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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& c; j# ^' U7 N$ h: E6 ~/ P0 z5 p
GONADOTROPIN
9 ^$ O0 f$ b& P  J* SRICHARD C. KLUGO* AND JOSEPH C. CERNY! B% v' l- I+ A2 @1 B, Y5 X$ {7 N
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan& Z. }. I) h8 n- ?/ Q
ABSTRACT
1 f& j( \6 Q2 m" sFive patients were treated with gonadotropin and topical testosterone for micropenis associated* w4 C; q: T: M1 V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-+ }6 i8 |* Z6 J) z6 U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) {, S+ f$ T( }* Ocream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! e% I+ Y9 }8 o% zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ w# f" T0 {' b
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 p9 J/ j5 b. Q7 R! ~4 zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response  k! }5 I/ m7 |+ S' I2 x; d7 b
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; A4 b% g# v) _- L4 b& w
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
5 J: x" y( R, H9 o3 R0 Kgrowth. The response appears to be greater in younger children, which is consistent with previ-
4 P9 Z/ Z: R3 P0 B! n) z8 T$ b. Uously published studies of age-related 5 reductase activity.# R8 c9 x& u. ~: u; k6 Q
Children with microphallus regardless of its etiology will  l& |5 M; w7 D
require augmentation or consideration for alteration of exter-7 E" Y, o# G# B" ?" l
nal genitalia. In many instances urethroplasty for hypo-! f* \; p1 m$ i' s9 g2 i5 m+ Z
spadias is easier with previous stimulation of phallic growth.1 [5 ^+ W2 G2 H0 ?
The use of testosterone administered parenterally or topically* v( g; K) t; F# y
has produced effective phallic growth. 1- 3 The mechanism of
) r9 f! B, y9 r" _7 r3 yresponse has been considered as local or systemic. With this
5 H6 ?8 h' q5 z/ q/ ^# a- u. x9 a0 [& _' ^7 Lin mind we studied 5 children with microphallus for response
  O2 |5 {! t6 Y9 m% |3 u8 }( X& S: Fto gonadotropin and to topical testosterone independently.* f; _9 F: I+ U4 m
MATERIALS AND METHODS. I8 D5 E" b. K9 Q/ q
Five 46 XY male subjects between 3 and 17 years old were' m. ~7 k# P5 H, g+ x7 _# D
evaluated for serum testosterone levels and hypothalamic8 d0 F3 n3 t  U4 r8 a6 Q1 Z
function. Of these 5 boys 2 were considered to have Kallmann's
, @' t9 b; X8 R. L. U' Esyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( K1 l8 X4 s' L# x  q8 Q3 R( E
lamic deficiency. After evaluation of response to luteinizing
  C/ d: ^# w  a. B/ q( B: ~hormone-releasing hormone these patients were treated with
* p+ D6 |: ~: x7 v8 v7 R1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, Y* Q0 J' |) x$ F/ L( N4 x" jafter completion of gonadotropin therapy 10 per cent topical/ D! L( r( R) k: b  ^: m: i
testosterone was applied to the phallus twice daily for 3 weeks.; A- u# L6 @1 Y7 n; [+ w6 `
Serum testosterone, luteinizing hormone and follicle-stimulat-
( c! D  w$ j2 Aing hormone were monitored before, during and after comple-9 V7 v# o) N: E
tion of each phase of therapy. Penile stretch length was+ y$ ^: g) T$ E4 J/ l& q# |! d5 p
obtained by measuring from the symphysis pubis to the tip of0 r" U: q# o3 ~
the glans. Penile circumferential (girth) measurements were/ E. C# O3 u. D2 o$ a0 G! }( q! Y. J
obtained using an orthopedic digital measuring device (see
6 z/ N; ^  l$ d" E: sfigure).
! P5 ^2 a4 I7 E  G; A. {RESULTS
$ H' n, W. D0 I; G# d- q/ [* v% {3 }Serum testosterone increased moderately to levels between
7 C7 d* H3 c0 f# c6 ~& H8 O& s5 w50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
- N* d) s0 T) L1 J6 `& tterone levels with topical testosterone remained near pre-
' o; F+ ?! I8 S+ a! ~+ X: A' i5 r4 Ttreatment levels (35 ng./dl.) or were elevated to similar levels
/ p+ K1 ]' R- rdeveloped after gonadotropin therapy (96 ng./dl.). Higher. x# a3 K: m8 ?
