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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
% e9 j$ H n, b! _* T: cGONADOTROPIN
( A0 w s0 m; }- W- g cRICHARD C. KLUGO* AND JOSEPH C. CERNY
; J# |0 U U4 AFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ w; H0 j# k' X6 [" s( a- MABSTRACT
5 t# V& z. I- H9 f0 r" X! A4 i* BFive patients were treated with gonadotropin and topical testosterone for micropenis associated) ^+ [" C! V( Z
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. q+ n& N- K a( j- M$ xtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ R3 c( Z' r' q' Xcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, J+ Y) D( u8 A2 sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 l1 y- L8 _% s( fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 y% h& W6 \) ?: r) \) tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# B- F# Y' {4 q/ ]/ Q% |+ [8 j4 Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 B# f6 O! |9 G' c/ T
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ R6 U7 h/ x4 pgrowth. The response appears to be greater in younger children, which is consistent with previ-7 }3 P- [9 W2 b1 _! j8 r4 `3 Z! \
ously published studies of age-related 5 reductase activity.
4 c) N* X# J; Z4 f! d8 P/ B9 gChildren with microphallus regardless of its etiology will0 B: V% N" j/ T |' j) R& R* m
require augmentation or consideration for alteration of exter-
. ]$ o7 v8 T5 I) `nal genitalia. In many instances urethroplasty for hypo-' p" e/ _5 m8 W( d) N( D7 e2 U
spadias is easier with previous stimulation of phallic growth.
6 }8 Y+ i, Y& D6 WThe use of testosterone administered parenterally or topically
+ I0 @2 b. y3 Qhas produced effective phallic growth. 1- 3 The mechanism of$ D8 @& c+ y+ d* K/ Q" B
response has been considered as local or systemic. With this' O7 x; m$ W' e9 u, |. Q
in mind we studied 5 children with microphallus for response
6 g# E0 U1 h7 R5 y9 b% b o; A5 kto gonadotropin and to topical testosterone independently.
0 ~- k+ f0 c) q. G# `MATERIALS AND METHODS
2 n* ~) S. m# M3 q- C7 sFive 46 XY male subjects between 3 and 17 years old were% q. z/ q2 h5 J/ |' m# z4 x& W7 t' u& ?9 L
evaluated for serum testosterone levels and hypothalamic
, _0 ?, v8 Z/ W) o2 Dfunction. Of these 5 boys 2 were considered to have Kallmann's; [# s) Y3 h+ Y! w s3 a4 q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 `% b% v; E: T" v9 N2 f
lamic deficiency. After evaluation of response to luteinizing
P7 Y: Q( _# m0 h# X+ u5 h R1 mhormone-releasing hormone these patients were treated with
5 p3 {' q2 o1 O8 j n1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% \4 [& X6 V8 \. B2 Q& y1 Iafter completion of gonadotropin therapy 10 per cent topical
. s6 V# }4 h+ |3 E9 _; ^& T! C% @testosterone was applied to the phallus twice daily for 3 weeks.
4 W- T: t Z9 t, TSerum testosterone, luteinizing hormone and follicle-stimulat-4 a( m6 |& f. G: e. Z4 n
ing hormone were monitored before, during and after comple-
% K0 Q" p( r6 s* S2 l) ntion of each phase of therapy. Penile stretch length was
1 z7 f$ M' c- @: Z( yobtained by measuring from the symphysis pubis to the tip of
: n; L' U; n# m2 |: g. tthe glans. Penile circumferential (girth) measurements were" f- X2 r- E( t* y4 [( `
obtained using an orthopedic digital measuring device (see: @7 X1 S" T+ Z5 i o& D3 g0 c7 i8 }
figure).8 Q) R* ?( p1 d
RESULTS) v0 b: B( `4 I3 ~# `0 \- q+ a
Serum testosterone increased moderately to levels between
1 g! l+ k/ b m* K2 y$ W# M50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 x+ e9 o) A/ J2 n: u8 ?terone levels with topical testosterone remained near pre-
) j* X. m( _, q. B' N' Ttreatment levels (35 ng./dl.) or were elevated to similar levels
- a6 s T( s' O Ndeveloped after gonadotropin therapy (96 ng./dl.). Higher6 M7 F9 a) C1 u$ ?* j. L) K& l
serum levels were noted in older patients (12 and 17 years old),
7 H& M1 E& W6 i0 jwhile lower levels persisted in younger patients (4, 8, and 10' F$ O$ v* _! h1 `6 V0 Y7 [$ Z D3 t
years old) (see table). Despite absence of profound alterations
! L: A4 { x* r' k) Iof serum testosterone the topical therapy provided a greater$ U/ ?4 C+ y, F
Accepted for publication July 1, 1977. ·2 Y+ f. b* E. ?$ q+ z x
Read at annual meeting of American Urological Association,9 H4 F" k6 Y5 `$ M* Z4 a' Z
Chicago, Illinois, April 24-28, 1977.
