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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# f) J- T8 C0 ^+ E: b
GONADOTROPIN
( L  L6 R1 \& W& u: }3 CRICHARD C. KLUGO* AND JOSEPH C. CERNY
7 r! [' w6 f# y! X/ m4 SFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! C0 U. S& M& I; q' ^6 o9 qABSTRACT
" e% w4 K: m0 Q3 k8 kFive patients were treated with gonadotropin and topical testosterone for micropenis associated
" X0 a1 i6 h; G6 h% }with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) {8 f  _; _+ X4 N8 i& jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% `+ J8 `6 ~" ~! N2 W
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
0 v) P7 w) X& {! S1 a* d6 w& l+ Ffor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% Q2 E! Y! k8 l7 b5 z3 ~% t5 `increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  O, w1 Z. k: ?5 C; L; N2 ]increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& l9 l) ~- S; E1 Q: _) Aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ ^8 z: Y  d# K* q( C: U) Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
/ [8 h' M% z# K: o6 Tgrowth. The response appears to be greater in younger children, which is consistent with previ-
( h; p9 j8 @2 m4 u( Y8 P. v2 M( Bously published studies of age-related 5 reductase activity.9 b/ R7 Y/ ^  f. D
Children with microphallus regardless of its etiology will
- h4 ^3 F. ?' N' h$ `require augmentation or consideration for alteration of exter-
+ _# S7 T2 s. `2 y& {2 f9 y" U$ Lnal genitalia. In many instances urethroplasty for hypo-
$ T7 l, ]' t4 Y& B7 X( ^spadias is easier with previous stimulation of phallic growth.
6 v  }6 Z. @7 H7 tThe use of testosterone administered parenterally or topically
3 ]# p1 n8 h& v+ Z0 yhas produced effective phallic growth. 1- 3 The mechanism of
$ T! M2 u& x+ z" ?' W3 Iresponse has been considered as local or systemic. With this) w. I' y% Q2 n
in mind we studied 5 children with microphallus for response; l, T! d! R8 q9 @9 O/ T8 U2 Q
to gonadotropin and to topical testosterone independently.6 ]' `  I9 H& ^4 c0 ~
MATERIALS AND METHODS
5 I, x6 d5 h5 g; n8 b/ DFive 46 XY male subjects between 3 and 17 years old were
# A% |$ O0 p6 z3 wevaluated for serum testosterone levels and hypothalamic
; [( Y2 N: ~1 D5 _# d$ o2 Bfunction. Of these 5 boys 2 were considered to have Kallmann's
5 m" Y* o7 J+ W3 _3 @2 d% R8 jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 U( p  K: f% d9 ~3 F/ o4 h  m8 u7 v
lamic deficiency. After evaluation of response to luteinizing
2 B) H/ N* W7 t8 Shormone-releasing hormone these patients were treated with
! E% h: Y; E; O1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ Y& ]4 f( N+ {' K) [# C- Q3 w
after completion of gonadotropin therapy 10 per cent topical
( Z, w6 y" Z' b$ x) C0 `testosterone was applied to the phallus twice daily for 3 weeks.( t  t& \. N5 {! F
Serum testosterone, luteinizing hormone and follicle-stimulat-5 `& ~1 I6 A# }" s% T* D
ing hormone were monitored before, during and after comple-6 K2 f$ J1 x5 e4 ~  B3 O
tion of each phase of therapy. Penile stretch length was
% k; o7 m- e/ p7 G: S" y0 F  }obtained by measuring from the symphysis pubis to the tip of
' {6 d) ~% y2 othe glans. Penile circumferential (girth) measurements were: N8 X% G& o7 V" S2 A& t7 V
obtained using an orthopedic digital measuring device (see
' G: w; j6 s: z( W. u( w! a; Bfigure).
. m+ |- Z8 Y0 h! g& a; e( X1 rRESULTS
' g2 E, s9 k  hSerum testosterone increased moderately to levels between3 o+ ]  {" c" y% p6 V. T
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- S8 E8 _, h  v! \, j4 M7 b/ ^
terone levels with topical testosterone remained near pre-6 P6 x' s$ V, ]
treatment levels (35 ng./dl.) or were elevated to similar levels" o/ ^3 M* \8 S% N1 F5 z
developed after gonadotropin therapy (96 ng./dl.). Higher# j+ H+ n2 {2 k$ I$ b+ w+ ]1 T
serum levels were noted in older patients (12 and 17 years old),0 U9 l- u, F; B
while lower levels persisted in younger patients (4, 8, and 10
# f8 v0 s5 B1 ?7 s# z: R. gyears old) (see table). Despite absence of profound alterations& x) q; c. Q; V- @# Q- q& N
of serum testosterone the topical therapy provided a greater: h3 c+ w! Q/ k7 z, l+ r
Accepted for publication July 1, 1977. ·- H9 ^0 W4 ^) U: M% w, c+ r
Read at annual meeting of American Urological Association,4 p" |' p4 D- e8 u! z6 ^  i& f7 ]3 S
Chicago, Illinois, April 24-28, 1977.! ^, g- r& |) K, m+ C
* Requests for reprints: Division of Urology, Henry Ford Hospital,
/ E2 ^2 X, c- O8 s0 h6 Z6 m2799 W. Grand Blvd., Detroit, Michigan 48202.