serum levels were noted in older patients (12 and 17 years old),
/ }, W+ v7 Q  F( a: a. uwhile lower levels persisted in younger patients (4, 8, and 10+ a5 k% ]$ v4 ~, l- x+ u3 F+ ~
years old) (see table). Despite absence of profound alterations, O: E6 u! v, x9 x2 G- x7 z& A
of serum testosterone the topical therapy provided a greater
: I( T8 x% a- X, s, U# X) p* CAccepted for publication July 1, 1977. ·+ A" r& e6 h1 O" A$ i& I. I+ K
Read at annual meeting of American Urological Association,0 C% d6 Q5 J5 j, I1 Q2 P
Chicago, Illinois, April 24-28, 1977.) y0 d8 _2 d8 m7 A8 y9 o7 v7 n: F% q
* Requests for reprints: Division of Urology, Henry Ford Hospital,) O/ |( i: q" S9 F9 N+ N0 B
2799 W. Grand Blvd., Detroit, Michigan 48202.
$ a& z3 @( F( ~  {, p5 Oimprovement in phallic growth compared to gonadotropin.
0 e) D4 G) B" U: P. d; z/ QAverage phallic growth with gonadotropin was 14.3 per cent: d: D. q9 ^% t/ C3 E6 A1 p( ?
increase in length and 5.0 per cent increase of girth. Topical+ f- \9 h9 @7 v7 E/ v
testosterone produced a 60.0 per cent increase of phallic length
4 h% ^3 W2 |% w. A. Qand 52.9 per cent increase of girth (circumference). The
# y" ^' T7 m4 q. |4 Uresponse to topical testosterone was greatest in children be-& ~  F# D3 i* |/ _/ N6 l7 a, {* L
tween 4 and 8 years old, with a gradual decrease to age 17
& g8 F, S+ C3 U; hyears (see table).
. |5 o7 @' n6 s$ n3 kDISCUSSION4 S6 @! i$ x' m# E4 B/ K. h7 k& W
Topical testosterone has been used effectively by other4 n3 t1 V1 H( F, Z0 L
clinicians but its mode of action remains controversial. Im-
# ~) ]# r3 b( _1 cmergut and associates reported an excellent growth response
' K/ `* s: Y9 I9 g# f/ E+ `) f4 S6 Y$ Dto topical testosterone with low levels of serum testosterone,. c# r  P" K6 d; L. K2 a9 Z7 Y
suggesting a local effect.1 Others have obtained growth re-# B/ q3 t1 z: Q$ s7 ^7 T
sponse with high. levels of serum testosterone after topical  M1 |2 o+ l) K5 v. v! n; G
administration, suggesting a systemic response. 3 The use of
' M* h5 n1 i% Q' _' @gonadotropin to obtain levels of serum testosterone compara-8 j4 a  W) H' g# }: f) f
ble to levels obtained with topical testosterone would seem to# W* d: V. J1 ?4 d8 G  |
provide a means to compare the relative effectiveness of
' ?  A1 h! t  v$ F% Gtopical testosterone to systemic testosterone effect. It cer-- A) m" T: \8 Y# J
tainly has been established that gonadotropin as well as par-; ]! ]( Q+ y/ {& j5 ]0 a' X
enteral testosterone administration will produce genital9 L! A% b! B2 F1 B. G) M
growth. Our report shows that the growth of the phallus was  [; O$ P0 `( T' i( m: r
significantly greater with topical applications than with go-
( M8 g2 Y% b# t9 n  ^" q- t% bnadotropin, particularly in children less than 10 years old.
. m% o) F' F2 {) F+ F- R- d; E! i1 jThe levels of serum testosterone remained similar or lower5 S. _9 ?) S* D4 L6 x
than with gonadotropin during therapy, suggesting that topi-
. D7 G! F+ _/ z2 L) r! F/ E* Bcal application produces genital growth by its local effect as& f/ I& x! K+ X% T1 K) y
well as its systemic effect.
