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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND6 \7 j0 H- U" ?, Q) t5 o' \9 J" V
GONADOTROPIN5 g$ D' `7 R( R9 k/ d
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 L4 Q( ?: Q* V# y) h* K2 X5 _! G
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 F; H5 Y; ^8 e- E# ^0 O# ^4 F
ABSTRACT7 v0 ]9 u1 H) _* ]7 O
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) }! V; p6 ^5 g; Q7 |  H3 k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 X% E3 z/ M7 m9 n4 v' a/ ]. W0 L& ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ J' O0 U9 C# ~; T* Y- Gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, B0 w2 O; G$ ^; ^+ H4 ^% _for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ e- k% Z1 c" O8 R) E7 j7 Tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average) P; }) V/ [; `* N# _# r
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: `( X% a$ Q2 o" Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 ^# V$ ?( ~3 Z5 K/ tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, I1 T0 _) }! u, I6 ]/ z+ R5 Fgrowth. The response appears to be greater in younger children, which is consistent with previ-
2 f. g  Z: I& a4 R2 x7 ?ously published studies of age-related 5 reductase activity.
8 `" Z9 F# b) Q7 y. \1 S2 ?3 k: yChildren with microphallus regardless of its etiology will$ l% ?& W4 J5 J3 x
require augmentation or consideration for alteration of exter-
( a! B/ R. M! C1 I! M2 tnal genitalia. In many instances urethroplasty for hypo-$ j5 y" N. k8 I, O
spadias is easier with previous stimulation of phallic growth.
7 ?2 o3 {2 U( c1 ^4 |The use of testosterone administered parenterally or topically3 y9 [/ ?2 J/ w1 ^( G
has produced effective phallic growth. 1- 3 The mechanism of
8 c) K' M; n6 d9 K2 hresponse has been considered as local or systemic. With this
" b- E! J+ O; M+ Oin mind we studied 5 children with microphallus for response+ b- O& c: C5 |
to gonadotropin and to topical testosterone independently.0 v# q: W9 I- T0 Z* w8 T4 b7 A! T
MATERIALS AND METHODS
9 |4 z5 ^+ @* L) d8 f$ jFive 46 XY male subjects between 3 and 17 years old were7 l$ W# |5 {* Z
evaluated for serum testosterone levels and hypothalamic
7 q7 L0 U3 b- s; H+ A0 M$ gfunction. Of these 5 boys 2 were considered to have Kallmann's
1 @7 k9 s! b# l/ @! [$ ~/ i/ B! ~syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 ^2 |0 [" h& d9 j) llamic deficiency. After evaluation of response to luteinizing
6 y; p& [  G! |% n# M% W' Ghormone-releasing hormone these patients were treated with( W4 A& e- Z3 _& T& i: y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) d. c# h8 ]$ @6 e1 y
after completion of gonadotropin therapy 10 per cent topical$ {% h$ |: x/ |3 h% z& P& w- B: q
testosterone was applied to the phallus twice daily for 3 weeks.
( m8 @3 P5 \$ B9 I- Q' M/ cSerum testosterone, luteinizing hormone and follicle-stimulat-
8 O1 i% N8 Z7 Q' b; W, z/ Ring hormone were monitored before, during and after comple-
2 n* F3 k% `' K& r: @tion of each phase of therapy. Penile stretch length was
  w3 y' F8 g8 Kobtained by measuring from the symphysis pubis to the tip of
, \, v2 A4 M( l# X! J; z7 Ithe glans. Penile circumferential (girth) measurements were
' ^! u. ^* j' u4 O: [obtained using an orthopedic digital measuring device (see2 Q- s& |0 q( I" y* m
figure).
0 l5 w, k! I0 o7 p* }: ?RESULTS0 P0 f" X% d7 q7 @
Serum testosterone increased moderately to levels between
- Q; u+ i+ A- Z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 R* r/ b; f' q2 t( g* _$ B$ rterone levels with topical testosterone remained near pre-( }) {& q- w; x" w
treatment levels (35 ng./dl.) or were elevated to similar levels
: A" G) W' S, @9 m; hdeveloped after gonadotropin therapy (96 ng./dl.). Higher2 z+ S7 T5 ~, w. F, F+ S
serum levels were noted in older patients (12 and 17 years old),
" d  E; h; J1 |, M* X/ O+ Vwhile lower levels persisted in younger patients (4, 8, and 10. h, P: L+ ~5 K( g. D, q
years old) (see table). Despite absence of profound alterations
, U# X8 V8 q5 a5 Rof serum testosterone the topical therapy provided a greater
' w% q  Z% z0 M1 K. R  ?5 |. h! fAccepted for publication July 1, 1977. ·
9 ?  b8 r! s/ @& e4 ]' z& bRead at annual meeting of American Urological Association,
# @, S3 H# G9 ^  ~3 J! pChicago, Illinois, April 24-28, 1977.
# \4 X$ O" V1 ?, y& V% G' i* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 `/ s- f" \% h9 P' E) }2799 W. Grand Blvd., Detroit, Michigan 48202.
