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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) i3 e5 L/ N0 K$ [4 M! o" r0 D, e
GONADOTROPIN
, s9 c5 }9 x7 x6 R( lRICHARD C. KLUGO* AND JOSEPH C. CERNY
% j; t2 ?+ H% ~6 MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 L2 Y- o$ Q# h1 }8 \ABSTRACT
: [) C$ M; z; \2 w0 g' l$ CFive patients were treated with gonadotropin and topical testosterone for micropenis associated8 v0 g' u2 E# \6 l6 d" f( H, h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 v) m. a  i' b& U( u* `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
* E( ?; |3 Y8 m6 }8 ~: H6 Ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! U' K2 t! J$ y, `for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
, H2 @' }9 Y( q$ ~increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
* n2 g0 }$ U$ c, _, pincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 _0 M7 q- T0 F& n% Y! L
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# r( e6 Q- l' @* X  T; i' U2 Rstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( K" G3 `; t& \1 s9 m- mgrowth. The response appears to be greater in younger children, which is consistent with previ-3 Q# b+ ]  N! l1 M& {  v/ F
ously published studies of age-related 5 reductase activity.& I0 j* t% X" D. u. b
Children with microphallus regardless of its etiology will8 S2 X' E/ h- v$ J/ `9 I# I4 ~
require augmentation or consideration for alteration of exter-
1 f; d$ F# |4 B; U  h2 U1 u' t+ Xnal genitalia. In many instances urethroplasty for hypo-* ]% X) _8 A4 E% @* A% m
spadias is easier with previous stimulation of phallic growth.
6 ]: m0 e7 q5 PThe use of testosterone administered parenterally or topically$ X* o, V4 R: F1 P9 E) j
has produced effective phallic growth. 1- 3 The mechanism of4 P$ V, ?, q4 e
response has been considered as local or systemic. With this
+ T# K9 I5 d2 cin mind we studied 5 children with microphallus for response
8 E7 s9 o1 ], f; _7 R/ H% W& ato gonadotropin and to topical testosterone independently.0 `7 l% ]% N8 r9 L$ E' Q1 C* j; U
MATERIALS AND METHODS
: M, W' c3 L. w* p* EFive 46 XY male subjects between 3 and 17 years old were
6 {' k" ]0 z: ?) Sevaluated for serum testosterone levels and hypothalamic, m9 W0 a/ Q, `4 _' R
function. Of these 5 boys 2 were considered to have Kallmann's
  q$ E3 Z- {8 O: i0 ^syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ \$ d1 i8 x! l3 f; F
lamic deficiency. After evaluation of response to luteinizing5 c! p6 P( r) ?9 b% G5 F! M
hormone-releasing hormone these patients were treated with! \9 \, @( ^; I6 Z
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 R1 t6 A$ q# h& Y* u1 _7 fafter completion of gonadotropin therapy 10 per cent topical
# o$ q7 t& D8 P# Ktestosterone was applied to the phallus twice daily for 3 weeks.
3 g9 b3 K' l, K% ^/ g  t  nSerum testosterone, luteinizing hormone and follicle-stimulat-
& `/ B0 K  R1 A  O4 zing hormone were monitored before, during and after comple-
. a- h: W; c9 G. ~7 s" ction of each phase of therapy. Penile stretch length was
6 J5 \& e4 W5 T2 }obtained by measuring from the symphysis pubis to the tip of% E; A- ^+ U2 i1 ^
the glans. Penile circumferential (girth) measurements were
  f+ `: f! [; }) Lobtained using an orthopedic digital measuring device (see
  {: H" F+ O% C2 M1 E3 Afigure).2 ]8 P$ P  L  s% N
RESULTS% S9 F6 f  \  J0 J
Serum testosterone increased moderately to levels between
' y5 E9 A; y$ Y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ a% h; N4 m- A9 T5 Qterone levels with topical testosterone remained near pre-
0 f" q  k# A8 s, ^treatment levels (35 ng./dl.) or were elevated to similar levels
. f; |8 f  W$ z8 M; H8 \developed after gonadotropin therapy (96 ng./dl.). Higher
3 M% J* B# _5 _# Dserum levels were noted in older patients (12 and 17 years old),
% M) K3 l9 b+ Q' twhile lower levels persisted in younger patients (4, 8, and 10! b" Y+ e* L  P4 Z, R- V
years old) (see table). Despite absence of profound alterations- o" j2 n% @0 R7 f  Z
of serum testosterone the topical therapy provided a greater
/ `+ |* E, ]+ {7 }, tAccepted for publication July 1, 1977. ·! V8 R' r1 r5 c5 j$ Z' ^
Read at annual meeting of American Urological Association,6 x# ]% ~; z3 Q. j& L. G$ S
Chicago, Illinois, April 24-28, 1977.0 W/ e2 V. [! K" T
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% l% v. p5 M4 y1 A2799 W. Grand Blvd., Detroit, Michigan 48202.