; g4 V' E2 c3 N# F4 H( Mimprovement in phallic growth compared to gonadotropin.+ E8 d5 j( a! R  }( M& o5 v9 q
Average phallic growth with gonadotropin was 14.3 per cent
4 _4 H& s  r# N1 Kincrease in length and 5.0 per cent increase of girth. Topical
; E; z9 v% [) I2 Jtestosterone produced a 60.0 per cent increase of phallic length
' _& M; `- ]* D2 L; T7 d& _and 52.9 per cent increase of girth (circumference). The# ]% h2 }8 p9 p
response to topical testosterone was greatest in children be-
5 n  C( L9 U$ }: c# s( _tween 4 and 8 years old, with a gradual decrease to age 17+ g$ q! I% P% H' S' \
years (see table).1 v7 {* c# |1 s: H2 G8 o
DISCUSSION
, V/ V9 ]+ O& iTopical testosterone has been used effectively by other
# I7 x* \. d/ _. aclinicians but its mode of action remains controversial. Im-
: [  {) F6 e6 [9 T* Q  pmergut and associates reported an excellent growth response$ o- K# Z% K1 V
to topical testosterone with low levels of serum testosterone,
5 U( t: }4 H8 ^2 ^& v2 G  Ysuggesting a local effect.1 Others have obtained growth re-7 \9 t, y/ |' g
sponse with high. levels of serum testosterone after topical
2 U* E% p: r4 P# Z% C9 @8 k1 p) Radministration, suggesting a systemic response. 3 The use of. z- n0 o: n* u
gonadotropin to obtain levels of serum testosterone compara-
2 `0 @, O" o7 x: Y6 lble to levels obtained with topical testosterone would seem to
- f, `2 p) e( d  E% Zprovide a means to compare the relative effectiveness of2 j/ Z  [6 {1 y* k
topical testosterone to systemic testosterone effect. It cer-" {: ^( J- B% H
tainly has been established that gonadotropin as well as par-
* |7 z- T. Z1 {enteral testosterone administration will produce genital$ Y# R% c8 w5 h# Q8 F9 f; q8 n
growth. Our report shows that the growth of the phallus was
8 ^( }2 I. E& U! C$ v' R* G" psignificantly greater with topical applications than with go-9 A8 o+ f8 r+ u+ W1 d* x1 H" u
nadotropin, particularly in children less than 10 years old.
# r2 o: @8 t( {; T7 x3 |2 hThe levels of serum testosterone remained similar or lower
+ D, x9 H! E& B( f) W2 {( Dthan with gonadotropin during therapy, suggesting that topi-+ \- w- N& n+ m2 Y
cal application produces genital growth by its local effect as: E! k0 Z& I0 [3 K
well as its systemic effect.
/ e, y% u9 E6 m1 e1 \0 HReview of our patients and their growth response related to2 S! i  I# T7 k
age shows a greater growth response at an earlier age. This is
0 F8 z# s, z# O, y" g- Xconsistent with the findings of Wilson and Walker, who! u3 G: G8 W, L, E: F; o
reported an increased conversion of testosterone to dihydrotes-
* m) |+ f6 t3 f0 P  @tosterone in the foreskin of neonates and infants.4 This activ-  `5 I: t- y5 J
ity gradually decreases with age until puberty when it ap-3 O/ P, b, y  z! |4 X
proaches the same level of activity as peripheral skin. It may
! m& b' t/ g  i" `3 Awell be that absorption of testosterone is less when applied at( }- s+ Y. K$ g( T# f* v
an earlier age as suggested by lower serum levels in children
. c8 E' j6 _- @  q3 aless than 10 years old. This fact may be explained by the
3 X3 e0 S. s' \/ h- w! h1 `( i& j- hgreater ability of phallic skin to convert testosterone to dihy-6 ^& p; |0 Y$ h
drotestosterone at this age. Conversely, serum levels in older3 |# N" d& K5 N* F
patients were higher, possibly because of decreased local
6 X  O/ G! S' v7 a, p& a. h667
( d6 K: A8 F' ?  {4 b668 KLUGO AND CERNY! ^0 X2 B4 Z0 n) ]9 h" l
Pt. Age# ~3 U5 c3 e3 W8 d$ N7 f7 M  z, j
(yrs.)# U5 M1 v( N( I  s9 d
Serum Testosterone Phallus (cm.) Change Length/ A. {) x7 C9 y6 U
(ng./dl.) Girth x Length (%)9 h8 z9 k0 |# z5 w! o
4
4 ?* Z! K3 R# N. M* A8
3 y9 c3 J% K9 g- g10: m! q0 f2 X5 W8 m) {& g9 {* A
12
* [( e* P- `( q4 k4 H" ]: X0 I17
9 E$ j+ ?! m# p+ _5 f- mGonadotropin
. w# k' h+ L3 u# i71.6 2.0 X 3 16.6! D9 j' ]+ a; a5 ?
