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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% w6 o& f, R M% j6 w
GONADOTROPIN
; `6 e6 y1 A- W6 H: [5 o7 ZRICHARD C. KLUGO* AND JOSEPH C. CERNY# e# s, V* L J' r: ^
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% c4 r1 S2 A* J' g6 r+ R' cABSTRACT8 j0 F4 p/ w8 Q! D q. a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' J9 Y) }" N) ~* P6 K3 b. q g/ b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) ~8 q$ c# c% u! x5 otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 \, S6 ~$ A! _- e3 pcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 E& K! j3 ]+ h: j7 ]2 o6 K& G
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 Y% s; I& b+ g2 A6 J- Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 r/ c% I) U; E7 C2 X& _increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response' |$ @$ z# m" n& @
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This& i+ K9 h# s! I4 G% X
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ ~$ Z: S( ?( Q3 |& _growth. The response appears to be greater in younger children, which is consistent with previ-
( R1 {4 K* l/ A) C) ]& B! ^ously published studies of age-related 5 reductase activity.0 T) x! o5 f6 u' i% B6 Q( o: w
Children with microphallus regardless of its etiology will; u# \9 ^) t! p! t2 \9 ~& x
require augmentation or consideration for alteration of exter-
8 N j Q' P; c! Tnal genitalia. In many instances urethroplasty for hypo-0 n% Y* A, }! E7 J7 ^
spadias is easier with previous stimulation of phallic growth.
% \2 Q: _# x' q" ^% r* LThe use of testosterone administered parenterally or topically* k" h5 V, A" ?3 O. ]3 q: E
has produced effective phallic growth. 1- 3 The mechanism of" c& y4 M- L2 L) ~# r
response has been considered as local or systemic. With this
) x* R0 ], {! w2 i& w9 _$ ]in mind we studied 5 children with microphallus for response7 F8 B* n. |! l2 r
to gonadotropin and to topical testosterone independently.6 d7 J3 J4 Y0 a( N
MATERIALS AND METHODS
$ L; ~1 [3 d# A& t0 [Five 46 XY male subjects between 3 and 17 years old were
- _, U, x N; p) eevaluated for serum testosterone levels and hypothalamic
; a3 E. a8 m: Z+ O$ B- d5 Mfunction. Of these 5 boys 2 were considered to have Kallmann's
* M+ J! B6 }; f+ l- E. F/ o9 [syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; l& M% ]1 d4 _lamic deficiency. After evaluation of response to luteinizing
" J) ]7 R2 g( A! Thormone-releasing hormone these patients were treated with; ^5 \. |! D# ^, A; ?2 X# U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks' b, S8 W4 N" M! f W* ?4 D
after completion of gonadotropin therapy 10 per cent topical" b6 Z' }" [1 v8 y, N) m z9 A
testosterone was applied to the phallus twice daily for 3 weeks.. I7 ~* b4 T$ j7 T
Serum testosterone, luteinizing hormone and follicle-stimulat-) j" ? ]9 |8 |, L6 a" d' [1 y. x$ @
ing hormone were monitored before, during and after comple-& }9 }! }+ x. r6 v( A) u
tion of each phase of therapy. Penile stretch length was: [- h, T& j) S5 n; L4 n
obtained by measuring from the symphysis pubis to the tip of
: W, r* h0 F* B, t0 ~the glans. Penile circumferential (girth) measurements were5 f1 o7 k2 s0 e
obtained using an orthopedic digital measuring device (see6 d6 W v( |) W' y! @3 B* C
figure).
+ e7 }6 U/ E7 r" C$ F' o, RRESULTS6 p# s. Y3 `9 @ g0 K
Serum testosterone increased moderately to levels between
: J9 ~! R- ]8 r) n" W8 h50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-( ~+ e/ S2 \7 v' C
terone levels with topical testosterone remained near pre-+ w8 {) j8 U/ {( r f1 S U
treatment levels (35 ng./dl.) or were elevated to similar levels8 G, R/ r% r7 h% @& t7 _
developed after gonadotropin therapy (96 ng./dl.). Higher. A: M$ M* e R5 m4 j
serum levels were noted in older patients (12 and 17 years old),
# `% u9 Z, d4 P' D) s% c+ y: m2 ewhile lower levels persisted in younger patients (4, 8, and 10
3 f- L, [* e, C; {; v+ Iyears old) (see table). Despite absence of profound alterations/ v( ?% `- ~4 Z! V2 N
of serum testosterone the topical therapy provided a greater" e$ e3 O, z4 Z2 ], H- ^) U$ M
Accepted for publication July 1, 1977. ·
7 V( p9 T5 m% T2 U+ HRead at annual meeting of American Urological Association,
; H3 t$ C! Z! A$ V2 o* LChicago, Illinois, April 24-28, 1977.
