were monitored before, during and after comple-% z# U4 ]0 Z& i: K' X0 l! n
tion of each phase of therapy. Penile stretch length was
( W7 T- {  Z1 K! q+ N9 S$ }' ?obtained by measuring from the symphysis pubis to the tip of( P% [. M1 ?4 Q1 U
the glans. Penile circumferential (girth) measurements were: K0 n. [1 l' x, Z  [3 r/ K
obtained using an orthopedic digital measuring device (see9 V- ], @0 j/ e' d* N7 ~
figure).
7 ]' m/ r  [# T& N5 I4 ERESULTS
6 k' A  v$ [: k; M6 qSerum testosterone increased moderately to levels between
$ m/ L$ s; A( X7 \8 F2 f* q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ ~) H' {" O0 L4 Cterone levels with topical testosterone remained near pre-( S2 ?, u! r& ?2 M# J' W; B
treatment levels (35 ng./dl.) or were elevated to similar levels
& I( Q! J8 h# p- Wdeveloped after gonadotropin therapy (96 ng./dl.). Higher% J! [- `4 S" h$ J7 O
serum levels were noted in older patients (12 and 17 years old),  Z6 o( Y2 S$ x0 n) ~8 w0 \  z
while lower levels persisted in younger patients (4, 8, and 10# v- n5 L1 G) X) d
years old) (see table). Despite absence of profound alterations
4 w4 x  e5 t3 X! b) Wof serum testosterone the topical therapy provided a greater' A2 [. H* b8 \& V& {
Accepted for publication July 1, 1977. ·
8 C3 H7 m- D; j2 ORead at annual meeting of American Urological Association,- }4 n  z# L( H) G+ E! I
Chicago, Illinois, April 24-28, 1977.
' W' X$ N' M, L) X1 C5 W* Requests for reprints: Division of Urology, Henry Ford Hospital,
. Z  m+ \* F/ ]8 H" x. o* C2 D! r2799 W. Grand Blvd., Detroit, Michigan 48202.5 n. p% Z& W1 q1 b' E
improvement in phallic growth compared to gonadotropin.# s, n! M0 F$ o: ~
Average phallic growth with gonadotropin was 14.3 per cent- \9 o% @% h  F" Q
increase in length and 5.0 per cent increase of girth. Topical' C8 h4 Q+ K: R+ g! C
testosterone produced a 60.0 per cent increase of phallic length
# I! Y4 a4 Q; A2 X: c  u; b1 Land 52.9 per cent increase of girth (circumference). The
+ @3 u8 L  t/ d/ H9 R6 Zresponse to topical testosterone was greatest in children be-
9 n+ d/ M: y7 P1 W3 T/ \7 N/ X9 ztween 4 and 8 years old, with a gradual decrease to age 17% M0 S3 Z. _% f) P3 p$ q' L( L
years (see table).% \) R6 H8 m8 I) ~
DISCUSSION
4 V* V) [0 @/ E$ I9 A. g' F! |Topical testosterone has been used effectively by other5 y, W1 b7 `1 U: [5 m3 y
clinicians but its mode of action remains controversial. Im-4 _+ {; x) @2 k8 @3 L
mergut and associates reported an excellent growth response( e* T# Z# n  h2 I  O) [
to topical testosterone with low levels of serum testosterone,
" \! E" A% D8 `) h+ U3 Isuggesting a local effect.1 Others have obtained growth re-
7 o) k+ q; Y/ h# gsponse with high. levels of serum testosterone after topical
4 g8 ^$ r) f: V" v" k+ ?administration, suggesting a systemic response. 3 The use of
! }5 l, V  H3 J8 D, _gonadotropin to obtain levels of serum testosterone compara-6 }) k& G9 u% c. u% P  I: K
ble to levels obtained with topical testosterone would seem to
$ r0 b8 M- Q% o% H0 r6 fprovide a means to compare the relative effectiveness of
  @9 v" E+ d# F5 N8 H$ Y9 `2 N! W' Ltopical testosterone to systemic testosterone effect. It cer-
" O7 ~+ G: ~- U' K+ Dtainly has been established that gonadotropin as well as par-# x$ L% A4 f$ B) ]! u
enteral testosterone administration will produce genital
. P. _+ n5 q  j! rgrowth. Our report shows that the growth of the phallus was
, {6 c3 R' G! }  V, r& lsignificantly greater with topical applications than with go-, u# R) N% B0 q6 T. x2 F- F
nadotropin, particularly in children less than 10 years old." n1 H6 L+ E, {2 q; u+ v6 n8 T
The levels of serum testosterone remained similar or lower
/ |2 E0 Z( f9 l2 `than with gonadotropin during therapy, suggesting that topi-
: ]3 e5 y. }( U3 Y# f- d% Q; l$ acal application produces genital growth by its local effect as
6 c( S9 b+ H6 G8 ?" A/ ^& awell as its systemic effect.