50.4 4.0 X 5.0 20.0
* r5 [1 h5 g/ g" m: a0 G22.0 4.5 X 4.0 25.0
; \) k! t; e( W* p7 g84.6 4.0 X 4.5 11.1
) [2 @/ l  q$ u- `85.9 4.5 X 5.5 9.0' ]% y( k2 n, G$ e* T
Av. 14.3+ Y% C. K/ Y9 l( N
45 H+ A' @" m. A7 z, P
82 C# G$ q9 f. Y- Y
10- V7 _3 [3 Q$ T5 b
12
% F9 m9 Z! O  T: E) D17
; N) V6 [5 {% I' ^( _( b6 |Topical testosterone
- L6 _. y9 [; B7 V$ e6 X34.6 4.5 X 6.5 85' H( N- p$ R, |. C
38.8 6.0 X 8.5 705 R! Y' y. O4 A; r0 I$ g
40.0 6.0 X 6.5 62.5+ `! O# ~: \$ X
93.6 6.0 X 7.0 55.5; l8 i( K, G; v" s; D
95.0 6.5 X 7.0 27.2
7 e3 d6 ^7 @* k' J+ c+ s; CAv. 60.0# l) u2 O& h) C- c; `0 w
available testosterone. Again, emphasis should be placed on2 H6 ?3 U; O" ?
early therapy when lower levels of testosterone appear to
* }& B! e& U) y6 D( B  U4 ~provide the best responses. The earlier therapy is instituted
! k: O5 Z0 O5 v: d- o9 m, Dthe more likely there will be an excellent response with low% t  \4 `" l( C( L' A
serum levels. Response occurs throughout adolescence as
1 N: ?1 I# n7 J& Y! f* Rnoted in nomograms of phallic growth. 7 The actual response
1 a5 b6 W& @8 \to a given serum level of testosterone is much greater at birth& r  y$ S) _9 M$ i: j! `$ [# m
and gradually decreases as boys reach puberty. This is most
# n- W7 ~. n) o! u/ plikely related to the conversion of testosterone to dihydrotes-0 l0 d8 J; i) E9 }$ J
tosterone and correlates well with the studies of testosterone
1 K5 J1 _' b! Y) D6 Sconversion in foreskin at various ages.
  a& ^3 M; S5 ~: HThe question arises regarding early treatment as to whether
$ X: H. s. e: F6 pone might sacrifice ultimate potential growth as with acceler-, Y3 X: D$ H9 H; Q/ @% b* h
ated bone growth. The situation appears quite the reverse) |) I0 B9 H) {' A8 K, o
with phallic response. If the early growth period is not used. B) c$ }' @$ C3 r3 P
when 5a reductase activity is greatest then potential growth
1 W& L. C" T* t3 I- Dmay be lost. We have not observed any regression of growth$ ?" i. Z9 v% o0 ~' r7 b+ ^
attained with topical or gonadotropin therapy. It may well
4 T$ \( [. W0 Vbe that some patients will show little or no response to any1 R. V; C9 F5 j7 o5 L
form of therapy. This would suggest a defect in the ability to3 b9 v0 A5 k, m/ w2 x& p1 `4 M
convert testosterone to dihydrotestosterone and indicate that( b% ^/ F6 C+ E3 L
phallic and peripheral skin, and subcutaneous tissue should
5 w8 C2 O3 Z8 n0 a+ A3 G! b8 Y  Fbe compared for 5a reductase activity.$ n% z' x  c* U( E4 {  @
A, loop enlarges to measure penile girth in millimeters. B,
- N6 D! ?% z2 _8 cexample of penile girth computed easily and accurately.