1 M- d o+ z3 Z! ]* Requests for reprints: Division of Urology, Henry Ford Hospital,5 h1 P5 q3 ^1 y1 z% K, {
2799 W. Grand Blvd., Detroit, Michigan 48202.. Z& t6 T, F" `8 s6 x& ~
improvement in phallic growth compared to gonadotropin.
- y# R9 L: g ]5 i2 u9 a0 GAverage phallic growth with gonadotropin was 14.3 per cent- t* w. ^% p- O0 }; g/ A9 f
increase in length and 5.0 per cent increase of girth. Topical
0 N R+ O# Q% A% I$ _3 b/ Atestosterone produced a 60.0 per cent increase of phallic length
. t$ b* G' ~4 y0 `, Rand 52.9 per cent increase of girth (circumference). The7 z$ `! l# ]7 x' R2 n% G1 V
response to topical testosterone was greatest in children be-$ V; |) O* C" V& Z3 W. V
tween 4 and 8 years old, with a gradual decrease to age 17
0 ?5 w1 @( y. A: T+ ^9 ] c3 qyears (see table).
$ a4 C' u$ S% w9 M, aDISCUSSION: T! {' g1 u, I2 I# S. b0 d
Topical testosterone has been used effectively by other
- _, Y: _) e* o0 Oclinicians but its mode of action remains controversial. Im-
, }9 f {% [% j' `9 s# Wmergut and associates reported an excellent growth response
9 G x/ Q2 ?1 F( nto topical testosterone with low levels of serum testosterone,
% a* o4 Q) s [, Msuggesting a local effect.1 Others have obtained growth re-
- ^& p, O' X* Z% ]3 r- U: I7 }1 c$ @sponse with high. levels of serum testosterone after topical1 H- T& [9 n6 r( D: Z( h
administration, suggesting a systemic response. 3 The use of
" K3 o6 ~8 n* |gonadotropin to obtain levels of serum testosterone compara-! ]: S; J6 r: L5 G* m* X& D/ S
ble to levels obtained with topical testosterone would seem to. W" b" q4 J/ V% W
provide a means to compare the relative effectiveness of5 Z7 v+ e4 |$ E# a& P+ a7 q# s$ H
topical testosterone to systemic testosterone effect. It cer-
' @' [2 o; o5 V" |* w [2 I3 \4 ]tainly has been established that gonadotropin as well as par-
1 Z6 w: e2 M+ Y5 Jenteral testosterone administration will produce genital
' |7 b9 r- P7 U3 i) q" pgrowth. Our report shows that the growth of the phallus was
( Q% d: k# Z. J" L4 y; B; Esignificantly greater with topical applications than with go-8 Y; K( N T1 R0 r
nadotropin, particularly in children less than 10 years old.
* @- M7 S6 j9 Q* F# K/ {" sThe levels of serum testosterone remained similar or lower0 q! a( Z4 p/ f" i3 G
than with gonadotropin during therapy, suggesting that topi-# p7 |( A- r8 c! `
cal application produces genital growth by its local effect as( C) [+ Y' e9 ^) F! y8 S: L
well as its systemic effect.1 r* ?8 ?4 c0 v+ ^! m; Z( c( I
Review of our patients and their growth response related to0 p4 I, R8 U* \, b
age shows a greater growth response at an earlier age. This is. M& j, O+ G o3 O- q+ z( t7 ^
consistent with the findings of Wilson and Walker, who$ y5 K2 [" ~0 S1 E6 c
reported an increased conversion of testosterone to dihydrotes-
9 @7 T* z+ L! v1 F _0 Btosterone in the foreskin of neonates and infants.4 This activ-6 X J; G8 j/ m
ity gradually decreases with age until puberty when it ap-7 `0 {/ `# k9 I
proaches the same level of activity as peripheral skin. It may/ y% u v9 z B% j- G% a. Z8 b1 b
well be that absorption of testosterone is less when applied at* _0 w- D4 G7 Y
an earlier age as suggested by lower serum levels in children9 G1 t) `% n- \5 w1 n
less than 10 years old. This fact may be explained by the
8 t* n+ c5 u' e0 Q( Sgreater ability of phallic skin to convert testosterone to dihy-
( C3 H$ p* @& L% v- B' L8 J$ Sdrotestosterone at this age. Conversely, serum levels in older$ _( k- m8 E$ r: _1 c# h
