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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, G7 `: g5 m/ e. H9 I+ ]! L
GONADOTROPIN
  a/ l, j5 i' w, uRICHARD C. KLUGO* AND JOSEPH C. CERNY! _- x6 F2 [# q- L3 p
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' B: a( w- @- U/ _
ABSTRACT; W8 ~8 [6 X: w. o1 J
Five patients were treated with gonadotropin and topical testosterone for micropenis associated! k, E# w( ^- t, P( Q) g
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# I' D$ g& c' A2 ltropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 z, {" @& h6 Y' f* C: Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* m; l& z0 \' W+ w/ a5 z/ {
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 ?$ j) K7 C- Eincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average) B* {; A5 p7 R# H- o. b
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% w. G& ~( n- d% Z9 Aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; V5 z' z$ D$ P. f+ \4 @7 `* D: ?; B
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* ~. m% R) L3 L& f
growth. The response appears to be greater in younger children, which is consistent with previ-5 l, i; J! f" z( m" y* q" p. x
ously published studies of age-related 5 reductase activity.
; T' ]+ N/ H4 h: e  QChildren with microphallus regardless of its etiology will
& V( d1 \1 h+ O) Jrequire augmentation or consideration for alteration of exter-
& E) z% H7 L% X6 d: p4 N) Wnal genitalia. In many instances urethroplasty for hypo-
  P+ C& ]) D" r9 m. I: Nspadias is easier with previous stimulation of phallic growth.; K( t  W  M! b$ r" b8 e# `
The use of testosterone administered parenterally or topically
4 p2 v9 a4 E/ chas produced effective phallic growth. 1- 3 The mechanism of; f' D$ i6 w% U- Z+ Y
response has been considered as local or systemic. With this. T: A4 f7 C" h5 U
in mind we studied 5 children with microphallus for response/ q% {" d- \% G( k! w9 Z0 V9 D: M
to gonadotropin and to topical testosterone independently.2 @# y$ R# _, y; [0 i: X$ [# t
MATERIALS AND METHODS  c1 H- D* H2 l" E8 C7 G6 x( ?0 l4 A
Five 46 XY male subjects between 3 and 17 years old were9 P- E. j8 X# z  r7 h" M! `
evaluated for serum testosterone levels and hypothalamic9 r  I$ A, g, @  N1 `7 K
function. Of these 5 boys 2 were considered to have Kallmann's, L! {5 w" i  `7 [- v# ]1 d
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 x( n4 W- Y9 ?8 S4 G0 f4 U0 d4 tlamic deficiency. After evaluation of response to luteinizing1 D  e$ C# ?0 K" A9 ]; W, c% {
hormone-releasing hormone these patients were treated with0 M& \1 V; c8 ?
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& A$ J4 D7 Z' E  k4 }after completion of gonadotropin therapy 10 per cent topical; ?% u$ O8 N: A, R: \
testosterone was applied to the phallus twice daily for 3 weeks.
+ N$ m! K  ^1 }+ CSerum testosterone, luteinizing hormone and follicle-stimulat-$ D. y% M9 q, M) m, o
ing hormone were monitored before, during and after comple-
# Q7 N2 h$ `$ L# b  Vtion of each phase of therapy. Penile stretch length was) T: z4 T, H7 q- p2 R
obtained by measuring from the symphysis pubis to the tip of
7 {. ^4 S1 K+ B* Z6 qthe glans. Penile circumferential (girth) measurements were2 W/ x! ]0 z. E9 f
obtained using an orthopedic digital measuring device (see& q5 B' s" @+ y6 H: H& Z* ?
figure).
4 P% \( v; Y) f! X7 K% i% l5 I# NRESULTS) L6 j: h% d! |4 Z
Serum testosterone increased moderately to levels between+ g+ P  d$ Y) d; m& _, [  ^  h0 g
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ ?, S, k) d& W% u8 _
terone levels with topical testosterone remained near pre-
+ |* n8 |. H5 e, o2 a* z7 wtreatment levels (35 ng./dl.) or were elevated to similar levels9 @0 t3 o0 ^$ R
developed after gonadotropin therapy (96 ng./dl.). Higher0 i& C- X0 f; t
serum levels were noted in older patients (12 and 17 years old),  `; j4 r& E1 f6 J
while lower levels persisted in younger patients (4, 8, and 106 w7 X2 |9 F, k" _# y- L$ Z
years old) (see table). Despite absence of profound alterations/ e# `; S4 j" i& x2 R2 M
of serum testosterone the topical therapy provided a greater
1 R) V0 P1 v( x, DAccepted for publication July 1, 1977. ·
: t5 N+ n3 i7 j$ k4 vRead at annual meeting of American Urological Association,1 o! w, z2 }" N3 S2 k+ q8 n
Chicago, Illinois, April 24-28, 1977.
