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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 j& @+ W5 r0 v7 K$ Q
GONADOTROPIN
1 n! p; q a3 v: h+ ^* GRICHARD C. KLUGO* AND JOSEPH C. CERNY
: \& E+ o% |1 L/ R! J$ i; x: yFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
/ G) Y4 O5 X9 t- D, X+ |ABSTRACT* H4 N4 P) k" f
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
9 q# q8 e. f+ wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- y& }; Z+ d% o- B' q8 H
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* t( ?. m1 V# J3 X9 K
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* g. v. S. d- Q4 ?; a. ?/ E6 Sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 R+ X& g& Z9 E- y) L
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average' j: B' V$ F- {
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. ~3 q6 Z& ^( O' S7 j+ moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ ]& ~& t- |/ N5 B, b- _study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile# I6 I3 s& N8 P: E3 l% w+ a) t
growth. The response appears to be greater in younger children, which is consistent with previ-
7 _+ S6 c# R- _( ~9 n4 s, B* [9 `# o9 r0 oously published studies of age-related 5 reductase activity.
: A/ O# g1 A; I8 ~. QChildren with microphallus regardless of its etiology will
! k9 i1 N: W& H8 j6 e1 f0 Drequire augmentation or consideration for alteration of exter-: p ~" q# j+ }. V, p' ~/ d3 W
nal genitalia. In many instances urethroplasty for hypo-
7 H9 ^" b( d+ e* Y6 Y+ z- Jspadias is easier with previous stimulation of phallic growth.! _$ \( G3 X& @+ d( B9 A- h' p
The use of testosterone administered parenterally or topically
8 J2 O( p2 n7 N% T/ d+ l+ |1 Lhas produced effective phallic growth. 1- 3 The mechanism of- K3 a; I8 F3 F: @& y8 Q% Z2 q& Y
response has been considered as local or systemic. With this0 m3 t# f+ _# v- X1 I$ t
in mind we studied 5 children with microphallus for response
1 \9 d7 O' x( s# F! Cto gonadotropin and to topical testosterone independently.
4 P! B v3 e- l+ U/ Z3 D) F8 RMATERIALS AND METHODS3 Q# F6 E8 b: ~& r. w! P# X, }
Five 46 XY male subjects between 3 and 17 years old were4 G. }# p7 f1 ~
evaluated for serum testosterone levels and hypothalamic1 Y* H0 R% f& O0 f2 Q
function. Of these 5 boys 2 were considered to have Kallmann's
% x- V. B) p# e% R+ Y4 xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" r4 P. k9 R+ Ilamic deficiency. After evaluation of response to luteinizing
) o1 _, A5 B, B0 x' n0 Fhormone-releasing hormone these patients were treated with' T4 `3 i3 \2 x {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks h; j) }+ r5 q" o: o1 p. e5 K+ M
after completion of gonadotropin therapy 10 per cent topical( } }- I( @$ X+ i1 G9 l
testosterone was applied to the phallus twice daily for 3 weeks.& i, c6 c9 v& T+ A4 P" r
Serum testosterone, luteinizing hormone and follicle-stimulat- }0 y' G* A2 j4 j. ]3 C I
ing hormone were monitored before, during and after comple-: d" @! A1 U' e+ O$ }
tion of each phase of therapy. Penile stretch length was+ T9 e2 n& o7 @" j- X9 s# ]
obtained by measuring from the symphysis pubis to the tip of
$ A$ L7 f5 L0 c) Y3 T) Uthe glans. Penile circumferential (girth) measurements were* A9 I' H2 I2 x, _
obtained using an orthopedic digital measuring device (see& M& m& S( w9 U! `
figure).
+ w; M- J1 R8 x! k8 ^( a9 vRESULTS6 \- n! I% U) g. m. h
Serum testosterone increased moderately to levels between+ [( u$ D/ P/ R. P& ^
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
8 Q: v5 ]/ }/ r% Q; j' Gterone levels with topical testosterone remained near pre-9 G; @, e: Z9 P* F
treatment levels (35 ng./dl.) or were elevated to similar levels
/ H% C8 w* d/ r `developed after gonadotropin therapy (96 ng./dl.). Higher/ V1 f) D# k6 [7 W/ L0 F8 S( ]
serum levels were noted in older patients (12 and 17 years old),3 U/ i1 e4 S: R3 g/ u) z
while lower levels persisted in younger patients (4, 8, and 10
, k9 K2 h4 |! \' B/ Tyears old) (see table). Despite absence of profound alterations
L" Z# @ I! g" J! k9 d+ b% qof serum testosterone the topical therapy provided a greater9 S& t* D3 Y; d% I% k! n
Accepted for publication July 1, 1977. ·
& v9 P. d3 Z8 p* ^7 F, `" _Read at annual meeting of American Urological Association,! u6 Y% j3 ]2 P8 u8 Z. E1 {$ V
Chicago, Illinois, April 24-28, 1977.
