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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 P) {) w: q# {- ?, g5 x6 p1 bGONADOTROPIN
/ ]9 k- g8 l, w- P: L8 }RICHARD C. KLUGO* AND JOSEPH C. CERNY
2 v& z3 w* I$ v0 PFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan( P+ r! M% U6 S0 ]
ABSTRACT
2 _' m7 p/ P3 `. IFive patients were treated with gonadotropin and topical testosterone for micropenis associated
; w! W1 f2 Q% Y1 h* ^6 \with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 a* ^6 o X! P; R4 E: Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
X* Y; C8 z$ `# F7 Scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 Q$ F3 B$ g: }, o( Y9 yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 @- N" F5 k" E& o8 K9 ?# D
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ K* p& z- R% Z6 T
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response9 z* r6 ]/ @* W& F; ?7 }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This2 _( ^1 s6 \* q& a% v' H
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
7 i; e/ g Y4 F/ C' R1 X, Agrowth. The response appears to be greater in younger children, which is consistent with previ-
* P+ [9 T" v# `+ `7 J4 qously published studies of age-related 5 reductase activity.
. T7 X. N$ t% Z. G% yChildren with microphallus regardless of its etiology will
, |% H* H. d5 A& f8 l# Orequire augmentation or consideration for alteration of exter-
: D1 E5 l' X$ U( U9 v' jnal genitalia. In many instances urethroplasty for hypo-. M0 J; W$ J X V- E2 [* d
spadias is easier with previous stimulation of phallic growth.
5 H q& y `& L% HThe use of testosterone administered parenterally or topically7 C- h1 E* O8 E1 G+ x7 z
has produced effective phallic growth. 1- 3 The mechanism of) b& `5 [- Q) {7 Z ?
response has been considered as local or systemic. With this
% Y# E2 e4 D' T k; d( Min mind we studied 5 children with microphallus for response
) M- {( ~# ]" E2 X( D$ j! zto gonadotropin and to topical testosterone independently.
8 g+ I% @: T. I( zMATERIALS AND METHODS0 B9 D) u M. ~! f1 o- Z: t. i6 f
Five 46 XY male subjects between 3 and 17 years old were2 m$ [4 V0 c' \3 S. R( C) x
evaluated for serum testosterone levels and hypothalamic( R6 y* n6 n5 q Y( U
function. Of these 5 boys 2 were considered to have Kallmann's
: l) D* E! v- c3 w+ X$ Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 j: D' o2 c0 Q3 Z- I# n2 E, ~lamic deficiency. After evaluation of response to luteinizing0 K; {# T9 P# [, \
hormone-releasing hormone these patients were treated with4 [/ x9 E E8 W& [& c" x3 t2 E. V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks2 r# R: G8 U- u3 p( m
after completion of gonadotropin therapy 10 per cent topical
% Q7 F8 R" X( O" q) btestosterone was applied to the phallus twice daily for 3 weeks.1 C! q: D0 |. G' u
Serum testosterone, luteinizing hormone and follicle-stimulat-
; M& N. c7 u0 k# sing hormone were monitored before, during and after comple-) M' e2 v) B! A6 L. B
tion of each phase of therapy. Penile stretch length was
5 w7 Z+ `$ \! R, i. \obtained by measuring from the symphysis pubis to the tip of
) r8 h: C7 O' o9 ~: g* @2 E, mthe glans. Penile circumferential (girth) measurements were; |% @* Y) B p8 b
obtained using an orthopedic digital measuring device (see
1 w$ A C2 \ Y2 B# b5 _figure).
9 z" Q$ L& H0 J! i; MRESULTS
& f8 J0 O7 v$ @7 }6 h# iSerum testosterone increased moderately to levels between: G/ k: J/ ]8 B( i4 {1 u
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 d7 B0 m, M& F- A7 F* D: I; X$ [0 Y
terone levels with topical testosterone remained near pre-
- A* u [* r( l( S/ l/ ?treatment levels (35 ng./dl.) or were elevated to similar levels3 k0 k* m e- ?8 `/ I2 _
developed after gonadotropin therapy (96 ng./dl.). Higher
! `3 S3 e4 j. l6 @( eserum levels were noted in older patients (12 and 17 years old),; Y+ D' A) x/ z6 I8 S; _0 C2 |
while lower levels persisted in younger patients (4, 8, and 10
0 O* K, |! S3 C' J( c2 _years old) (see table). Despite absence of profound alterations& }/ T6 b, m7 D9 Y7 h
of serum testosterone the topical therapy provided a greater3 W. f- e/ \4 q0 ?5 T
Accepted for publication July 1, 1977. ·
( O4 q/ d% @* J# N( eRead at annual meeting of American Urological Association,& ^1 I Y) _9 R
Chicago, Illinois, April 24-28, 1977.