- ~  x7 W  ?# \2 p8 jReview of our patients and their growth response related to
" |( E6 t( C' Y* @2 g' qage shows a greater growth response at an earlier age. This is
# c8 C: T2 Q- V4 A0 M$ T2 Iconsistent with the findings of Wilson and Walker, who" P4 K6 J4 e* X3 M
reported an increased conversion of testosterone to dihydrotes-
0 m% g3 T& a+ b! B4 A4 e5 W: Ztosterone in the foreskin of neonates and infants.4 This activ-
7 s# W+ J+ A2 d& ^- xity gradually decreases with age until puberty when it ap-
* g/ O' P- A: }+ n) O  ?6 rproaches the same level of activity as peripheral skin. It may
* L* ^0 q, @+ u; S( rwell be that absorption of testosterone is less when applied at2 h7 x, N4 [' D3 [
an earlier age as suggested by lower serum levels in children& ]+ t- ]& t' h$ ~& Y$ b
less than 10 years old. This fact may be explained by the
7 h- X+ N2 y8 i4 ngreater ability of phallic skin to convert testosterone to dihy-
* M, F% k3 q, R2 t) @+ y. B6 hdrotestosterone at this age. Conversely, serum levels in older$ B# t# x4 V, S% Z7 ^
patients were higher, possibly because of decreased local
/ Z+ i9 a# m7 x9 q667/ \. r8 @* Y! f3 x/ i
668 KLUGO AND CERNY
$ t* `4 _5 y9 T( {% lPt. Age5 a. ^; K4 q! m! u* E
(yrs.). G4 D& j8 }, V, D+ `9 x
Serum Testosterone Phallus (cm.) Change Length# N5 ?# w, v/ m) V! _& B4 Q: z& |
(ng./dl.) Girth x Length (%)8 K% r% Z& g) x0 w$ s; y1 }
4
' [; X5 `. {4 D' p  F/ t8
! X& o$ a) K, k% Z' c5 f, F10- g' \3 N5 Y/ j3 T8 Z+ q6 h
12
9 Y5 i: t& c. C& I) M17
7 a! q$ F  R) L- ~& MGonadotropin
/ d- c8 D- f+ G% M% N" D5 w71.6 2.0 X 3 16.6
5 d1 P$ l& h; N- ~" \! `50.4 4.0 X 5.0 20.0
# |$ k' V' |8 O( S/ k6 n; y22.0 4.5 X 4.0 25.0
4 Y' f8 O- K- S84.6 4.0 X 4.5 11.1
* g) C; h( _# t. B+ T1 X8 j85.9 4.5 X 5.5 9.0
& a9 W3 g7 s8 _* C% r; P8 ]- y9 xAv. 14.3
* w# ~6 A9 A0 n0 g; z4
" j2 r% q6 I0 K8 V8
. Y" b. T) {: S$ u2 x0 v: t10
( Y5 q0 R2 V4 @% ]& K) B12
; M. ~9 A4 q4 `, h$ a1 y" H17
. l( A& q5 e4 E( b  p2 L/ u0 VTopical testosterone, d/ e/ Z4 c. j' d6 C' L
34.6 4.5 X 6.5 85
3 g0 a, L9 x5 {; {% w7 f38.8 6.0 X 8.5 704 ^4 K$ A% m' _( \8 n& N4 _4 `
40.0 6.0 X 6.5 62.57 D6 C* b$ ^8 H7 W) E  l2 B
93.6 6.0 X 7.0 55.5, m; ]7 n) y+ {; p0 l
95.0 6.5 X 7.0 27.2
/ Z4 i1 U; n7 h& r! }Av. 60.0/ S. r# `1 q6 M" ^0 w1 a/ y
available testosterone. Again, emphasis should be placed on
0 Q* |' h& T" M5 p' I4 uearly therapy when lower levels of testosterone appear to
; s5 T( [: V$ N6 H+ N# `provide the best responses. The earlier therapy is instituted% M$ P# r8 u& A7 E
the more likely there will be an excellent response with low
6 k: }1 H5 t& T& g! f: u6 C; kserum levels. Response occurs throughout adolescence as
* O* _, ?+ R0 {, Inoted in nomograms of phallic growth. 7 The actual response1 t. h' R) i. N* }' {4 A, ^% S2 ^! }
to a given serum level of testosterone is much greater at birth
) i+ u7 i* D7 e; g/ Z- b8 Zand gradually decreases as boys reach puberty. This is most
( x8 i1 u* }0 Y, i7 W. hlikely related to the conversion of testosterone to dihydrotes-2 s7 Z6 C* N% |  C
tosterone and correlates well with the studies of testosterone) @- A( S  S6 U) P: r
conversion in foreskin at various ages.2 ?0 F: n( z5 Y% S+ `  m
The question arises regarding early treatment as to whether; x5 k" Y! y1 q2 @7 s  [1 f! c
one might sacrifice ultimate potential growth as with acceler-
% t% n7 ?0 v6 e8 a& e7 _ated bone growth. The situation appears quite the reverse
8 b0 ^# b1 F( C6 P  Y- `with phallic response. If the early growth period is not used
* e1 ~4 W) G9 j* v5 ?# o5 F* iwhen 5a reductase activity is greatest then potential growth
* r' j6 X8 W. S. Q5 r6 n; Y! Z; Ymay be lost. We have not observed any regression of growth
& @1 ]" y* h/ V+ w! T. f6 @attained with topical or gonadotropin therapy. It may well+ d2 f& p8 _! G
be that some patients will show little or no response to any6 _4 ~& Q- B  H6 z2 z  f( k. r' U
form of therapy. This would suggest a defect in the ability to3 ^5 O- x* i; H) s. j
convert testosterone to dihydrotestosterone and indicate that0 D" m  D1 A, d
phallic and peripheral skin, and subcutaneous tissue should
- U$ l( A3 \8 T% a. ybe compared for 5a reductase activity.