0 [) q' R" T( Q6 d* Requests for reprints: Division of Urology, Henry Ford Hospital,
# g: D& d Q% s% w2799 W. Grand Blvd., Detroit, Michigan 48202." ^: S: b) b2 N& X! r- o8 R0 b
improvement in phallic growth compared to gonadotropin.+ y/ e% ]: G6 N& ~$ d. Y
Average phallic growth with gonadotropin was 14.3 per cent
. x! h% o# m3 r+ N" uincrease in length and 5.0 per cent increase of girth. Topical
; v) @. c7 F' ftestosterone produced a 60.0 per cent increase of phallic length
( T& Q* l5 s* z, c3 `+ }, Fand 52.9 per cent increase of girth (circumference). The* |2 b/ h( K- C0 n/ A
response to topical testosterone was greatest in children be-) m7 V6 | w& Y9 X+ Z) q6 [6 e2 z
tween 4 and 8 years old, with a gradual decrease to age 179 D' L! d0 k+ U
years (see table).
# `5 [5 f/ X" Z; rDISCUSSION
* Y G. a; f* \; n4 NTopical testosterone has been used effectively by other
2 `% ^) i2 \1 v$ q2 N/ Sclinicians but its mode of action remains controversial. Im-2 w6 i3 U* M+ h$ e$ B
mergut and associates reported an excellent growth response
) W6 J' M* ?, Vto topical testosterone with low levels of serum testosterone,
& w" i8 [( c5 ysuggesting a local effect.1 Others have obtained growth re-
/ M. j% {( w- ^' x/ ` v: d# [$ isponse with high. levels of serum testosterone after topical
3 A6 s( x( h9 A$ s# _+ H: V7 sadministration, suggesting a systemic response. 3 The use of
( S# W3 r- [- ]) a# Kgonadotropin to obtain levels of serum testosterone compara-
, S2 t: Q( Y! d& ?# @0 Oble to levels obtained with topical testosterone would seem to
3 ?' {8 Z/ ]7 u7 }7 w: Aprovide a means to compare the relative effectiveness of
6 k p; P# V( i: M( Ftopical testosterone to systemic testosterone effect. It cer-- n# C8 R1 s$ I
tainly has been established that gonadotropin as well as par-
' A1 J9 O& f' r( f {' u( l8 ^enteral testosterone administration will produce genital- N/ p4 A' u6 x* U
growth. Our report shows that the growth of the phallus was
8 Q1 ]2 l' ]% T- Ysignificantly greater with topical applications than with go-
: h. I6 [5 n$ l4 c: n rnadotropin, particularly in children less than 10 years old.1 Z7 m/ m5 X( ^& N3 k
The levels of serum testosterone remained similar or lower* i) M/ ~ Q/ ^
than with gonadotropin during therapy, suggesting that topi-
3 i2 G4 q3 j/ U; U, lcal application produces genital growth by its local effect as. h3 z3 ^- A. Z8 B; ?
well as its systemic effect.
, u$ t6 C8 j% `: yReview of our patients and their growth response related to
5 p6 B, Z. b: Z4 B5 eage shows a greater growth response at an earlier age. This is
- k& o0 w- L( oconsistent with the findings of Wilson and Walker, who/ o* g7 c2 o8 C1 w
reported an increased conversion of testosterone to dihydrotes-
6 {' T {6 p, V* {, b- Mtosterone in the foreskin of neonates and infants.4 This activ-
( j1 _$ K S$ ?4 m' uity gradually decreases with age until puberty when it ap-5 u `, V0 b k1 z; k
proaches the same level of activity as peripheral skin. It may2 l W8 u* X8 O
well be that absorption of testosterone is less when applied at# k6 ]% o+ j7 |1 ?( R# j
an earlier age as suggested by lower serum levels in children
$ u9 W' B [! }- _less than 10 years old. This fact may be explained by the
( f& @) u1 A3 t7 X) A* Egreater ability of phallic skin to convert testosterone to dihy-
0 ]: W3 {3 n5 g. q- Q, c. ldrotestosterone at this age. Conversely, serum levels in older' U9 |' j% w$ y/ z! |
patients were higher, possibly because of decreased local) G- Y' {" }$ J/ i6 m
667
* P% v" p0 _! p& Z668 KLUGO AND CERNY
. Y4 e. u/ c% A4 B* H8 J/ G+ |Pt. Age) N" F( \/ F7 X# I
(yrs.)
