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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) V- D: r- ]: b2 t6 ]
GONADOTROPIN
  r2 e$ j% c5 {4 y# lRICHARD C. KLUGO* AND JOSEPH C. CERNY: _, F$ o6 o+ T3 o- e3 N8 C/ ~3 `
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' b, D! F: N: [- W1 zABSTRACT) L; q5 D4 o0 H, ~
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 S$ F0 R1 ]( G3 s# U! ?+ k& c( Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; M* F/ w) m8 d  B  ^2 q) Z3 H2 wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' M" ~" _' B& P% \1 Gcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
3 J+ b# y7 F2 o! ^6 F! Lfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" G# e0 d7 b1 ]8 W; [0 D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
  A7 k( x& ?3 U; ?increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 f+ L1 a4 f1 V/ B2 n+ }1 ?( uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 K$ G  M9 @3 K  D
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 l* T, e3 T$ m2 h. |, n
growth. The response appears to be greater in younger children, which is consistent with previ-# k" j8 g  `$ D, a/ A  ?, P
ously published studies of age-related 5 reductase activity.2 |2 m- q' Q& z( l# y1 ~
Children with microphallus regardless of its etiology will
  c" Q" `% R+ Y' Y% S1 k) zrequire augmentation or consideration for alteration of exter-0 v& \$ ]% V! f% H0 @; i) K
nal genitalia. In many instances urethroplasty for hypo-8 i) j' _$ Y, ~+ |0 P6 ?5 g
spadias is easier with previous stimulation of phallic growth.
% @! i- N% L9 d, o$ RThe use of testosterone administered parenterally or topically: }/ T9 n- Y( p. ?1 U
has produced effective phallic growth. 1- 3 The mechanism of  T8 y9 L3 }  Q0 K) @: E* J5 q
response has been considered as local or systemic. With this0 Y+ s/ B; b6 V! g# y
in mind we studied 5 children with microphallus for response) l7 W% |% R* _4 O
to gonadotropin and to topical testosterone independently.  ^7 @( N/ I+ p! ~" s
MATERIALS AND METHODS: L- O; V1 H0 c9 K: p) Y
Five 46 XY male subjects between 3 and 17 years old were
9 u: Z* A, Q; s8 j" J, y! sevaluated for serum testosterone levels and hypothalamic+ M$ Y; z0 Z" o0 j
function. Of these 5 boys 2 were considered to have Kallmann's# O% X8 T$ I$ H- x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
  S9 k4 A* y. v9 j. K7 D, L. plamic deficiency. After evaluation of response to luteinizing
! K  K' m% M% d1 g+ B' D. X* M8 rhormone-releasing hormone these patients were treated with
5 w+ }8 o" q6 x1,000 units of gonadotropin weekly for 3 weeks. Six weeks( K0 v) f3 E/ x& [
after completion of gonadotropin therapy 10 per cent topical7 T7 f/ f- @9 ]! k3 i+ \& h
testosterone was applied to the phallus twice daily for 3 weeks.1 B) B0 [% \; }" t& k$ h) j
Serum testosterone, luteinizing hormone and follicle-stimulat-9 @  i8 l& {4 ]
ing hormone were monitored before, during and after comple-& d0 L3 Z3 z0 e1 G5 N/ V
tion of each phase of therapy. Penile stretch length was
- @" ~$ \( r2 Fobtained by measuring from the symphysis pubis to the tip of
( Y- x6 z# k  x) C, F: othe glans. Penile circumferential (girth) measurements were* r3 Z7 [6 a0 X2 e5 e% q
obtained using an orthopedic digital measuring device (see3 G( R/ D6 S/ S1 b  j
figure).
6 ^0 r4 g% y" L6 O% }3 D3 h8 LRESULTS  d1 i4 |6 v3 C8 |+ d
Serum testosterone increased moderately to levels between. m& E" J9 f  ~% H, J/ `1 E
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-4 P( g0 D9 L- O+ ]: Y/ u
terone levels with topical testosterone remained near pre-# S. X: n: C" y) y' h1 F  Z% J
treatment levels (35 ng./dl.) or were elevated to similar levels
8 j" B7 V& {6 T& Pdeveloped after gonadotropin therapy (96 ng./dl.). Higher& Z0 y5 t0 D; I) U6 y
serum levels were noted in older patients (12 and 17 years old),
: E) X( L: n0 B5 I+ k" g3 owhile lower levels persisted in younger patients (4, 8, and 10: `3 h; Q8 H2 c7 K6 s! Y6 y9 |) M. G0 z
years old) (see table). Despite absence of profound alterations. ]6 A+ P1 p& l
of serum testosterone the topical therapy provided a greater* B1 e+ n- K0 }; i& }/ ~
Accepted for publication July 1, 1977. ·0 Q" ~0 g, K6 ^* G5 v+ t, |( X
Read at annual meeting of American Urological Association,
$ [& G, r2 S. }1 m% eChicago, Illinois, April 24-28, 1977.6 K: l5 _3 T* J2 ~6 a
* Requests for reprints: Division of Urology, Henry Ford Hospital,6 l/ c; M5 D$ E" K6 Z2 o/ u