, ]$ v% K2 j4 h0 Kimprovement in phallic growth compared to gonadotropin.
2 `+ V  Y& w' N! ~$ tAverage phallic growth with gonadotropin was 14.3 per cent
/ a3 c$ Z( o* W0 D* V  E) v& M4 gincrease in length and 5.0 per cent increase of girth. Topical$ [! n- d/ L& {* a
testosterone produced a 60.0 per cent increase of phallic length% M% M* k4 Z  p# `' u/ R4 q4 y' B
and 52.9 per cent increase of girth (circumference). The
  p: s, K6 Y2 k1 z8 L" d! Gresponse to topical testosterone was greatest in children be-
# y6 [* p. w& D3 d  d1 M" Mtween 4 and 8 years old, with a gradual decrease to age 17
9 k6 `$ L9 m- tyears (see table).+ M2 u3 _  \  E' y
DISCUSSION& j0 K; z( Z9 W4 M- x& h7 m
Topical testosterone has been used effectively by other
0 T9 [: G! I7 W. z! g0 z3 qclinicians but its mode of action remains controversial. Im-
; }3 U5 |2 {( X% X; L* lmergut and associates reported an excellent growth response
' t# s6 E- q* }8 b$ E) v. B) m' O* oto topical testosterone with low levels of serum testosterone,
3 E. c+ w& P6 ?* p2 q* B3 V; X1 xsuggesting a local effect.1 Others have obtained growth re-, r  i9 N; h/ i
sponse with high. levels of serum testosterone after topical3 g+ j" V9 h* l" Z5 p4 J( P
administration, suggesting a systemic response. 3 The use of
  l' a% N. b, T# F. ^gonadotropin to obtain levels of serum testosterone compara-/ `' F& c1 O* s6 V1 |" V
ble to levels obtained with topical testosterone would seem to: t. K3 v9 A3 r, Q) [
provide a means to compare the relative effectiveness of. m5 A4 z8 N$ P9 q0 @  E9 Q
topical testosterone to systemic testosterone effect. It cer-
7 [! D/ }" s$ z. [# `tainly has been established that gonadotropin as well as par-" p$ i4 V" t  b& Q" E& R
enteral testosterone administration will produce genital! g% v* f0 c) A( O5 J
growth. Our report shows that the growth of the phallus was4 I5 k) b  N- q! b# a
significantly greater with topical applications than with go-
" t& p( x1 s, C# x& bnadotropin, particularly in children less than 10 years old.
1 I' ~  G2 p* u& g: xThe levels of serum testosterone remained similar or lower
" B; w* H- M2 Z9 H% V# M6 U6 c2 Ethan with gonadotropin during therapy, suggesting that topi-
+ [" L  K8 I  \cal application produces genital growth by its local effect as* Q- y) O$ U& L$ b& }. n
well as its systemic effect.
5 U+ f5 t& T6 [8 H9 dReview of our patients and their growth response related to
5 R2 E1 N" U0 k+ |  {age shows a greater growth response at an earlier age. This is
% e2 }' T. M7 e/ H3 Vconsistent with the findings of Wilson and Walker, who
0 i* L' P  N. Q/ h" ^3 Treported an increased conversion of testosterone to dihydrotes-
/ ~( e" n) x; u1 q  Etosterone in the foreskin of neonates and infants.4 This activ-
$ Q2 B! G5 Q9 Z4 `. ^ity gradually decreases with age until puberty when it ap-9 ^( A% M2 E+ w
proaches the same level of activity as peripheral skin. It may
; @$ b) Z0 L. h7 `4 @$ _- M6 Hwell be that absorption of testosterone is less when applied at
! e2 p. }8 N* k, ~1 yan earlier age as suggested by lower serum levels in children
& `* p7 o3 A/ n2 o+ zless than 10 years old. This fact may be explained by the/ H* `7 l& a& M2 p9 D
greater ability of phallic skin to convert testosterone to dihy-6 s" g7 l/ e2 n
drotestosterone at this age. Conversely, serum levels in older
8 @/ B2 }7 m; C/ c! [* C, jpatients were higher, possibly because of decreased local
4 M7 T- A7 I+ E667
, Z3 o* k% N6 r4 x9 p+ M8 k668 KLUGO AND CERNY& a: f. P3 U* b
Pt. Age/ n& E! p/ J5 m
(yrs.)