2 l  e* s/ s; v* Q, m! e- M' W5 aimprovement in phallic growth compared to gonadotropin.
$ z  y. }) E, \$ ^9 VAverage phallic growth with gonadotropin was 14.3 per cent
9 E; N- F3 x: A: l  c9 r+ Hincrease in length and 5.0 per cent increase of girth. Topical# T" z3 c1 D; u; B4 V; Z
testosterone produced a 60.0 per cent increase of phallic length$ a0 U- e$ _1 t+ U, m
and 52.9 per cent increase of girth (circumference). The- M% W! ~2 R6 P; J0 r
response to topical testosterone was greatest in children be-
6 m7 E: U" _- V1 T0 r9 n4 ~tween 4 and 8 years old, with a gradual decrease to age 17% p4 V8 r7 M+ w2 J5 I# N
years (see table).. D: K& b5 s" ?; Z
DISCUSSION
& c) z3 k. A* p* b. t. E, }Topical testosterone has been used effectively by other
9 I2 i. c6 ?: W- Sclinicians but its mode of action remains controversial. Im-
! n, F! b3 Z( b# r$ \) i2 fmergut and associates reported an excellent growth response: [6 E+ I9 H- ^- J5 B5 U7 `  S6 l+ C6 o
to topical testosterone with low levels of serum testosterone,
3 {& U5 `9 j) |: d& t3 [7 Z# asuggesting a local effect.1 Others have obtained growth re-
0 x5 `% j) Z  L+ M7 q  y4 m3 p6 D. i% q  Hsponse with high. levels of serum testosterone after topical" G; P1 q4 j. d
administration, suggesting a systemic response. 3 The use of. {. I3 f7 I/ n" S, i7 D" T) o
gonadotropin to obtain levels of serum testosterone compara-5 x& M4 G; o1 b  \/ r0 Z
ble to levels obtained with topical testosterone would seem to! X6 E! k& K/ f$ A
provide a means to compare the relative effectiveness of
# P5 U2 t2 ~5 h  z- w2 qtopical testosterone to systemic testosterone effect. It cer-% i1 e  Z" G' H1 Y+ p
tainly has been established that gonadotropin as well as par-. P$ L* ]' J0 a* O6 ^
enteral testosterone administration will produce genital/ R6 [9 [4 K, p' _& q
growth. Our report shows that the growth of the phallus was
  d5 v3 ~9 H) u  Q2 Msignificantly greater with topical applications than with go-1 Y/ @2 f3 I) s  I! T
nadotropin, particularly in children less than 10 years old.; {$ W, |  m9 M" V6 c0 F
The levels of serum testosterone remained similar or lower
: h1 u$ W6 T+ r+ Q% qthan with gonadotropin during therapy, suggesting that topi-
7 j7 p. m* B9 @$ f+ o6 V/ ucal application produces genital growth by its local effect as6 k2 Y7 `" J, Q9 ~
well as its systemic effect.
! ]& }0 @3 ?3 P" j  DReview of our patients and their growth response related to
+ w# t1 N2 \# L) n0 |3 vage shows a greater growth response at an earlier age. This is; q7 s1 s0 j% d1 n# {2 I
consistent with the findings of Wilson and Walker, who: [) |. n8 E$ z+ o
reported an increased conversion of testosterone to dihydrotes-
$ B1 A. o4 n+ I3 {tosterone in the foreskin of neonates and infants.4 This activ-
" E5 u/ ~7 ^6 @- i: ^. ?6 Jity gradually decreases with age until puberty when it ap-
7 {: D  V) R& ]) U1 C' p8 W4 qproaches the same level of activity as peripheral skin. It may, m; z. C7 P6 {$ D$ M4 \
well be that absorption of testosterone is less when applied at
" W* Q3 t/ F/ z* I. Ean earlier age as suggested by lower serum levels in children5 y; K$ p: J8 ^( r# c
less than 10 years old. This fact may be explained by the
$ D' Y* j; @: A) |. Zgreater ability of phallic skin to convert testosterone to dihy-
* m' k: Y% d# R5 _. ~+ Ndrotestosterone at this age. Conversely, serum levels in older0 @6 `% G$ G/ L
patients were higher, possibly because of decreased local0 ~- w9 k+ ^1 ?. H5 E
6670 l( G+ I! y# }. V6 f1 w
668 KLUGO AND CERNY
: e0 n4 B$ c+ f2 S! `Pt. Age# X/ c& [9 G) M) g9 J* G
(yrs.)