" [9 F2 |( r! s+ k- Y' A* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 O2 n* c& u% h2799 W. Grand Blvd., Detroit, Michigan 48202.
$ t9 W5 g, ~, e* E& G5 oimprovement in phallic growth compared to gonadotropin.
2 F% m1 @ E4 K, Z4 c. z1 [Average phallic growth with gonadotropin was 14.3 per cent3 a4 h+ F& r8 {% F6 i, h- w
increase in length and 5.0 per cent increase of girth. Topical
6 o' [9 F2 n7 @! m2 M( }testosterone produced a 60.0 per cent increase of phallic length
, v9 t4 _/ |+ P7 Q; p ^and 52.9 per cent increase of girth (circumference). The
/ D7 g# { B, presponse to topical testosterone was greatest in children be-+ _+ H8 n3 c6 W6 F* \
tween 4 and 8 years old, with a gradual decrease to age 17
8 j t8 u _% {. M5 B$ l* fyears (see table).
. c5 b/ a2 s% L$ ~+ v; _0 kDISCUSSION
) X2 i2 x5 G) \2 q$ B- t( ITopical testosterone has been used effectively by other
1 f' A/ z9 \) z( s8 m7 \clinicians but its mode of action remains controversial. Im-
/ G2 f! Q; b0 U4 {2 hmergut and associates reported an excellent growth response8 j/ B/ L8 b( ^) G; g
to topical testosterone with low levels of serum testosterone," Y/ |( h9 D9 v. _
suggesting a local effect.1 Others have obtained growth re-* M9 |% H6 X, D( H5 K. c! h% T
sponse with high. levels of serum testosterone after topical- G7 ]7 |6 @2 n( `
administration, suggesting a systemic response. 3 The use of0 G( ]9 |- W0 Z, Q
gonadotropin to obtain levels of serum testosterone compara-
- ~$ y3 J6 |- H p$ l7 Fble to levels obtained with topical testosterone would seem to0 C& ?8 k1 f9 v# c" Q9 W
provide a means to compare the relative effectiveness of% s3 \4 @$ g( l6 c
topical testosterone to systemic testosterone effect. It cer-) y- x) U* l- a+ l* X8 E8 k1 e' n
tainly has been established that gonadotropin as well as par-. Q, y4 Y7 G) U. }- M8 D9 R
enteral testosterone administration will produce genital
' h# G3 Z" _" w2 D7 i. y; @growth. Our report shows that the growth of the phallus was
9 M2 x6 K' R8 K& bsignificantly greater with topical applications than with go-
1 r& g' w& ^9 P% s. Bnadotropin, particularly in children less than 10 years old.0 @4 c d) ]3 _* V' j
The levels of serum testosterone remained similar or lower
+ K6 i4 d8 N1 ^- [2 L( u. f; R3 Zthan with gonadotropin during therapy, suggesting that topi-( I, E- p* T# u4 k4 [ e7 X
cal application produces genital growth by its local effect as
1 K0 x6 [/ r5 F' r8 [# r, Ewell as its systemic effect.5 b; q) h3 s6 G
Review of our patients and their growth response related to
& O8 Y& g9 X+ Q# e5 Gage shows a greater growth response at an earlier age. This is3 }" B! M& A/ J
consistent with the findings of Wilson and Walker, who
1 V8 k. Z: v3 l# m2 ?5 e O* vreported an increased conversion of testosterone to dihydrotes-
2 f2 i- }# S( ^% _6 ctosterone in the foreskin of neonates and infants.4 This activ-8 F7 Z5 C0 n& K, G O2 U
ity gradually decreases with age until puberty when it ap-
) o% x0 A8 @- U; Q- }+ d* vproaches the same level of activity as peripheral skin. It may5 U7 _, E0 I O$ v& x! u
well be that absorption of testosterone is less when applied at2 V3 ^$ l- }% y1 P' G" V
an earlier age as suggested by lower serum levels in children- A6 I9 I( h6 u1 k" L% V! N
less than 10 years old. This fact may be explained by the
) g& {4 N4 O; K# [/ Rgreater ability of phallic skin to convert testosterone to dihy-" p x1 q: v$ V5 W: h1 P
drotestosterone at this age. Conversely, serum levels in older
2 o" Y' B# U! d, j* J: Ypatients were higher, possibly because of decreased local8 F9 U J$ S4 r$ v3 s- e9 H
667
3 `8 J/ K7 L1 x; U/ |668 KLUGO AND CERNY2 O6 g2 v3 C0 n, B) Z
Pt. Age$ H* v& B; ~9 A T6 o
(yrs.)