& V$ G, {) C+ @4 X& D4 a9 v( M* Requests for reprints: Division of Urology, Henry Ford Hospital,% I8 C( r+ A; B
2799 W. Grand Blvd., Detroit, Michigan 48202.
) O! f$ ^/ L/ Z$ Vimprovement in phallic growth compared to gonadotropin.
" P7 {7 h/ p1 G! W6 F3 gAverage phallic growth with gonadotropin was 14.3 per cent
" b4 [) S& Y. S- q5 Lincrease in length and 5.0 per cent increase of girth. Topical8 y _; ^3 ]6 d3 F1 K" o! h* x/ t
testosterone produced a 60.0 per cent increase of phallic length
; Y! f/ B) l" }; Mand 52.9 per cent increase of girth (circumference). The+ F, G0 G: i5 @+ |
response to topical testosterone was greatest in children be-
3 a" R* E& k) i ]9 |tween 4 and 8 years old, with a gradual decrease to age 17
0 T' Q0 \- K: `years (see table).7 y' j6 G& G9 A p
DISCUSSION
& {' U% A, F; {1 F; b: m3 B* H5 [ PTopical testosterone has been used effectively by other
! l9 h( R$ o. Z) n7 Y6 oclinicians but its mode of action remains controversial. Im-
! T. u) f! W! Q5 ]8 Ymergut and associates reported an excellent growth response
& i) w$ w) {& b1 sto topical testosterone with low levels of serum testosterone,
6 t' n% l# f9 G0 a2 D5 ]1 Dsuggesting a local effect.1 Others have obtained growth re-
2 C5 h, T# f- u; f- I9 v6 csponse with high. levels of serum testosterone after topical
' _4 B( n2 N! m {administration, suggesting a systemic response. 3 The use of
* A0 N: ~" B" {4 k y' wgonadotropin to obtain levels of serum testosterone compara-' v( _: _; Q Z3 x |7 ]
ble to levels obtained with topical testosterone would seem to9 |$ Q" K7 U: Z9 X0 k
provide a means to compare the relative effectiveness of% p$ f, } o( i7 d5 {
topical testosterone to systemic testosterone effect. It cer-7 j8 }8 o/ [# X6 `: N J, t$ b2 y
tainly has been established that gonadotropin as well as par-, z. I' T9 D& E0 k( _. F
enteral testosterone administration will produce genital
' Z# u% a5 m* R0 ?- p% y3 Jgrowth. Our report shows that the growth of the phallus was
/ X d" R# E/ w+ N# Tsignificantly greater with topical applications than with go-
1 C" N: H3 f1 ]2 S0 w* e7 L- c5 mnadotropin, particularly in children less than 10 years old.
) z8 Z1 X- |! H! e/ K8 ~The levels of serum testosterone remained similar or lower
; Y1 `; u1 \" X* d. C. Q1 Tthan with gonadotropin during therapy, suggesting that topi-" Q1 i: a; B0 @8 s) q+ H2 W" W
cal application produces genital growth by its local effect as
2 |9 e9 \- h3 g, ~well as its systemic effect.
$ A4 G) B3 ?: [; I" UReview of our patients and their growth response related to8 m( q3 n( |: R& F, m
age shows a greater growth response at an earlier age. This is
# W( u6 I0 d# x/ c* L2 R1 Nconsistent with the findings of Wilson and Walker, who
) N: S, g; g0 n xreported an increased conversion of testosterone to dihydrotes-4 P& I7 v4 h8 }0 m5 k) @
tosterone in the foreskin of neonates and infants.4 This activ-
7 c4 n# o- _- R% S/ L( iity gradually decreases with age until puberty when it ap-
! s) i( M3 D, iproaches the same level of activity as peripheral skin. It may' v3 J% U h4 m
well be that absorption of testosterone is less when applied at
0 @4 d. I5 F8 ~2 `: A& O8 K/ yan earlier age as suggested by lower serum levels in children
* X1 h* c: I3 C' Q! A' h8 O1 u. eless than 10 years old. This fact may be explained by the' L5 Y' o. U2 y6 r4 l6 h
greater ability of phallic skin to convert testosterone to dihy-/ l' K6 n7 @2 W- k
drotestosterone at this age. Conversely, serum levels in older
. e( \5 C$ Y( }/ z6 c+ s, Kpatients were higher, possibly because of decreased local. L9 t0 c3 k7 W8 {- r
667
; j# [4 o$ a5 |5 D9 k) @668 KLUGO AND CERNY
9 i+ E7 B% s1 z; pPt. Age$ Y- i$ {' e& Q0 b# L
(yrs.)