8 \. w. P9 V) [7 KSerum Testosterone Phallus (cm.) Change Length  l0 A3 K6 r# a* Q& x: ^
(ng./dl.) Girth x Length (%): L: G( @# Z+ J6 O6 ?! @$ X( A+ `
4+ `; ]5 a1 f: u2 G
8
  [+ y' U1 Z  h5 V% v% v2 C9 R10& a! Q# q, f; ]- z, m! d
12
6 G4 _. E* G& u; O17
% B' }2 z. K% z9 y# t0 z& FGonadotropin- o1 X3 ?" x2 E0 d
71.6 2.0 X 3 16.6* ]- x" _! q) X6 B2 t
50.4 4.0 X 5.0 20.0
, Q! u5 ?! a" h# Q22.0 4.5 X 4.0 25.0
9 t/ s7 q+ d! v' g/ g2 ^84.6 4.0 X 4.5 11.1
5 w0 ?: b. [6 w( K85.9 4.5 X 5.5 9.0
4 C+ K0 i1 N- ~* O' qAv. 14.3
. Y7 ]% P' m) t- D- \6 o4 x5 C4! e& `+ o" F! \9 @7 O& g
8
1 J" `9 M/ N4 @# j109 _2 G% z! r1 m, {
126 J' O5 Q* a  c% y# g6 u& y. F
17
0 i0 e3 f4 \! d# F; u# S* u+ bTopical testosterone, l% \' C, q3 K# \  I& d
34.6 4.5 X 6.5 85
9 J; B9 L* V1 h6 s+ m; y2 l38.8 6.0 X 8.5 701 I0 z3 @2 m/ b( h/ P
40.0 6.0 X 6.5 62.5' m1 I; K7 M1 G% B  v
93.6 6.0 X 7.0 55.5
& n- U/ J1 k9 `95.0 6.5 X 7.0 27.2
( U% h* y) b2 D) WAv. 60.0
% x6 D* J1 K, ?* [8 zavailable testosterone. Again, emphasis should be placed on
& ]0 K: J% Z# F  L+ |5 b9 p! Qearly therapy when lower levels of testosterone appear to
8 E# _  K5 B, G: ^% ^$ Z0 fprovide the best responses. The earlier therapy is instituted
1 f+ X: d$ l1 _the more likely there will be an excellent response with low
3 N" d2 z2 ^9 ?4 hserum levels. Response occurs throughout adolescence as9 e' O, B* S+ q9 u4 Q/ C
noted in nomograms of phallic growth. 7 The actual response" E; c' R1 n) {& g
to a given serum level of testosterone is much greater at birth
$ f) u3 S$ l% n* a7 D+ hand gradually decreases as boys reach puberty. This is most% e5 N. y' @- _
likely related to the conversion of testosterone to dihydrotes-
8 S/ \/ T: c; ^, \: T* g. z$ D8 ^tosterone and correlates well with the studies of testosterone; n9 L% C7 z* u6 ~, @
conversion in foreskin at various ages./ w. _- I$ s7 W
The question arises regarding early treatment as to whether
! v! T% g- C" {. q* \! lone might sacrifice ultimate potential growth as with acceler-
8 _2 E' U) _+ \4 a. Y, `ated bone growth. The situation appears quite the reverse
/ p/ k9 P, Q: `with phallic response. If the early growth period is not used( @# v4 O( f3 J4 Z; S8 P
when 5a reductase activity is greatest then potential growth' [5 I2 z" M. `( G
may be lost. We have not observed any regression of growth& Q4 v2 }( S. ^  s" G
attained with topical or gonadotropin therapy. It may well( Y" `9 y/ ]6 ?2 `1 }+ P
be that some patients will show little or no response to any
+ W! M6 m3 ?  W8 vform of therapy. This would suggest a defect in the ability to
* I  J9 q2 v* s& K- Sconvert testosterone to dihydrotestosterone and indicate that
& O1 _9 X- p7 `. Qphallic and peripheral skin, and subcutaneous tissue should
" K9 t& j  s3 A- mbe compared for 5a reductase activity.% b6 X$ J. c, W1 E: F3 D0 d
A, loop enlarges to measure penile girth in millimeters. B,
: m: g- g  U0 b& e7 t8 w" Uexample of penile girth computed easily and accurately.- _7 a9 I3 m" E+ Y
conversion of testosterone to dihydrotestosterone. It is in this
' P, \- G8 ~; e, Eolder group that others have noted high levels of serum
) {4 D9 k" q. f! Etestosterone with topical application. It would also appear( X  W9 N, e$ x3 U; C% K
that phallic response during puberty is related directly to the" E3 j( O: n2 t: Y5 s# N