; N! D1 s" D* Y4 Q: ]  W( z! FSerum Testosterone Phallus (cm.) Change Length
/ h$ l9 V/ J2 _+ N; P: S0 Q(ng./dl.) Girth x Length (%)
3 o/ G2 E, d" \* @4# f3 m% c7 b  q4 t4 d
8, A5 x3 r: W: x, g8 x9 T
10( I- V& q5 l  M. U( `& V& R
12! v. q# ~4 j/ b5 W' b6 C+ m3 i- d" m
17; b6 p  M  `! V, s3 O
Gonadotropin
" V1 A7 v. o+ E7 t7 Y7 T71.6 2.0 X 3 16.65 K) n$ z( Z, D. [% y
50.4 4.0 X 5.0 20.0; F  V0 B/ L- x2 C; P1 ^8 H* c' p
22.0 4.5 X 4.0 25.0
1 ~( h0 K; b( f6 Q* I  L84.6 4.0 X 4.5 11.1
0 Z6 V& h5 J- V  s: H" ?85.9 4.5 X 5.5 9.04 J4 H! V/ _* e' s" I
Av. 14.3
' w5 T5 _6 T- L9 s9 H7 m( a4# H$ \; K+ [: L! d- N; T! U
8
5 A$ `  V7 z  w% r6 y10
( Z" B5 C7 ]% |& J: h' ^12  z* V/ h5 A5 Y7 b
174 E. I/ r& y; _6 Z3 B$ k0 G
Topical testosterone! v( i% {' ^5 k
34.6 4.5 X 6.5 855 f! i2 i; t% a$ H7 ]
38.8 6.0 X 8.5 70  I# q$ C! k) S
40.0 6.0 X 6.5 62.5
! \& ]3 M+ R: \% v: M% n  }$ R93.6 6.0 X 7.0 55.53 ?+ Q3 t! m3 F$ Y, P. [0 o
95.0 6.5 X 7.0 27.2+ Z' k7 E% \" o8 R
Av. 60.0" ^) W. N* [# N( V% Q  I3 |2 ]5 b. A
available testosterone. Again, emphasis should be placed on
7 y" i; _7 X4 O3 N6 [early therapy when lower levels of testosterone appear to
2 y: P$ I  a9 O# bprovide the best responses. The earlier therapy is instituted9 }' E& g1 u! F9 M8 B
the more likely there will be an excellent response with low
* H- {+ q1 v' ?  w3 gserum levels. Response occurs throughout adolescence as- i" s3 D5 G0 K
noted in nomograms of phallic growth. 7 The actual response
' M1 j; _& l- D0 e! b  L2 Vto a given serum level of testosterone is much greater at birth2 z- \# ]* I& {2 _8 D
and gradually decreases as boys reach puberty. This is most1 @) h$ A' b  W
likely related to the conversion of testosterone to dihydrotes-$ `5 c. \  Q) `9 y
tosterone and correlates well with the studies of testosterone
+ U* N  {5 @" p7 o: B8 B' Zconversion in foreskin at various ages.
" j  {9 Y& t  K5 L! UThe question arises regarding early treatment as to whether1 R, Q' M4 \- u/ b4 z
one might sacrifice ultimate potential growth as with acceler-
' o$ P# X0 }+ I. X8 y& B, M' ~/ {ated bone growth. The situation appears quite the reverse
8 F% M+ O5 w% \  F4 F. gwith phallic response. If the early growth period is not used
# ]& b1 Q  b. p8 b9 K9 ]  ~7 ]when 5a reductase activity is greatest then potential growth# E# o" g3 o( Q- ^/ S: t5 x1 d
may be lost. We have not observed any regression of growth
2 x  N9 k9 @; Cattained with topical or gonadotropin therapy. It may well8 T  T- [$ o* T' }5 M+ L; i
be that some patients will show little or no response to any6 n5 w! ?; x0 k$ ^$ G
form of therapy. This would suggest a defect in the ability to
, X, D& U$ l0 a% m$ E4 }8 O+ ]0 v3 aconvert testosterone to dihydrotestosterone and indicate that) K$ q8 d7 S  E6 {, P2 M& l1 S& q
phallic and peripheral skin, and subcutaneous tissue should
: Q9 [- i! Y! r4 U4 Bbe compared for 5a reductase activity.0 f5 s6 o9 e; ~. o& N
A, loop enlarges to measure penile girth in millimeters. B,
: S* m/ \; P4 P# x% G& xexample of penile girth computed easily and accurately.