2799 W. Grand Blvd., Detroit, Michigan 48202.
  ^. C% N/ t2 r2 x4 [5 P! Iimprovement in phallic growth compared to gonadotropin.9 _: ?/ h" _9 W; f0 _" Z) W8 ?
Average phallic growth with gonadotropin was 14.3 per cent7 K8 M) w( l0 [
increase in length and 5.0 per cent increase of girth. Topical* N: u* |+ S7 S7 ~/ r: q$ D$ b& d
testosterone produced a 60.0 per cent increase of phallic length, c# ]0 C/ q2 M, Y3 q: n
and 52.9 per cent increase of girth (circumference). The
7 }+ \; e0 r# u- o* R: W  X2 qresponse to topical testosterone was greatest in children be-4 }1 G) A- E+ n: w' o/ ?
tween 4 and 8 years old, with a gradual decrease to age 17; [8 }4 I' N- d  r6 U# Z
years (see table).8 t0 b1 M  A- F0 h
DISCUSSION. O4 b) q# M& d! }' b
Topical testosterone has been used effectively by other9 v. C+ P4 s; X
clinicians but its mode of action remains controversial. Im-
, }# G: k% e  E1 o1 m) y" omergut and associates reported an excellent growth response+ ]0 c# U$ \& ~/ W
to topical testosterone with low levels of serum testosterone,0 q: e& l' _" A/ P; n
suggesting a local effect.1 Others have obtained growth re-* G9 D& \8 \  F" R
sponse with high. levels of serum testosterone after topical
5 F5 J) _  V" A5 o4 `9 i0 }administration, suggesting a systemic response. 3 The use of
$ z+ S4 ?# O4 b' c: Fgonadotropin to obtain levels of serum testosterone compara-
) n# ?+ W; Y' K# _8 t, j" yble to levels obtained with topical testosterone would seem to' `2 b: [2 Q0 `- i; R6 [  ~
provide a means to compare the relative effectiveness of: e) p' r5 B3 e9 f1 [
topical testosterone to systemic testosterone effect. It cer-2 I9 W( |9 m) j' w; K; j* n" ^
tainly has been established that gonadotropin as well as par-8 O. \( e9 w3 w) I5 Q
enteral testosterone administration will produce genital
2 b1 ~3 N* a; Lgrowth. Our report shows that the growth of the phallus was) z- W+ c- Y# w) y" u9 B
significantly greater with topical applications than with go-
' b1 s3 }/ I5 W1 }( T: qnadotropin, particularly in children less than 10 years old.
4 I( h" ?. X0 w3 v" T% q* F# qThe levels of serum testosterone remained similar or lower
6 ?5 Z0 j' c5 G1 s' H  ]) C  Hthan with gonadotropin during therapy, suggesting that topi-
: D1 [) V/ R2 x5 [7 {/ d& qcal application produces genital growth by its local effect as
3 d- \7 M5 D0 {6 \- g, F/ N) n9 awell as its systemic effect.. q9 s( n7 o# U4 K9 ]
Review of our patients and their growth response related to
8 O9 Y9 Y/ F. m3 P6 [/ J  q- oage shows a greater growth response at an earlier age. This is
) D% Y& b% R1 P: Mconsistent with the findings of Wilson and Walker, who
& r9 n: U! Z* Z7 M2 Breported an increased conversion of testosterone to dihydrotes-7 C, s  }* m% F5 `, ^) {0 a# y
tosterone in the foreskin of neonates and infants.4 This activ-3 N3 I! Y/ r  H
ity gradually decreases with age until puberty when it ap-/ D; @8 q- n: d6 `7 g% v( {9 ?% V1 b
proaches the same level of activity as peripheral skin. It may
6 x' z0 Z* ]) S- dwell be that absorption of testosterone is less when applied at' b3 E) Q0 s( }$ p$ k
an earlier age as suggested by lower serum levels in children
' p8 n& d! h1 Gless than 10 years old. This fact may be explained by the' V8 A; t, ~' Y: O7 k) A! [- ?
greater ability of phallic skin to convert testosterone to dihy-5 l1 j0 n0 D* T4 D$ X$ _* G
drotestosterone at this age. Conversely, serum levels in older! H2 }3 ~  L. ~# {+ \/ Z& r& h
patients were higher, possibly because of decreased local! Z9 C; T5 A) z
667% B" [# e/ D2 L) G
668 KLUGO AND CERNY! [! p" }) @$ \/ q8 E
Pt. Age
( D; [$ k$ d& t8 b5 w$ }( e$ P. s(yrs.)