serum testosterone level. There also is other evidence of local
: B9 |+ Y9 y) Q  P9 n! xresponse to testosterone with hair growth and with spermato-
% ]: a, }, K$ |1 ?$ \1 igenesis. 5• 6
6 V: x* H: u4 D+ @/ \8 UAdministration of larger doses of gonadotropin or systemic
* k% b/ }) {5 T6 `/ E6 c4 B4 e4 }' ~testosterone, as well as topical applications that produce5 @. q6 A% z, g5 _0 A
higher levels of serum testosterone (150 to 900 ng./dl.), will
; T, R+ Z  p. N2 a4 |also produce phallic growth but risks accelerated skeletal# Z% G( Q- @3 P% {' @
maturation even after stopping treatment. It would appear
' P0 M$ u( ?( M% ^1 y, d. B. [" @that this may be avoided by topical applications of testosterone- p7 T& L% R+ ^3 b6 I2 H
and monitoring of serum testosterone. Even with this control# f0 `$ z5 P1 ]: D' j
the duration of our therapy did not exceed 3 weeks at any: z0 ]  k# Y- a; l
time. It is apparent that the prepuberal male subject may
- V9 T. p" B0 msuffer accelerated bone growth with testosterone levels near6 H) ]0 W6 ?: f/ f
200 ng./dl. When skeletal maturation is complete the level of/ z% {) G8 X3 [& m& J
serum testosterone can be maintained in the 700 to 1,300 ng./
3 m7 f" _/ J" ]3 r6 [/ M" ^0 Xdl. range to stimulate phallic growth and secondary sexual1 W  T! w0 g$ i1 ?0 T  V! \
changes. Therefore, after skeletal maturation parenteral tes-! p; [; A: ~/ Z5 w
tosterone may be used to advantage. Before skeletal matura-
- u7 t& Y, L- M/ N( Q8 Vtion care must be taken to avoid maintaining levels of serum3 k4 G% n3 \1 H+ B
testosterone more than 100 ng./dl. Low-dose gonadotropin
' r1 H; _9 e7 r; s+ qdepends upon intrinsic testicular activity and may require
) T. b9 x7 I: B2 E. A' eprolonged administration for any response.0 u* [% ~+ e3 [) O% U3 [
Alternately, topical testosterone does not depend upon tes-
$ T3 h0 c: U) v9 m: Cticular function and may provide a more constant level of; d2 z3 D9 Q3 a* q/ ]
REFERENCES' i6 C) b1 V, Q6 ]
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! C0 m, z8 \( S
R.: The local application of testosterone cream to the prepub-% H, G# [6 B  l" m
ertal phallus. J. Urol., 105: 905, 1971.
) \5 X  j, m, O( v! Z" J3 P' h6 R2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ ?+ Y4 q0 v  o4 C) R* z3 Y- @5 w
treatment for micropenis during early childhood. J. Pediat.,
8 [% i# H' c! M. i0 x83: 247, 1973., s, u! K" ^) M7 g- T/ C
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ L! ^3 n+ z' Y0 M
one therapy for penile growth. Urology, 6: 708, 1975.  a0 o- \, d2 V8 p  Q4 m
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ C- \; O& ]  R1 X3 E5 S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, l; F  w# b: X0 Rskin slices of man. J. Clin. Invest., 48: 371, 1969.9 s& M  m6 x( h
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# Z9 n4 t, }/ s6 j8 R, l
by topical application of androgens. J.A.M.A., 191: 521, 1965.0 @6 c; A: @0 l: F) U" `
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
* ^& D& I; H) m$ R0 e6 B  P0 Y3 K2 vandrogenic effect of interstitial cell tumor of the testis. J.
" j# L% F3 o' r% k5 ?Urol., 104: 774, 1970.
# b/ Y" u' A. l; v) m7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-- N; v+ e2 [& Y$ ^9 v" D  D( o
tion in the male genitalia from birth to maturity. J. Urol., 48:
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