2 J$ U8 o4 f2 \1 [% ^Serum Testosterone Phallus (cm.) Change Length
* e, z* b6 q1 p/ H( W3 M* Z(ng./dl.) Girth x Length (%)
( C/ J/ v f% g0 y3 h4% _ h+ G, b, ~0 i+ W& }
8
( a; B: |/ k: D0 L10
5 v$ G1 x7 f% l0 x122 \. e1 `* C' J+ {
17% ~$ S l( p- s* G4 R7 P& x4 f
Gonadotropin
& ~) u. Z. L- Y) |/ h/ \71.6 2.0 X 3 16.69 H. a1 D# m- x1 t; R& ?
50.4 4.0 X 5.0 20.0
0 v$ I' k2 ^" u2 Y. O$ ?22.0 4.5 X 4.0 25.0+ f: B# R# y& A' @8 {3 P' j7 l
84.6 4.0 X 4.5 11.1) N! i% k! c4 T( o8 {2 Y
85.9 4.5 X 5.5 9.06 |$ Z4 q4 g5 m3 C2 c! m( b
Av. 14.3' n' q" v7 l# b# N# N
4
# v: l$ ]) c# j8
+ ~6 X8 a9 L! U& Y, @) k0 M10: F3 D" v; [" l6 P$ P6 s) V
12' J: y4 x. [# g6 K# v+ p2 s! }
17* s% g! e- \9 Z5 u
Topical testosterone' v$ `' p% r- E* {1 T& a& o- ^
34.6 4.5 X 6.5 854 H& @% h) x% t+ |% Q3 Y; K6 p: @3 D
38.8 6.0 X 8.5 70* z( ?- B; q. S3 v3 e* m
40.0 6.0 X 6.5 62.5
' s* u" r5 W& i' W0 b93.6 6.0 X 7.0 55.5
; S/ X9 ~% a' a6 @; N95.0 6.5 X 7.0 27.2
1 F% t5 g" P& d8 {Av. 60.07 V' m8 Z) Y# Q
available testosterone. Again, emphasis should be placed on2 \, U y) h% `9 P N' V
early therapy when lower levels of testosterone appear to+ i( o% c6 b& u8 _, J% V
provide the best responses. The earlier therapy is instituted
: G* g8 D8 D6 k+ Mthe more likely there will be an excellent response with low C. ^4 W7 I* T2 {( r3 P0 U
serum levels. Response occurs throughout adolescence as: U- Q" n3 R* b, |$ n" K4 v9 ^ k
noted in nomograms of phallic growth. 7 The actual response
7 \$ B$ @7 h( ]) K) X: Nto a given serum level of testosterone is much greater at birth
0 h5 k( W& {6 ~( [8 Tand gradually decreases as boys reach puberty. This is most
$ H. J" m8 e y, B2 Qlikely related to the conversion of testosterone to dihydrotes-- n6 y+ ^ Q( \# `
tosterone and correlates well with the studies of testosterone; @! k$ o7 ?9 p }. X
conversion in foreskin at various ages.% C9 \6 F6 Y9 b7 ~, } ]& `9 g
The question arises regarding early treatment as to whether/ w2 F6 @% w9 M0 U8 V- ]
one might sacrifice ultimate potential growth as with acceler-* I7 J( x* s3 c3 r7 R
ated bone growth. The situation appears quite the reverse+ O N+ f7 B4 s& q: N1 n+ `
with phallic response. If the early growth period is not used
0 N4 ]1 K, ~0 E% qwhen 5a reductase activity is greatest then potential growth; @9 i5 T0 W% C' Y& @
may be lost. We have not observed any regression of growth
2 C3 ]- l3 \5 uattained with topical or gonadotropin therapy. It may well4 m! [0 n' P0 W! p
be that some patients will show little or no response to any8 q+ c3 Y% {% i% ?
form of therapy. This would suggest a defect in the ability to( I8 d; B( d- W9 `( H8 B9 e
convert testosterone to dihydrotestosterone and indicate that
+ y% b4 D+ \$ A4 d7 Hphallic and peripheral skin, and subcutaneous tissue should, E% u& o. p7 d9 k8 |
be compared for 5a reductase activity.; T# b& L. t2 I2 @) {
A, loop enlarges to measure penile girth in millimeters. B,
) m/ f' [2 B6 _9 ], R. ?example of penile girth computed easily and accurately.