: u: L- [% |( m* g& T: sconversion of testosterone to dihydrotestosterone. It is in this( ^' d" i; v# T. K5 T+ |- ^
older group that others have noted high levels of serum
7 Y% Q4 i' |! M( j6 r) Ttestosterone with topical application. It would also appear* c# D: E6 n9 x6 {  h# j% c1 c
that phallic response during puberty is related directly to the4 b( |: v: Z( {5 b: y, |1 [: N) a
serum testosterone level. There also is other evidence of local8 C4 J. e; Z6 x' F
response to testosterone with hair growth and with spermato-
8 v) d. _3 ]: R! t/ x$ Sgenesis. 5• 6- C  S+ x' l) a; I6 f
Administration of larger doses of gonadotropin or systemic0 x% G- |3 ^  T/ }
testosterone, as well as topical applications that produce
2 S5 y* W  C5 P0 S( c! m- |1 dhigher levels of serum testosterone (150 to 900 ng./dl.), will+ G8 p$ l! M& J- @! C& {( `
also produce phallic growth but risks accelerated skeletal* }3 ?; e% Z  i) ~$ p/ |3 P
maturation even after stopping treatment. It would appear
0 k) v, U1 ~/ Q6 s2 t7 P# o, K1 e. _& xthat this may be avoided by topical applications of testosterone4 H; D* ]  I, C: r; S! |
and monitoring of serum testosterone. Even with this control  X0 M; p0 U8 }; c
the duration of our therapy did not exceed 3 weeks at any
7 h3 Y( U( G; k4 |- Xtime. It is apparent that the prepuberal male subject may* Y3 b% i8 n: m2 `
suffer accelerated bone growth with testosterone levels near
. E1 K" U7 V5 n3 {200 ng./dl. When skeletal maturation is complete the level of) T- Z0 v: b4 O& W# {
serum testosterone can be maintained in the 700 to 1,300 ng./
/ F( z! q7 a) E0 s" p1 O# T; Hdl. range to stimulate phallic growth and secondary sexual
/ h! c, G  A& U0 D1 [4 Gchanges. Therefore, after skeletal maturation parenteral tes-* t! R  Y  B0 E6 }$ {
tosterone may be used to advantage. Before skeletal matura-
* A0 z# z' o: L, Stion care must be taken to avoid maintaining levels of serum( p: j" n  N! ^9 ~3 f
testosterone more than 100 ng./dl. Low-dose gonadotropin5 q7 D4 H( Q0 D6 [& n# |
depends upon intrinsic testicular activity and may require
  g& F6 @2 O; S1 o7 N# L" q1 yprolonged administration for any response.+ o! c* }. u0 e' R' w
Alternately, topical testosterone does not depend upon tes-; m+ T8 C* c2 H3 g
ticular function and may provide a more constant level of
( ~2 K; d+ [7 ^. c4 b9 hREFERENCES
' J$ j! p3 ]8 j1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% }, ~& E& _1 q6 f& B2 ~
R.: The local application of testosterone cream to the prepub-2 A+ }; G' v# z; ^
ertal phallus. J. Urol., 105: 905, 1971.
; z  Q( J2 s9 h' i( n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- N' K# u% ]7 Y6 o
treatment for micropenis during early childhood. J. Pediat.,
# @& h1 I, T# M1 \- j) v) u83: 247, 1973.
) [; ~. ], Z# s3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, d+ ?) H+ e2 S0 f) ]  Y4 y: oone therapy for penile growth. Urology, 6: 708, 1975., ?/ U$ O4 F, P) {& D% X- o
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 D8 M& M) I2 S3 [5 Cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 \1 `6 g' K6 ~' T  J2 D
skin slices of man. J. Clin. Invest., 48: 371, 1969.& L8 r3 y, z% W' Y* I' v) f
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; G; I; U- _3 }by topical application of androgens. J.A.M.A., 191: 521, 1965.
* `5 ?- M! a3 ]5 I3 m1 j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
4 k5 [7 y7 X* G: Landrogenic effect of interstitial cell tumor of the testis. J.
" x! E/ ?/ q, X% ^2 jUrol., 104: 774, 1970.; ^: [! [4 Z! S$ U  S& _# i
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-9 g  w& X0 [) y: @5 o  X
tion in the male genitalia from birth to maturity. J. Urol., 48:
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