3 `0 b: J. b; D5 C3 w, mSerum Testosterone Phallus (cm.) Change Length6 t, [+ L: O: Z( _
(ng./dl.) Girth x Length (%)
' A/ t4 o$ G0 F7 w& [4
4 w8 t* f0 S/ s8: ]' F6 x8 a6 `* \3 U) k
10
9 K& _ ]6 [. }( i12
3 ?) {$ O8 b% B( b: u' V17
9 m, Y; d: C) ]) HGonadotropin
0 S& V) s( M% D H# _, |71.6 2.0 X 3 16.6
: W5 e, p/ L3 Z4 M( W0 c50.4 4.0 X 5.0 20.0% I$ v5 D e2 u: e
22.0 4.5 X 4.0 25.09 M$ K: @- A6 j( T3 O
84.6 4.0 X 4.5 11.1+ i+ |" Y0 O- C' y/ K) L: Q
85.9 4.5 X 5.5 9.09 f6 [6 F! Z* T
Av. 14.3. E. N* d Y. O! i9 t) p, ^
47 ^3 F/ Z) n) p2 l& d) ^; l
88 s$ n/ e% j9 L* p: B- s
10
2 m) c: @; P: Y, I$ V12* b/ c# W {1 t6 m8 o+ K
17
- l8 k" k7 {+ R9 KTopical testosterone, ~; u5 [4 [ P1 _- s' q% {/ L" e- Q
34.6 4.5 X 6.5 85% z: Z1 Y( v. s: e! ?1 v8 ]% \3 G
38.8 6.0 X 8.5 701 \9 X! u1 U* B( y: I! o# l5 g" A! Z
40.0 6.0 X 6.5 62.5
1 U. n0 l, O l7 v6 ^93.6 6.0 X 7.0 55.5 X+ I& y0 v; i* d# g' F* x
95.0 6.5 X 7.0 27.2
/ `& w5 Z* u# V/ m" c3 L7 _Av. 60.04 o1 P! S8 K3 B) b% n2 ]
available testosterone. Again, emphasis should be placed on' g8 K' f9 g: V; m
early therapy when lower levels of testosterone appear to
, e8 M6 V$ E3 C" t; tprovide the best responses. The earlier therapy is instituted0 N+ j1 g9 ~6 x( W7 f9 ^$ d
the more likely there will be an excellent response with low
9 V/ K5 x9 @5 b! G/ S3 dserum levels. Response occurs throughout adolescence as
6 ^' A* I$ @9 H" ?6 Knoted in nomograms of phallic growth. 7 The actual response+ p9 u" E" A# \5 t% b) U+ f, d
to a given serum level of testosterone is much greater at birth
4 e# D) Q/ y/ ~* f& B7 `# \and gradually decreases as boys reach puberty. This is most
) F1 J! i" O7 \2 d" }# ?likely related to the conversion of testosterone to dihydrotes-
( s+ ?3 N, B. ~+ N1 d1 Ctosterone and correlates well with the studies of testosterone
/ u6 w7 ^! s) E8 T& V" f. t0 iconversion in foreskin at various ages.
+ e N7 E: O1 e. n/ P' [The question arises regarding early treatment as to whether
* Y( d- R4 f4 Done might sacrifice ultimate potential growth as with acceler-
$ K$ U) Q4 ~0 ?9 vated bone growth. The situation appears quite the reverse
# Y/ @$ S$ Y; H4 c2 A, ]# @with phallic response. If the early growth period is not used9 B+ G5 M3 K0 J: F' M
when 5a reductase activity is greatest then potential growth( Z0 y" I4 w! r
may be lost. We have not observed any regression of growth
( p7 @8 s2 a3 N+ p+ `3 V" Mattained with topical or gonadotropin therapy. It may well7 E/ j7 f+ K( B# w3 k3 x4 J
be that some patients will show little or no response to any- z, ^0 {! Y f! ]7 [" K7 W
form of therapy. This would suggest a defect in the ability to
2 F0 ^; V$ k; e9 W) \ v( yconvert testosterone to dihydrotestosterone and indicate that5 _) E0 c8 f1 i- V5 h( [
phallic and peripheral skin, and subcutaneous tissue should$ b2 p5 A' o) \1 }/ H, ^7 f# W# L* c
be compared for 5a reductase activity.