" I; i4 V& v0 `conversion of testosterone to dihydrotestosterone. It is in this) j6 V$ a3 ^; c$ N
older group that others have noted high levels of serum# ^! |- a8 \) b/ ]
testosterone with topical application. It would also appear
( C0 q5 @& m% N; W0 F4 f: T; f# vthat phallic response during puberty is related directly to the
1 R/ m; v# G3 E0 I userum testosterone level. There also is other evidence of local
; m% V9 |1 T9 h, m6 {5 r- cresponse to testosterone with hair growth and with spermato-
" x) S; b$ W4 V* n0 ]( G3 m/ fgenesis. 5• 6! B( T, S) C' ]: I% x
Administration of larger doses of gonadotropin or systemic- {5 m4 d4 G/ L
testosterone, as well as topical applications that produce) z( N/ T$ B' w( P: c8 `
higher levels of serum testosterone (150 to 900 ng./dl.), will# ^# `/ F' l! G. k
also produce phallic growth but risks accelerated skeletal+ _6 O7 C+ O) o& E- D- b
maturation even after stopping treatment. It would appear
. e$ m1 d2 ]# vthat this may be avoided by topical applications of testosterone
' D0 J4 O6 e7 f4 e- @* _and monitoring of serum testosterone. Even with this control: ?1 D" N% N E4 N" Q9 @$ a
the duration of our therapy did not exceed 3 weeks at any
1 d n* C. [" T6 J. Ktime. It is apparent that the prepuberal male subject may
0 i; K/ {( X, u9 P) bsuffer accelerated bone growth with testosterone levels near3 {9 ~ n% e/ y
200 ng./dl. When skeletal maturation is complete the level of" U$ y) c# @; D( z* `$ p. s0 ]7 I
serum testosterone can be maintained in the 700 to 1,300 ng./
* |5 C6 d3 a* gdl. range to stimulate phallic growth and secondary sexual- k; | U- O0 y
changes. Therefore, after skeletal maturation parenteral tes-
! ^1 @' R1 O4 u9 `0 ctosterone may be used to advantage. Before skeletal matura-
& f% x7 A! Q; btion care must be taken to avoid maintaining levels of serum: x% r4 p$ d: N1 l. L( ~% k8 @& x
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ I: n& V; J# U$ B, @4 `depends upon intrinsic testicular activity and may require
3 h9 n4 }# ~: a/ ~3 S' Sprolonged administration for any response.
8 S& } c1 k- ]& P h. AAlternately, topical testosterone does not depend upon tes-! f ^" `# O! T/ {
ticular function and may provide a more constant level of- v2 }; t4 n. F& l9 K/ b
REFERENCES0 ~- ~0 o* B+ p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: @0 ?: `. n) @8 uR.: The local application of testosterone cream to the prepub-
& t4 M- ]( U; A+ T1 w2 eertal phallus. J. Urol., 105: 905, 1971.
! W R& L0 Z6 W0 ~ H* t O, T2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 Q0 x; m' {. X% ctreatment for micropenis during early childhood. J. Pediat.,1 Z, f" L: C; b, e) W- J
83: 247, 1973.4 K& n7 x" K r ?4 J+ q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
$ j8 l8 e7 X( A+ Q/ ?$ l. d+ S" aone therapy for penile growth. Urology, 6: 708, 1975.
0 T, d5 b3 ?, k2 i4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- p d- y8 t( c9 k8 g2 X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: c( B! k% d8 k* v( R( F
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* t# Y& i) u1 U T& D% d5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 P$ v4 G% n1 l; z9 q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
9 N7 \" b5 a3 c8 ]+ Y& f$ o6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ Z( i p) K1 Z& O5 O8 ?1 B+ g
androgenic effect of interstitial cell tumor of the testis. J.
- X$ N6 Y Q% H* Z& ]3 BUrol., 104: 774, 1970.9 d* J4 ^: O4 y2 h; H) o
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-/ C' w2 F' U v3 h& A' l
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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