1 A7 E( K& [; k3 Z1 U- |* Requests for reprints: Division of Urology, Henry Ford Hospital,) U# g2 Q+ j; L
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 T3 h, s" W2 kimprovement in phallic growth compared to gonadotropin.& |4 v3 |8 a7 a8 K' d
Average phallic growth with gonadotropin was 14.3 per cent
* X  @- s* D) o5 Xincrease in length and 5.0 per cent increase of girth. Topical
: T, ?. Y& }; utestosterone produced a 60.0 per cent increase of phallic length
% q5 U. E. y7 C; h  Kand 52.9 per cent increase of girth (circumference). The- L' K' v' t" b- h+ A6 i
response to topical testosterone was greatest in children be-
9 I" z5 |& ~; k" O, Jtween 4 and 8 years old, with a gradual decrease to age 17( C' Z* S  z; d. `0 b
years (see table).! Z- m4 g& Q; E" r
DISCUSSION8 M2 [4 X! c7 Z0 R9 p- z1 H1 ?
Topical testosterone has been used effectively by other
+ A$ E9 B  b. r; j( Uclinicians but its mode of action remains controversial. Im-
9 F+ W2 l& e3 ]  kmergut and associates reported an excellent growth response. k6 R3 f, X/ v7 `7 Y, n( b
to topical testosterone with low levels of serum testosterone,
" X: |3 f! n" ysuggesting a local effect.1 Others have obtained growth re-
8 Q' o/ k" H4 u; B% x: osponse with high. levels of serum testosterone after topical
4 T+ ^! l$ T+ ]& n3 G  E# |( ~& Hadministration, suggesting a systemic response. 3 The use of- m7 z3 a( M& P
gonadotropin to obtain levels of serum testosterone compara-
6 c. m3 Y- M. o; F0 Zble to levels obtained with topical testosterone would seem to
4 l6 Q6 @- ]8 L+ ]0 V6 Eprovide a means to compare the relative effectiveness of
$ Q0 X0 H8 u1 Htopical testosterone to systemic testosterone effect. It cer-/ O. a8 A/ n1 p- J
tainly has been established that gonadotropin as well as par-" X9 B  H' U) `. }# Y+ }  D  L3 Q
enteral testosterone administration will produce genital
( ?* D0 {; A* E2 xgrowth. Our report shows that the growth of the phallus was
$ r0 \  Q2 e+ E' d& Ysignificantly greater with topical applications than with go-
; L4 g5 n! b) a3 S4 }9 Fnadotropin, particularly in children less than 10 years old.1 c& E0 u! o9 X8 k2 R3 _4 x1 ^
The levels of serum testosterone remained similar or lower
3 Q  Q3 {/ y! L  ythan with gonadotropin during therapy, suggesting that topi-' C: m  C% m. Y8 ]% n  m
cal application produces genital growth by its local effect as
. ?4 H& M% t+ k7 U" P' ~- owell as its systemic effect.; G/ E4 W! P1 x" o+ ~7 p
Review of our patients and their growth response related to
8 N, [3 G7 `* ^4 J* m! gage shows a greater growth response at an earlier age. This is1 ~) s7 i2 o9 S8 U0 K! E5 e2 }2 C
consistent with the findings of Wilson and Walker, who
9 }4 S- f/ i4 Ereported an increased conversion of testosterone to dihydrotes-' o3 ^& Q, r+ j% x  O
tosterone in the foreskin of neonates and infants.4 This activ-/ `8 Y: @  B5 ~6 y6 y$ P- c# d, I
ity gradually decreases with age until puberty when it ap-
7 e  l" w0 W8 f1 ^proaches the same level of activity as peripheral skin. It may
4 Y* d+ s3 J! Owell be that absorption of testosterone is less when applied at3 B" @) b/ Y' D5 L; F& q
an earlier age as suggested by lower serum levels in children
4 f5 n4 R4 Y7 Z2 D* Eless than 10 years old. This fact may be explained by the
/ D& G# u& ~; G) Z5 Bgreater ability of phallic skin to convert testosterone to dihy-: G6 h! b5 n0 n. y
drotestosterone at this age. Conversely, serum levels in older