$ X7 c2 L% r0 D) s3 W- m9 WSerum Testosterone Phallus (cm.) Change Length* D; \4 p9 A" P5 G& h; z: ^
(ng./dl.) Girth x Length (%)
' }& V/ D1 n7 F& ~) G1 w* X41 D' K6 a4 ]! r( j* ~* \
8# x" ^- o4 a* E3 i% m
10, O/ {. y% ]* `2 h- X2 P1 [
12
% ~1 A$ t5 ]0 }! h1 [( ~0 D0 L170 y2 S2 j, P& H  t* Y
Gonadotropin
- R8 b4 G# o$ B* S% o; ]  r$ {) p71.6 2.0 X 3 16.6
+ T* E! C7 D& H8 k9 \8 f- J50.4 4.0 X 5.0 20.0
7 C) k% X! O* `22.0 4.5 X 4.0 25.0
5 k9 N! S! U) E$ l  `4 h3 n1 s84.6 4.0 X 4.5 11.1# M0 x1 j9 C5 N3 U$ |0 H8 w
85.9 4.5 X 5.5 9.00 q" G1 O9 J/ M6 }' p. J. s
Av. 14.3
; u! `: c% _  o4
5 G6 T, H2 X, m7 q6 `  `8
% @3 c1 v; }  A: s4 _' f100 a: E3 L1 o2 k1 h
127 y* I. u4 n! a% U% I
17
: F+ o0 L6 x0 u. |6 u2 f6 C1 aTopical testosterone
5 G5 S$ }$ M" L34.6 4.5 X 6.5 85# ^* |: u& c1 ~. H9 `6 t& n, J8 M
38.8 6.0 X 8.5 709 E8 p: m$ q7 U( R  _
40.0 6.0 X 6.5 62.5. A4 `' |1 X8 z: ]
93.6 6.0 X 7.0 55.5
+ F( F% ?0 u+ {. s95.0 6.5 X 7.0 27.2
/ Z9 d2 V% T$ g! BAv. 60.0& f9 D7 E) c5 d! W8 ^" t
available testosterone. Again, emphasis should be placed on& [' {$ G5 u  d
early therapy when lower levels of testosterone appear to
* t2 b+ w$ \. l/ E' pprovide the best responses. The earlier therapy is instituted  w! w. z% _4 j7 ]
the more likely there will be an excellent response with low
2 q; V( z2 g: u4 u" N9 h; X( Tserum levels. Response occurs throughout adolescence as; r# _: H# i4 O" I+ I3 q- ^
noted in nomograms of phallic growth. 7 The actual response
, Y# H+ v6 e' f. q3 v. |' Kto a given serum level of testosterone is much greater at birth