$ L$ R# U* M. ~) h- p4 m( MSerum Testosterone Phallus (cm.) Change Length/ z1 T" M' x: N5 }
(ng./dl.) Girth x Length (%)5 N/ _$ ?4 P u5 D( A8 K
4
) s8 v( v) Q5 I9 T$ ^7 F9 K& T8
7 M- U. \+ j0 M10$ B3 I8 \2 L' M# p/ _
129 Q$ |, f* b" G, I
17
0 c, [( }6 v- n+ R/ l$ EGonadotropin
y- T0 A3 }- c- b7 b' `71.6 2.0 X 3 16.66 v8 D: D N9 s, }9 s
50.4 4.0 X 5.0 20.0! j+ B: i: L, m% [( o
22.0 4.5 X 4.0 25.0
/ _6 d1 T& r- Y0 c84.6 4.0 X 4.5 11.1
& D+ i: P0 @0 @. \" ^85.9 4.5 X 5.5 9.0
. f+ R7 P: n+ M- n( N9 `4 jAv. 14.3. G/ s# G" r# ~7 b( O2 o6 H x% Y
4
: P7 [1 H5 U) H: U5 c5 Y+ q8$ X1 [' n, F$ v' F, v- O
10
+ p. E( [ a4 X4 t12' T U- K# ^" F6 O; K9 i
17 X, }" Y9 R" e5 g# Z: R
Topical testosterone4 d1 E& M: p4 k( r+ e6 z
34.6 4.5 X 6.5 85
* @* J7 o" T& K$ q/ ]/ J38.8 6.0 X 8.5 70) ]3 P, s) ^- |7 T' s, Q" z
40.0 6.0 X 6.5 62.5, a$ a. Y7 Q* q# n1 o" i2 |8 U
93.6 6.0 X 7.0 55.53 Z; f) J" x7 L
95.0 6.5 X 7.0 27.2+ H! B9 @4 v( h( T' k
Av. 60.0
6 F/ f$ A' [8 `' Vavailable testosterone. Again, emphasis should be placed on
0 f# G2 W2 X+ \7 cearly therapy when lower levels of testosterone appear to* B) U. p4 U' t. b
provide the best responses. The earlier therapy is instituted! C: _! ~# {( O& K" ~9 o
the more likely there will be an excellent response with low; U% k! L: z4 j# o2 a( g
serum levels. Response occurs throughout adolescence as! ]$ _3 e; n$ S a3 L! k6 q
noted in nomograms of phallic growth. 7 The actual response8 s- M6 e' [# X Q
to a given serum level of testosterone is much greater at birth7 {6 d8 K6 s) S* t, b
and gradually decreases as boys reach puberty. This is most; W6 N" T K* s. _+ O% B
likely related to the conversion of testosterone to dihydrotes-
, W- P# t: v& z% X9 jtosterone and correlates well with the studies of testosterone7 k# n* P8 [7 l2 r6 N
conversion in foreskin at various ages.: p$ E7 e9 h/ V1 z
The question arises regarding early treatment as to whether
l' V1 \4 G0 K# v2 q5 Rone might sacrifice ultimate potential growth as with acceler-3 C5 D9 }/ a$ m* p
ated bone growth. The situation appears quite the reverse
% W9 t) i& n4 s! W/ J" n. t4 dwith phallic response. If the early growth period is not used
$ F& {8 r, Z& }" Nwhen 5a reductase activity is greatest then potential growth
- C, \# D' @* emay be lost. We have not observed any regression of growth
; m# P7 w1 \0 r! z; y0 t! jattained with topical or gonadotropin therapy. It may well
O: k8 E- P5 D9 e/ Wbe that some patients will show little or no response to any
7 O1 `% o0 ]% C8 x) G7 I# Uform of therapy. This would suggest a defect in the ability to4 P$ L" i# X, e# Q+ v3 Z5 Q! m7 ?
convert testosterone to dihydrotestosterone and indicate that
$ w) h( Z7 D$ {/ i4 Xphallic and peripheral skin, and subcutaneous tissue should
; I. C5 ]: a4 Y' Y9 O7 Fbe compared for 5a reductase activity.