3 s5 ^& F2 l; r, O- @A, loop enlarges to measure penile girth in millimeters. B,
( m) ~- u6 z% Z( g9 l: z; c1 ^example of penile girth computed easily and accurately.
: N8 t+ s; W+ D6 ^! m* [conversion of testosterone to dihydrotestosterone. It is in this
* M; I& R5 z, @) Golder group that others have noted high levels of serum
* F5 j1 I& f# h9 J+ Z; S: r2 Ltestosterone with topical application. It would also appear* F7 r& V# U% M7 L1 E8 X. m7 Y
that phallic response during puberty is related directly to the
3 u) W' J9 x7 L, V+ F: e K: bserum testosterone level. There also is other evidence of local
) L) `6 x% |& r* Z9 l& Yresponse to testosterone with hair growth and with spermato-
o8 C& Y6 Z) t7 g' fgenesis. 5• 6) G3 l- M: F/ H" K# I- r$ G
Administration of larger doses of gonadotropin or systemic/ r. v6 V. S2 F
testosterone, as well as topical applications that produce
! s1 _, g1 H ]" t8 ohigher levels of serum testosterone (150 to 900 ng./dl.), will
2 K- v; |- y: M0 [: ?also produce phallic growth but risks accelerated skeletal F: q& W( u* B& r$ \9 p
maturation even after stopping treatment. It would appear, u* ]; v4 O; Y
that this may be avoided by topical applications of testosterone9 n" X5 h1 O P4 j" c& D
and monitoring of serum testosterone. Even with this control
: |* @8 I/ s1 Z5 ^the duration of our therapy did not exceed 3 weeks at any% M4 w9 p! ~- Y% {3 Y9 M. t( w
time. It is apparent that the prepuberal male subject may
! J3 P0 K5 B$ W8 Psuffer accelerated bone growth with testosterone levels near5 z6 L4 b* O% Z
200 ng./dl. When skeletal maturation is complete the level of
$ X: a6 b( M" {: h, tserum testosterone can be maintained in the 700 to 1,300 ng./+ ~& @9 h; p1 k# j
dl. range to stimulate phallic growth and secondary sexual
- }9 j) `6 Q- s# Y( ~changes. Therefore, after skeletal maturation parenteral tes-" {: G2 d2 q. \' O9 [1 A) e
tosterone may be used to advantage. Before skeletal matura-8 W$ a& \4 A8 n& ~- [
tion care must be taken to avoid maintaining levels of serum. f8 o5 Y/ A4 g. K
testosterone more than 100 ng./dl. Low-dose gonadotropin
, P; O8 X5 t4 p, I# r* ~( j( Jdepends upon intrinsic testicular activity and may require
+ {7 {7 z8 |$ A) N1 K5 Z7 @' Xprolonged administration for any response.( a1 V: n) l( s/ p
Alternately, topical testosterone does not depend upon tes-8 v7 a. J3 c% J1 n* ^/ B
ticular function and may provide a more constant level of
/ u. K# ?$ L2 FREFERENCES* E! N& S9 L1 A9 E4 _0 Y- L
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ C9 l, t, e( u. h: V, [R.: The local application of testosterone cream to the prepub-9 C% h8 e: B4 D7 b, D, i
ertal phallus. J. Urol., 105: 905, 1971.# r' s; W; Q7 x0 a" `8 X
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
D/ j8 G0 d) k5 |treatment for micropenis during early childhood. J. Pediat.,
! U" [# I8 E& K0 i W7 M& u! M83: 247, 1973.
# V7 J6 B( g5 W* e4 p- P$ ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 Q% [; H5 z0 k! H
one therapy for penile growth. Urology, 6: 708, 1975.
, ?4 D% V* n; s& n1 w; Z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: k; T! ]1 H6 ?# cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 O! ?* v a. rskin slices of man. J. Clin. Invest., 48: 371, 1969.' r. T! d V( L! |1 a) o+ s1 t
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. K! X. I8 n. i+ ]/ y5 g1 bby topical application of androgens. J.A.M.A., 191: 521, 1965.
+ L7 l7 K- l7 r* x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 x( w* G z5 d9 ]3 @androgenic effect of interstitial cell tumor of the testis. J.
1 [+ }7 e) [& m* XUrol., 104: 774, 1970.
/ G2 h6 K- `3 H7 w% d7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 l* J# V% {: e. J: N9 U6 ition in the male genitalia from birth to maturity. J. Urol., 48: |
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