9 E$ Y0 C( y' p5 e$ y( Land gradually decreases as boys reach puberty. This is most
# c4 P4 p' ~# ]0 L& {; Llikely related to the conversion of testosterone to dihydrotes-% W) ]4 X3 r4 e' N* C1 P
tosterone and correlates well with the studies of testosterone
5 R" ]' L/ }% x% V5 P$ Wconversion in foreskin at various ages.
6 i/ j& v: {" o! v2 i7 CThe question arises regarding early treatment as to whether; b, F) B$ U; T' L! [% U- k
one might sacrifice ultimate potential growth as with acceler-
- V0 D7 R4 L  f. Iated bone growth. The situation appears quite the reverse! K, k& u( F5 o; E$ e* Q
with phallic response. If the early growth period is not used0 F; |( ?# d5 w* b8 r0 b
when 5a reductase activity is greatest then potential growth
  q: m4 w7 I# j3 a) u, @+ ^" lmay be lost. We have not observed any regression of growth3 c9 w" P, X$ {
attained with topical or gonadotropin therapy. It may well
* P8 {( k5 ]2 Y3 |/ ?be that some patients will show little or no response to any
" p6 k  r, ]! w' z: I( aform of therapy. This would suggest a defect in the ability to
1 v5 D3 A8 u: S; b% {5 p/ M& C4 pconvert testosterone to dihydrotestosterone and indicate that
( d# n* z" e7 \! z$ ephallic and peripheral skin, and subcutaneous tissue should
; M2 t" \; C7 d; kbe compared for 5a reductase activity., R  y9 _) J* U* E' b7 o1 d$ o
A, loop enlarges to measure penile girth in millimeters. B,# H0 |6 U7 f& Q" b2 U# }
example of penile girth computed easily and accurately.! ?) P9 T6 j: D- K1 d
conversion of testosterone to dihydrotestosterone. It is in this+ A8 W0 p- Q( F6 n8 U, P2 t
older group that others have noted high levels of serum
) Z% |5 X) w; V/ ^* I4 C: ?testosterone with topical application. It would also appear
5 @4 g4 m, ]7 s+ B9 F# [that phallic response during puberty is related directly to the
/ C/ L# j1 ]# r: C8 I9 f9 Userum testosterone level. There also is other evidence of local/ U4 _- ]- o) R4 [) _
response to testosterone with hair growth and with spermato-
: h2 L5 d- E8 X6 Hgenesis. 5• 6, W/ x8 t( \. O" e
Administration of larger doses of gonadotropin or systemic! B1 o/ x3 T8 y& S& N
testosterone, as well as topical applications that produce  ?6 o4 c1 l4 R& V5 [" a
higher levels of serum testosterone (150 to 900 ng./dl.), will5 _& G4 a' w, B9 D7 i2 q
also produce phallic growth but risks accelerated skeletal
! W& t! q: S9 J% p* A7 ?maturation even after stopping treatment. It would appear
) l" b2 X' @5 s/ A( `0 D' Sthat this may be avoided by topical applications of testosterone3 D6 `) h3 ?3 L9 {( E/ N  p
and monitoring of serum testosterone. Even with this control
- s6 R4 w" S$ F  Uthe duration of our therapy did not exceed 3 weeks at any! Y3 @8 c1 k4 C' e" k5 ~7 `
time. It is apparent that the prepuberal male subject may
( K1 [; z" A6 lsuffer accelerated bone growth with testosterone levels near
2 X3 l+ t$ h6 n( j; V$ ~4 b4 r200 ng./dl. When skeletal maturation is complete the level of/ J" B9 _9 B; a. C: z/ P3 o+ j. F
serum testosterone can be maintained in the 700 to 1,300 ng./0 k1 W5 l( ?$ q- d8 R: p9 R
dl. range to stimulate phallic growth and secondary sexual0 j' Q* w, Y1 ~1 \: A5 T, p" D
changes. Therefore, after skeletal maturation parenteral tes-" G# [( D2 w$ t! u7 `
tosterone may be used to advantage. Before skeletal matura-" n% G5 @+ ~9 K
tion care must be taken to avoid maintaining levels of serum
: n2 w) `: H1 etestosterone more than 100 ng./dl. Low-dose gonadotropin
2 V* n! {! m; |3 N0 a9 y. `- Pdepends upon intrinsic testicular activity and may require0 S7 G) O- \, J, q8 E! i
prolonged administration for any response.) l2 C9 R$ d( _" m
Alternately, topical testosterone does not depend upon tes-
0 g2 k" a0 y: [5 w) Y# Fticular function and may provide a more constant level of
0 w: S# i( G/ W& O' BREFERENCES$ {( N1 d+ s( X3 |' p1 ^
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; M5 I% t- @8 yR.: The local application of testosterone cream to the prepub-
, U5 ~! l) e1 |4 l$ p: Q/ b3 @ertal phallus. J. Urol., 105: 905, 1971.1 E' H7 E8 V: _7 _3 C) I
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone: y' N3 S2 Y  z7 y  p
treatment for micropenis during early childhood. J. Pediat.,
8 K# v* O2 z/ ^- }2 c) m83: 247, 1973.
  x  y5 Z0 Z8 _' [3 M9 m3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
0 }& _/ d' g8 i) S  f* Y- [: q" done therapy for penile growth. Urology, 6: 708, 1975.
+ e; S1 H  e- |* K" I! N& n& m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- q0 a, a) c6 L0 }3 vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 R' Z1 K8 k6 k
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' Q- v% {) |! c5 U5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth& b5 w( I! s0 u) Q: L7 p' `
by topical application of androgens. J.A.M.A., 191: 521, 1965." _7 j; w5 p) `3 R
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 }) `4 M' D9 e1 Q$ D. B4 gandrogenic effect of interstitial cell tumor of the testis. J.
/ e$ s, C' ~: wUrol., 104: 774, 1970.  m7 }0 o" f$ ^. i* I2 M& t
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
: a/ s. Y1 `( g, C- c: ction in the male genitalia from birth to maturity. J. Urol., 48:
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