" _; D9 g% Y* ?0 @! |7 FReview of our patients and their growth response related to
1 t+ k; j, ^# d. A5 y% uage shows a greater growth response at an earlier age. This is0 i6 N5 T& J+ m, R9 R( v8 |
consistent with the findings of Wilson and Walker, who
' j. N  \5 @( S4 Xreported an increased conversion of testosterone to dihydrotes-
* Z! z1 ]% t1 a4 {tosterone in the foreskin of neonates and infants.4 This activ-% z  q: x6 U) _7 S! v- p, A( {, k. t
ity gradually decreases with age until puberty when it ap-
) B- n5 j# i) f! X, H& a2 c( Pproaches the same level of activity as peripheral skin. It may
2 L$ [: M# k9 S# K! z8 jwell be that absorption of testosterone is less when applied at6 @9 u1 q9 w4 i9 z- L, y$ k
an earlier age as suggested by lower serum levels in children, W- v6 f9 B" K3 f# S; Q' }
less than 10 years old. This fact may be explained by the# ?+ r! f/ @7 Q9 c/ ]! x
greater ability of phallic skin to convert testosterone to dihy-3 H; q6 ~$ I6 `3 Q; e$ L
drotestosterone at this age. Conversely, serum levels in older5 p! h0 `" e  M9 E
patients were higher, possibly because of decreased local
$ c. z5 Y% g$ q' y667  j; l% t9 }6 P
668 KLUGO AND CERNY
2 }: p& ?  `8 A6 h2 U) ePt. Age/ a9 F, Z' n8 E9 o3 a3 ]9 q
(yrs.)
- J0 K0 j# K' V! h4 ASerum Testosterone Phallus (cm.) Change Length
5 R2 J" n" c% K. k" V1 O(ng./dl.) Girth x Length (%): ^, e, k$ R. w& z  @
47 v& X9 M0 `+ t5 [; c7 M0 M
8
( l: o$ v1 R" X2 p10: X$ P( d, Z$ ?& p5 L5 i* J, W
124 J7 k9 q; t/ U6 B
17$ n5 `9 Y, i7 l* X% L1 d
Gonadotropin
% {$ s; s3 O4 H7 [" V71.6 2.0 X 3 16.6" w! L# L& Z% a$ x' s
50.4 4.0 X 5.0 20.0& [( N9 m; H9 t1 Q) Q
22.0 4.5 X 4.0 25.0
5 h7 A! W( g! `1 h84.6 4.0 X 4.5 11.1
& Z7 m( e1 {' [# D$ l85.9 4.5 X 5.5 9.0+ ]0 b7 B) ]0 E7 e1 C" H( F
Av. 14.3$ f0 H+ x& k# M7 b/ b- T3 l
4
8 k- A. j5 J& {/ r8# O, I( Q6 k, B( `/ s! m
10
9 b6 W2 a$ m! }# P7 o. D! K, ~12
4 H! a+ p' {3 w# [1 S17
% g8 J* B: g9 Y. f& I7 RTopical testosterone% f+ q3 X2 H+ M% a2 J$ M/ f
34.6 4.5 X 6.5 85
+ B0 y7 j3 d+ C& X38.8 6.0 X 8.5 70
! @9 p' Z% f0 q# {' H8 ^6 ^3 `40.0 6.0 X 6.5 62.5- y5 Z1 A- G/ u, J. P
93.6 6.0 X 7.0 55.59 m3 P, O- c6 z4 Q8 b& }
95.0 6.5 X 7.0 27.2
2 B. L9 V9 v7 l8 R5 Y! V2 j  RAv. 60.07 ?8 A  n0 `1 F$ w( R& p0 }
available testosterone. Again, emphasis should be placed on6 J; N8 [! i7 d- F1 r; R
early therapy when lower levels of testosterone appear to1 @& j6 {( }$ @" q
provide the best responses. The earlier therapy is instituted+ b  e# ?' l8 T1 c" o7 ~- D  E
the more likely there will be an excellent response with low  K( V2 @5 g$ |) `4 ?6 \: s! _
serum levels. Response occurs throughout adolescence as
% Q, |: P5 q$ U' O3 q( enoted in nomograms of phallic growth. 7 The actual response- B- V' k$ H3 `! |* p# Y
to a given serum level of testosterone is much greater at birth5 q! N( d& R8 k7 D9 G
and gradually decreases as boys reach puberty. This is most4 V; ~* Z7 d! e# Z/ Q
likely related to the conversion of testosterone to dihydrotes-
: C2 F3 f5 D  i/ y* m4 Utosterone and correlates well with the studies of testosterone; s8 y/ L0 E; j0 B1 v
conversion in foreskin at various ages.8 W6 R6 ?/ ?& ]6 f4 x
The question arises regarding early treatment as to whether- i/ `, h9 z, Q% e7 L5 ?
one might sacrifice ultimate potential growth as with acceler-" U% ~$ h1 Q6 ^7 S0 k' i) t4 X
ated bone growth. The situation appears quite the reverse
2 ~1 [; O* T) _! pwith phallic response. If the early growth period is not used, E" n7 M5 g. @% A
when 5a reductase activity is greatest then potential growth
' T; v/ W/ T, A: x; L8 k- Y4 kmay be lost. We have not observed any regression of growth
' A! S7 F, O: @8 Tattained with topical or gonadotropin therapy. It may well. x4 a4 e, l6 F2 A1 e
be that some patients will show little or no response to any
% z8 Y1 Z4 k# }3 T" t" }8 P' Rform of therapy. This would suggest a defect in the ability to
  B, n: j2 @# o2 c0 }2 cconvert testosterone to dihydrotestosterone and indicate that
# v) Q" I' ?; D6 B( e1 ephallic and peripheral skin, and subcutaneous tissue should, V5 w2 C+ {+ V$ |+ [1 ^
be compared for 5a reductase activity.