0 b8 X) v: o. npatients were higher, possibly because of decreased local
9 X' G/ {2 ~# U1 D9 m! u667
  ~/ U  V6 B: n% q2 i668 KLUGO AND CERNY% X. ?0 J4 y, r' `( `& M  Z
Pt. Age5 a. w5 v% a/ n1 U( _/ z9 J2 w' H
(yrs.)- |" `5 Z+ V( e" A+ P. \
Serum Testosterone Phallus (cm.) Change Length
% c' U3 |5 j9 o. f(ng./dl.) Girth x Length (%)
9 o0 o  @$ K; q( {9 {* R4
2 N" ]+ O# w1 z# l8 p84 l4 Y$ P1 F& h% {5 i. R& z
10
( J/ {. y: F3 G7 m128 j$ ^' R2 y" e& u9 U
17
9 s6 i1 x8 I- M# K- p! ^5 IGonadotropin2 _; ]+ g$ e5 Z/ T+ B. Q: [
71.6 2.0 X 3 16.6; p& @& m7 M6 f8 M- I& i
50.4 4.0 X 5.0 20.0
9 B3 v/ n; V) K/ O' V* Q' W22.0 4.5 X 4.0 25.0+ G3 o" O& I6 o. h$ i
84.6 4.0 X 4.5 11.1# c% J' e+ C# Q5 ?+ G/ b
85.9 4.5 X 5.5 9.0+ u! p' w; `2 Y8 K
Av. 14.3& _" ^+ g* z& n+ |: F
4$ \0 V1 u8 P  ]' R
8
. I: z+ o# K2 V6 }# }10
, J# O7 _  ]/ X2 Y) V( @, z12
: z2 w! k- D7 U, j- e& X17( g: M3 N$ Q& L0 ]2 H/ j
Topical testosterone
8 {: M9 u, X; k2 w34.6 4.5 X 6.5 85% j: w/ S; N; v* u0 D
38.8 6.0 X 8.5 700 h' k- o$ T4 K3 W9 G- g
40.0 6.0 X 6.5 62.50 X0 V; q3 [6 ^: q9 `: F( ]0 V
93.6 6.0 X 7.0 55.5* o3 F7 Q0 K) ~$ w
95.0 6.5 X 7.0 27.2+ s* N& ?7 p( Z' \* j9 D
Av. 60.0. Y/ S, b% Z& H
available testosterone. Again, emphasis should be placed on4 V8 G2 O. M1 O/ l! a2 F$ g" k! g
early therapy when lower levels of testosterone appear to2 B+ t% r! z6 p% t
provide the best responses. The earlier therapy is instituted) M" R: p3 {# |. B' D  B# O
the more likely there will be an excellent response with low' ~' @7 H% y1 i) m# R
serum levels. Response occurs throughout adolescence as; r& J. m3 `8 G+ H" ?2 H" z7 P
noted in nomograms of phallic growth. 7 The actual response
$ F: @9 t' O( h7 _' sto a given serum level of testosterone is much greater at birth4 o, \% a& j# ~& T0 v
and gradually decreases as boys reach puberty. This is most5 o, l& n. t0 z  F7 H: B
likely related to the conversion of testosterone to dihydrotes-3 k7 K5 y) j; U9 n
tosterone and correlates well with the studies of testosterone- O6 d% y* A8 z0 k+ s: }9 F
conversion in foreskin at various ages.  c. X( i- Y4 D& k1 p8 d. h3 m
The question arises regarding early treatment as to whether
" ~/ [5 C1 o- `) @: Y( n+ S) mone might sacrifice ultimate potential growth as with acceler-5 U+ h6 |' U/ v: V
ated bone growth. The situation appears quite the reverse
: m0 k" K& {7 g7 f' \with phallic response. If the early growth period is not used+ Q+ v1 d3 v! @4 y, \2 a- [' v) a
when 5a reductase activity is greatest then potential growth
1 |. ~% J& J6 hmay be lost. We have not observed any regression of growth; Y+ |3 F& I: q6 D
attained with topical or gonadotropin therapy. It may well3 D, P* |+ @1 H& p) L
be that some patients will show little or no response to any
, t1 B- K& m: o; Fform of therapy. This would suggest a defect in the ability to% U% W6 j, M- }/ a1 I5 {5 w
convert testosterone to dihydrotestosterone and indicate that
% ^* u" M6 p$ z4 {" B7 x! ~2 Cphallic and peripheral skin, and subcutaneous tissue should
& ~( h4 ^& [. Q/ n- v$ ube compared for 5a reductase activity.+ F) s) k! W& ]! ]; h
A, loop enlarges to measure penile girth in millimeters. B,: I+ D$ a, I  A. A
example of penile girth computed easily and accurately.7 l6 @0 `. y0 a( r" W
conversion of testosterone to dihydrotestosterone. It is in this5 A8 |* b5 U$ }* y
older group that others have noted high levels of serum
8 P- Y4 z  G( ?* c( Wtestosterone with topical application. It would also appear