1 F7 q6 a6 w+ |% T2 e$ ^5 Sconversion of testosterone to dihydrotestosterone. It is in this
! R; X7 n5 `8 ]1 @5 Z' O! W& Tolder group that others have noted high levels of serum
" T' |( Y1 q/ `! _: Y( w* J7 Atestosterone with topical application. It would also appear
0 e- ?& f* ^3 q: I1 n& ]that phallic response during puberty is related directly to the  g# N0 N1 i" t- N! E3 R
serum testosterone level. There also is other evidence of local
: O/ i2 }) h" u' u# Fresponse to testosterone with hair growth and with spermato-+ x# P( n$ \8 `2 U9 e! _
genesis. 5• 6
, C& |- X( \+ S. rAdministration of larger doses of gonadotropin or systemic: |  Q* k; d# i# e' I
testosterone, as well as topical applications that produce, E% w4 z$ J: \. ?
higher levels of serum testosterone (150 to 900 ng./dl.), will5 \1 ?5 i  Y$ W; u7 h4 }; |/ b7 |
also produce phallic growth but risks accelerated skeletal
/ C5 l; U9 S& R1 \% _% q7 j' o! Nmaturation even after stopping treatment. It would appear
1 m3 c) d. |$ M2 N$ S$ Kthat this may be avoided by topical applications of testosterone& q0 q, D' u" {6 @
and monitoring of serum testosterone. Even with this control  `  ]8 \/ s! f! l" N
the duration of our therapy did not exceed 3 weeks at any  L% d4 R7 E/ S0 E' U8 g2 o: q, G
time. It is apparent that the prepuberal male subject may* @2 Y% [" Z2 D) `( \; {8 ~0 O
suffer accelerated bone growth with testosterone levels near3 q; l4 E4 e& y# I/ X
200 ng./dl. When skeletal maturation is complete the level of
8 {# A3 t" i5 j+ m; o, Yserum testosterone can be maintained in the 700 to 1,300 ng./) f& s$ c% d0 \5 X' m6 M
dl. range to stimulate phallic growth and secondary sexual
) J& R5 I# q# s0 Qchanges. Therefore, after skeletal maturation parenteral tes-; @* F: q& l2 P) H$ z! c
tosterone may be used to advantage. Before skeletal matura-! `; ?6 E! t- ?/ U
tion care must be taken to avoid maintaining levels of serum
# }, ~* }9 N. I8 @* mtestosterone more than 100 ng./dl. Low-dose gonadotropin2 g4 w* C0 o! p
depends upon intrinsic testicular activity and may require0 B  C$ S% ~4 |$ H4 L5 y1 P
prolonged administration for any response.8 t/ \! h1 r0 }( _) z
Alternately, topical testosterone does not depend upon tes-: R. V" N8 a* T/ E) }1 K
ticular function and may provide a more constant level of
; a2 ^0 D" K% W+ o0 vREFERENCES
7 {: f1 [8 J/ r4 ~. |, z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 R$ j2 T( _! n, P" g6 f7 L0 SR.: The local application of testosterone cream to the prepub-0 H5 t( c# X0 c) l+ D' Y8 m' \8 S
ertal phallus. J. Urol., 105: 905, 1971.1 {( e  E/ l/ G1 M
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' {1 E# d) Z) I; r- \$ }1 H9 Otreatment for micropenis during early childhood. J. Pediat.,. @% w2 y: u7 c5 N9 j7 f2 A# _8 Z
83: 247, 1973.
9 u  b$ [! `3 ?! e) Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-4 z2 \0 H+ w0 G% F' |! B$ k
one therapy for penile growth. Urology, 6: 708, 1975.8 h* B' P: O7 d' w2 F9 [8 }6 W
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 O0 M9 F0 |% l- o4 F* cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' x. q$ d8 d9 M6 p" ?skin slices of man. J. Clin. Invest., 48: 371, 1969.* F+ B7 d2 O- D/ ^, w
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 x* Z9 c. I- B8 H) O5 a/ N8 tby topical application of androgens. J.A.M.A., 191: 521, 1965.1 T+ K( H: ]+ ]6 t; m! k+ K* A
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; c; t7 |& M  h5 O2 D3 uandrogenic effect of interstitial cell tumor of the testis. J.: N/ W" V: T7 f
Urol., 104: 774, 1970.
1 {- Q2 T7 F2 a+ h7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ r- L, H" _% e7 Q! m+ _  rtion in the male genitalia from birth to maturity. J. Urol., 48:
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