- c7 M1 k1 N% q0 j/ k- {A, loop enlarges to measure penile girth in millimeters. B,; z/ I# p' `9 L( X2 Y
example of penile girth computed easily and accurately., F  x8 x& {  M- z! H& t' u( |5 Y2 N
conversion of testosterone to dihydrotestosterone. It is in this
& d* D2 V- h! V$ g9 U. solder group that others have noted high levels of serum4 b# J& Z* U3 r9 H! H3 w
testosterone with topical application. It would also appear! a' |+ o# U# e! B% r! N
that phallic response during puberty is related directly to the
  g( T5 R" |$ ^! N3 wserum testosterone level. There also is other evidence of local2 C  Q% C" @1 ^' z
response to testosterone with hair growth and with spermato-# }" g" Y7 u0 a+ L: Q9 G
genesis. 5• 6
# k# ~: Q7 _: J; J0 y" q' Z7 T3 @Administration of larger doses of gonadotropin or systemic
0 p6 E5 ]# g, n- k4 Y8 }testosterone, as well as topical applications that produce
7 T, X0 o7 x+ p4 f7 l1 C6 b  @higher levels of serum testosterone (150 to 900 ng./dl.), will4 I+ K3 P+ c/ Y9 ~
also produce phallic growth but risks accelerated skeletal
3 J0 e$ Z$ X' Umaturation even after stopping treatment. It would appear
& m: N8 a( ^) [5 f; O+ `9 rthat this may be avoided by topical applications of testosterone- B, A( _: Q9 F7 S+ e
and monitoring of serum testosterone. Even with this control
. }) R/ v; S2 r5 b& Ythe duration of our therapy did not exceed 3 weeks at any
  D; f% Z8 Y1 n5 Ftime. It is apparent that the prepuberal male subject may
$ c7 E% B! l( }- w! l0 O: x6 Vsuffer accelerated bone growth with testosterone levels near: Z. \" e1 @# q; O# q
200 ng./dl. When skeletal maturation is complete the level of
: R5 j. v9 g8 b0 Oserum testosterone can be maintained in the 700 to 1,300 ng./. T& e- f  n5 h* \
dl. range to stimulate phallic growth and secondary sexual
. D% w$ k4 G8 y8 t. s5 T0 x2 lchanges. Therefore, after skeletal maturation parenteral tes-0 r9 D: V2 c, \1 }' d6 S
tosterone may be used to advantage. Before skeletal matura-
5 M, p' |2 {9 I( P& Htion care must be taken to avoid maintaining levels of serum: S5 [6 W! M* M
testosterone more than 100 ng./dl. Low-dose gonadotropin" U  a4 |4 o: K9 k1 g  W) e
depends upon intrinsic testicular activity and may require- @9 T: H% o8 M+ z+ c
prolonged administration for any response.
& L% T: C' T3 R  ?* D: B$ I7 sAlternately, topical testosterone does not depend upon tes-
/ u( Q* Z1 E/ g2 g7 wticular function and may provide a more constant level of3 E2 T# ]2 m  G
REFERENCES% R1 k7 ^; }5 c" V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 B" D) w( C# t- WR.: The local application of testosterone cream to the prepub-
1 ]6 o2 s8 F2 b' y' }  Gertal phallus. J. Urol., 105: 905, 1971.! J4 K; o' C/ k
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 a  Z" b" M! o' ?4 H% t' E2 _3 p- }treatment for micropenis during early childhood. J. Pediat.,0 Q/ a* P# v; L6 g  z6 R
83: 247, 1973.# a) u1 Q+ Q) ]3 J
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( F; c- ~1 Z  J" W% k
one therapy for penile growth. Urology, 6: 708, 1975.
8 q9 @& s; T& i$ y8 G: P5 s" t4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 G; F/ l* t* A1 L# f
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# J2 T& Z  u6 G  _3 X( F: @skin slices of man. J. Clin. Invest., 48: 371, 1969.. @7 c6 y) P- n% [5 l- p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ e6 a4 N3 b0 ~0 o! ?by topical application of androgens. J.A.M.A., 191: 521, 1965.6 @' u  i! F! D# v' O: P+ U7 P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 b, S8 U8 Q7 e* f; q+ r" sandrogenic effect of interstitial cell tumor of the testis. J.
- T7 w. C2 q3 O- |" IUrol., 104: 774, 1970.( w' v% X/ V  \0 P: J0 J
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 p0 s! @2 K0 S# H9 \tion in the male genitalia from birth to maturity. J. Urol., 48:
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