+ a1 m! Y$ p/ F# H2 D/ fthat phallic response during puberty is related directly to the
& n  T! F+ V* Qserum testosterone level. There also is other evidence of local
' b' W% {( B# P* j% v- ~response to testosterone with hair growth and with spermato-- s+ T( Z0 N! j
genesis. 5• 6* U1 v2 t1 ]( J; z2 P" S
Administration of larger doses of gonadotropin or systemic
+ u8 n! z; Y- W" V5 y/ C( Y9 O6 [: ?testosterone, as well as topical applications that produce
9 T0 V0 L9 U2 c/ thigher levels of serum testosterone (150 to 900 ng./dl.), will
: x& O7 |/ @' x, I' T2 a' Ialso produce phallic growth but risks accelerated skeletal
" x& h# M& L1 ]$ x$ d  s0 Y, h6 ?maturation even after stopping treatment. It would appear
' v2 l/ x1 ^: J$ d& Mthat this may be avoided by topical applications of testosterone- {, e( _  |  h4 U
and monitoring of serum testosterone. Even with this control  b2 Z# d. P; M  Y
the duration of our therapy did not exceed 3 weeks at any& {8 T( ^! {5 ]
time. It is apparent that the prepuberal male subject may' U8 \: s7 `, P3 A" j
suffer accelerated bone growth with testosterone levels near  P! E$ G. E- [6 P7 @7 i, _- t
200 ng./dl. When skeletal maturation is complete the level of
" w1 F4 O2 l: D) Bserum testosterone can be maintained in the 700 to 1,300 ng./
( a5 A5 ?' Q5 v1 d) R9 Ndl. range to stimulate phallic growth and secondary sexual
& D. I% l1 n6 [2 Jchanges. Therefore, after skeletal maturation parenteral tes-
2 P' _8 F% U2 r0 Z6 o( Wtosterone may be used to advantage. Before skeletal matura-
" h6 O2 R* i6 a' J, `tion care must be taken to avoid maintaining levels of serum, z' Q& j1 X; J
testosterone more than 100 ng./dl. Low-dose gonadotropin
* h$ A8 `$ w/ h  \" Hdepends upon intrinsic testicular activity and may require: ~5 x6 E5 ]! F9 S
prolonged administration for any response.
# S. o: n& h9 S9 ^Alternately, topical testosterone does not depend upon tes-
0 I/ k0 l# P- a+ tticular function and may provide a more constant level of
; ~# Z/ @9 S8 s6 U, j  _0 s5 nREFERENCES
6 ~. q; n6 S' k$ f, c0 J1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 ~5 N4 M( v' q1 ]R.: The local application of testosterone cream to the prepub-
; u, M  T" c/ ^2 p, D( R8 K8 Certal phallus. J. Urol., 105: 905, 1971.
# V: R: C1 H5 p+ v- f! X, U2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) c6 t. P& ]) }, F  J. M0 \treatment for micropenis during early childhood. J. Pediat.,
- a/ J5 L6 \7 B& C" y# K0 A83: 247, 1973.
5 T4 ]$ W% r/ Q8 L, ]3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 K# B; y, V$ d/ W+ W3 Wone therapy for penile growth. Urology, 6: 708, 1975.- S; \& w: D' x3 \: a2 e+ F, F
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 V/ w3 b4 F6 @3 P+ x% I
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 Y. j4 |8 C9 M) v0 K. n5 k6 V
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. B8 c$ h9 F" N( L* G" l5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- i4 y8 _/ Q7 L, _% a
by topical application of androgens. J.A.M.A., 191: 521, 1965.
0 H6 F" z1 d* l; n8 u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, ^1 y( S; m# R
androgenic effect of interstitial cell tumor of the testis. J.' @& g6 F' Y6 ]3 s
Urol., 104: 774, 1970.
* w' y* r1 e( D2 {+ k7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 j; l8 p1 ~" F9 [- R8 @; Y$ ?5 V! u
tion in the male genitalia from birth to maturity. J. Urol., 48:
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