( s5 \ m: p! l! Y) f9 OA, loop enlarges to measure penile girth in millimeters. B,
* C j9 x. Z& @example of penile girth computed easily and accurately.6 g* l/ G4 E8 E. O3 y
conversion of testosterone to dihydrotestosterone. It is in this
1 Z. r& [/ v* Nolder group that others have noted high levels of serum! G; ^! k; X9 P! P7 w
testosterone with topical application. It would also appear
6 @, w5 A2 ?& o \) J+ Sthat phallic response during puberty is related directly to the
- u3 v; z7 U$ k. P2 z/ v2 s# jserum testosterone level. There also is other evidence of local" w5 e% j2 P B/ ~
response to testosterone with hair growth and with spermato-
. r) K. C" g- u7 ygenesis. 5• 6: v, Y: y: @7 ]
Administration of larger doses of gonadotropin or systemic- E1 @( p5 X7 G1 w/ ~: q
testosterone, as well as topical applications that produce
! E2 `- H3 E* M8 ?5 j( D9 P/ fhigher levels of serum testosterone (150 to 900 ng./dl.), will
4 r( _4 Y: b( ]- q; Balso produce phallic growth but risks accelerated skeletal
4 l" V/ Y( Y5 s1 @maturation even after stopping treatment. It would appear
8 G# A$ z# b7 m' U" u0 y, Dthat this may be avoided by topical applications of testosterone
. E4 t, A$ T7 j ]3 `. l$ Fand monitoring of serum testosterone. Even with this control. d7 v5 a( }+ U5 g0 B+ c8 x1 _3 r
the duration of our therapy did not exceed 3 weeks at any$ `1 ^4 D$ s# k
time. It is apparent that the prepuberal male subject may; ?, V) h% S T/ U4 _' Y
suffer accelerated bone growth with testosterone levels near- |8 J- p h Q! s# B, c; E
200 ng./dl. When skeletal maturation is complete the level of0 M# z4 e8 I9 Y
serum testosterone can be maintained in the 700 to 1,300 ng./( r3 w. ~/ j8 @' }
dl. range to stimulate phallic growth and secondary sexual& m) j2 V7 \9 K& {6 x' N
changes. Therefore, after skeletal maturation parenteral tes-3 e: c' K, G# R N# I
tosterone may be used to advantage. Before skeletal matura-
. U$ l3 ?+ Y* G3 r Ftion care must be taken to avoid maintaining levels of serum9 m+ u! W% ]5 e* W$ S
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ ~' Z3 ~! j0 k: ^- U6 O! Zdepends upon intrinsic testicular activity and may require
; Y) k- b; S8 [' xprolonged administration for any response.
. S7 P6 ~$ X& K& M0 q) Q% D) m$ WAlternately, topical testosterone does not depend upon tes-
( k- e1 O, Z) o% v4 L2 g6 q+ fticular function and may provide a more constant level of0 ~/ n b& e; f/ E' N' s6 }
REFERENCES
; t: w5 ~1 f. O, S/ f- n4 E; J+ l& s1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 G; f% |6 I D8 _; R8 |( Y( X% V% U
R.: The local application of testosterone cream to the prepub-
. h0 [. u6 ]5 Y1 K' {ertal phallus. J. Urol., 105: 905, 1971.
4 ]* L$ Z, b0 K: S; s+ E n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 r5 @/ d0 p) @' j- h1 ^1 j
treatment for micropenis during early childhood. J. Pediat.,
& U" t& K! T2 ]; o83: 247, 1973.2 h" K }4 [: r* O
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, U4 S, g6 e$ n7 ^one therapy for penile growth. Urology, 6: 708, 1975.
/ S$ ^' E2 S1 J* ]+ P- d: L4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' H8 u; L/ i& ?: o2 r
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, j0 d; w. y T; Cskin slices of man. J. Clin. Invest., 48: 371, 1969.
0 M, p1 r# _, A. D: M! o* m5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ S5 E; b7 b/ e1 }* B* s8 Lby topical application of androgens. J.A.M.A., 191: 521, 1965.
9 N4 D" h v0 d: d6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local x: R: X- S$ i% C" q8 A
androgenic effect of interstitial cell tumor of the testis. J.& u; O. f( @ a) I
Urol., 104: 774, 1970.
4 O+ R, D$ T6 a7 r7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
A$ L" b& g5 I2 m& `tion in the male genitalia from birth to maturity. J. Urol., 48: |
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