patients were higher, possibly because of decreased local: `6 a' W$ X7 H) L+ [
6671 l3 c' ]5 @. }( [2 s
668 KLUGO AND CERNY
0 V0 B; W# M. J$ x1 \% LPt. Age+ ]' z0 Q% I& ]
(yrs.)! ~: i- g9 R$ }: b. J
Serum Testosterone Phallus (cm.) Change Length) c3 \; e4 u7 E( z
(ng./dl.) Girth x Length (%)8 O& U8 c' F1 G3 c9 T3 f }
4
& X# T! q, l8 i3 j5 x8
" G$ @8 o; ^; P g, L% X3 c101 Z2 o, u5 D0 [/ _" o/ J+ S$ `: U% Y
12
' Y: s u$ ^2 P- p) A5 Q2 i176 }6 Z7 r, o5 _. y$ W+ `* a6 O
Gonadotropin) ` F B! ~( @6 r6 N
71.6 2.0 X 3 16.6! P1 P5 h( i' o, W9 y3 G0 T+ c
50.4 4.0 X 5.0 20.03 C% |. ?, G" ?0 S1 `
22.0 4.5 X 4.0 25.0( v" y) E# U7 c- }7 d
84.6 4.0 X 4.5 11.1
0 Q4 d- m' |( E" J; f, d3 c85.9 4.5 X 5.5 9.0: ^2 q/ J% t( Z; p" X* A
Av. 14.30 f9 C4 P( ^0 j/ v2 a. A
4
O0 s- Z" N2 J8 ]% B89 Q5 }! X- {) a/ p! Z# o
10& ?) C! R! S7 i+ f
12
3 h- l- P1 d+ P1 _17
0 q$ z) m& H" m0 ]' TTopical testosterone+ M2 E8 [ v {) U' l# ]
34.6 4.5 X 6.5 85
' N9 ]# O; R1 R) s& N) a: l! @. E38.8 6.0 X 8.5 701 b/ M6 ]/ Z; }' J8 x5 _2 C4 m
40.0 6.0 X 6.5 62.5
& o& v9 E9 G+ `# w3 G93.6 6.0 X 7.0 55.5
& Z. U% G! A: q8 t- k! B/ P, q0 b95.0 6.5 X 7.0 27.2
2 Z9 r) {: ?( ]Av. 60.0: }- n# Y3 y2 E( E# z2 J
available testosterone. Again, emphasis should be placed on. k/ D9 }3 q5 Y9 l( C0 N2 K
early therapy when lower levels of testosterone appear to
) F! f( x+ P6 A* yprovide the best responses. The earlier therapy is instituted
& E% T Y6 t/ R+ R7 b9 a& g$ f8 K3 Hthe more likely there will be an excellent response with low
9 q/ p: h0 ?# K3 e+ g* Bserum levels. Response occurs throughout adolescence as# H; ~" a2 b N& L+ C! V* t! N0 G( x7 V
noted in nomograms of phallic growth. 7 The actual response
3 I: B. _0 ]) nto a given serum level of testosterone is much greater at birth
7 L# c: @ S; a! J, X. xand gradually decreases as boys reach puberty. This is most
) F: y. e2 ~5 G% {, j( Klikely related to the conversion of testosterone to dihydrotes-4 L9 c5 ]4 Q' W2 i8 d; B _0 _
tosterone and correlates well with the studies of testosterone
0 j' m3 _' `* K2 ^; ]9 X3 T/ pconversion in foreskin at various ages." ?& C* n* E8 G- o( E
The question arises regarding early treatment as to whether
5 {/ d" C; K0 n3 ^: `8 rone might sacrifice ultimate potential growth as with acceler-
; U. G/ O4 _5 w6 M8 Q% {! xated bone growth. The situation appears quite the reverse: }+ ?6 j( P% \8 |0 ^* w, u( g
with phallic response. If the early growth period is not used
# d3 Y( H) g3 o. e; L# Qwhen 5a reductase activity is greatest then potential growth
+ U# G# A! \7 amay be lost. We have not observed any regression of growth
/ V) t" G) A- A' V9 e- G$ ?attained with topical or gonadotropin therapy. It may well0 Z! k+ X9 k6 e) d3 q5 E) a% r
be that some patients will show little or no response to any4 E0 R. K# G) B
form of therapy. This would suggest a defect in the ability to/ z) o" G' x% b M9 I7 C# ~
convert testosterone to dihydrotestosterone and indicate that0 X8 S1 \5 d* b" D; T
phallic and peripheral skin, and subcutaneous tissue should
& \9 T# R6 z7 z) s2 T6 Lbe compared for 5a reductase activity.3 t5 u$ ^& A2 H0 q7 O8 Q. i
A, loop enlarges to measure penile girth in millimeters. B,4 Q9 ^+ E4 }. U" K$ H
example of penile girth computed easily and accurately.3 v2 h8 k6 X! {, g) w# k
conversion of testosterone to dihydrotestosterone. It is in this, e: v2 ?2 z6 @) K9 r Z+ m- \5 L! N5 q
older group that others have noted high levels of serum& i w# T/ C4 @ X