# m5 P- F5 Z/ G4 G% oA, loop enlarges to measure penile girth in millimeters. B,' s: S1 o3 v6 e% C, k
example of penile girth computed easily and accurately.5 S& ?$ p- t' N& N% ?
conversion of testosterone to dihydrotestosterone. It is in this: y; o9 ]7 E4 C8 ?/ j4 u- k
older group that others have noted high levels of serum
! i( T2 b* G0 ^testosterone with topical application. It would also appear
( J" `4 \- b9 C; V/ Jthat phallic response during puberty is related directly to the
% z( K, y+ Z) K; |0 F+ c0 X' Fserum testosterone level. There also is other evidence of local& s& s' u& H7 k8 i
response to testosterone with hair growth and with spermato-
. S; k" k4 x* U- ?3 l7 c% \genesis. 5• 6# @2 }% f( c  x5 Z) b, P; T4 B
Administration of larger doses of gonadotropin or systemic4 k: k6 s+ ]0 x1 Q; g* ]
testosterone, as well as topical applications that produce
# L9 B# H9 j" {, z/ A% Mhigher levels of serum testosterone (150 to 900 ng./dl.), will7 a' w; r9 I" I' z$ L* u$ |
also produce phallic growth but risks accelerated skeletal
: k; `8 r' D- f' N( l- Ymaturation even after stopping treatment. It would appear' J: t# B9 _/ ]& T
that this may be avoided by topical applications of testosterone
( |0 O  ]% d' Y2 e4 oand monitoring of serum testosterone. Even with this control# W6 l0 f, f/ d% b2 O& y
the duration of our therapy did not exceed 3 weeks at any
# X$ k, }6 ~+ w# j' B* ~time. It is apparent that the prepuberal male subject may" q. q" i6 \- g0 @$ n
suffer accelerated bone growth with testosterone levels near+ p' h8 @2 Y7 }% N* U0 J$ K
200 ng./dl. When skeletal maturation is complete the level of
0 |( R8 F  N6 ~) n& \6 E, hserum testosterone can be maintained in the 700 to 1,300 ng./
4 a* H) T# L; d, Y5 Hdl. range to stimulate phallic growth and secondary sexual
9 d) b1 w$ h9 q# Ochanges. Therefore, after skeletal maturation parenteral tes-
3 ?* n* N0 m& f3 Ktosterone may be used to advantage. Before skeletal matura-+ e% z2 T- G* ?3 L* O
tion care must be taken to avoid maintaining levels of serum7 b/ q( f( _4 d% ^9 q7 i
testosterone more than 100 ng./dl. Low-dose gonadotropin
5 m8 k6 T  m3 n7 Ydepends upon intrinsic testicular activity and may require
  O9 z1 H/ R3 Dprolonged administration for any response.+ p' V$ Q2 ~( C. X" [2 ^/ @
Alternately, topical testosterone does not depend upon tes-
& u/ M5 Q. e! }ticular function and may provide a more constant level of1 @8 c; L7 S( I. l- c8 T" x+ v
REFERENCES
; M' J$ V& |2 w+ O! [1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
% k9 w& q# E( Q; i1 xR.: The local application of testosterone cream to the prepub-
4 J; s; F: u& Lertal phallus. J. Urol., 105: 905, 1971.
; A0 e9 T9 p/ c  ~0 ^! B  ]2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ P! Y9 @( J% }2 I! Y
treatment for micropenis during early childhood. J. Pediat.,. k5 j, x% v# o  s
83: 247, 1973.
& t' K! Y7 R% K! K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: Z* c# ?1 {4 j6 Y2 B) @* C
one therapy for penile growth. Urology, 6: 708, 1975.6 O% q8 |' R8 Y* h% Z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone0 {' m* n9 _6 G2 N/ A
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: P0 x" t/ H/ ]. u( _6 yskin slices of man. J. Clin. Invest., 48: 371, 1969.! V  G/ B- L! y1 O
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! ~% Y; @3 @4 g4 a+ A8 w4 r, y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
$ D! ?% |! ~( s8 m* r; p7 y6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
( A8 O6 ^3 v, z  Handrogenic effect of interstitial cell tumor of the testis. J.
  d+ ^9 R! G: \Urol., 104: 774, 1970.
$ E+ }1 K8 s  \4 b, o& z1 ?7 K7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& x/ b, X$ g' T' C! e9 U' ^tion in the male genitalia from birth to maturity. J. Urol., 48:
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