testosterone with topical application. It would also appear
, n. M' }( A3 t8 gthat phallic response during puberty is related directly to the
2 l! ^6 h; {6 Y7 P$ _2 [& @1 Gserum testosterone level. There also is other evidence of local, }9 ?% ~7 ~. D7 B2 o5 q
response to testosterone with hair growth and with spermato-! C9 u% }9 B, w
genesis. 5• 61 }5 @) p4 X; K
Administration of larger doses of gonadotropin or systemic
. x$ B: L7 b8 ]8 H/ ctestosterone, as well as topical applications that produce
6 ~! j( r- {2 Q7 B' `higher levels of serum testosterone (150 to 900 ng./dl.), will, D) r ?* M4 B! F) I# i
also produce phallic growth but risks accelerated skeletal
% Q6 Q( {9 q6 V5 b* lmaturation even after stopping treatment. It would appear8 ^1 Q* Q8 b" i! S
that this may be avoided by topical applications of testosterone
/ W: j# e7 Q$ @+ l+ Dand monitoring of serum testosterone. Even with this control0 A/ Z; v: B' \
the duration of our therapy did not exceed 3 weeks at any
0 w0 P1 S& r1 g! r; [time. It is apparent that the prepuberal male subject may, c& s9 e2 r2 c* N
suffer accelerated bone growth with testosterone levels near3 L, T& J6 u0 M a" Y
200 ng./dl. When skeletal maturation is complete the level of* w! D) C0 |, y0 d9 [- f* ]+ n1 @
serum testosterone can be maintained in the 700 to 1,300 ng./, N! V- G) A, u6 _" c
dl. range to stimulate phallic growth and secondary sexual
4 a' ?- Y8 K$ |, W# i8 m/ Hchanges. Therefore, after skeletal maturation parenteral tes-3 r* c3 w$ ?6 X' i, ^
tosterone may be used to advantage. Before skeletal matura-4 c% J- J/ A2 ?* l6 G
tion care must be taken to avoid maintaining levels of serum
: U; ]! z& } c6 [, Gtestosterone more than 100 ng./dl. Low-dose gonadotropin
( Z P' Y( ?6 u. _8 vdepends upon intrinsic testicular activity and may require
: \! H7 Q+ Q1 O4 T! g; ]1 [0 b% d0 Lprolonged administration for any response.% r8 e. O7 Z2 c0 \- s
Alternately, topical testosterone does not depend upon tes-( |; `8 z$ @! z+ c4 `6 P. h+ [
ticular function and may provide a more constant level of
* o2 w; q4 y# r f8 BREFERENCES
; ~ j/ A S5 W" r5 \1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 c( g* t: ^: k# S/ WR.: The local application of testosterone cream to the prepub-: g) ~4 f0 n) M( o
ertal phallus. J. Urol., 105: 905, 1971.5 w/ T3 {0 J2 r, C% f3 R
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 N5 Q. L* |7 E+ O |
treatment for micropenis during early childhood. J. Pediat.,+ l+ f9 |/ k. [7 c# s
83: 247, 1973./ Q/ u/ B5 } \ q5 A- s* T$ v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* e/ D: u4 M4 `. s2 _+ f
one therapy for penile growth. Urology, 6: 708, 1975.
4 }* l8 z, y' v; q; b, U4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: o) L4 F8 I7 _4 w& L* i- e% K8 pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) t R6 R- h! {' j, Oskin slices of man. J. Clin. Invest., 48: 371, 1969.
( ^6 j/ i; J( R8 q5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ ?; ^# U* `6 r2 Pby topical application of androgens. J.A.M.A., 191: 521, 1965.% V% B, [' d& B0 u$ z* K
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ k3 ~4 q' i. ~2 e Z3 [. b
androgenic effect of interstitial cell tumor of the testis. J.
8 y/ A6 h6 F1 F+ [Urol., 104: 774, 1970.* u3 X0 S: w( |
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
c: w; S: _! {7 G) Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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