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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* r7 s$ Z1 Q) p$ h# h0 c
GONADOTROPIN4 q- ~/ K' p9 N
RICHARD C. KLUGO* AND JOSEPH C. CERNY
+ A( O% p P* ~7 IFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: N2 [8 K) Q: z7 E+ E# i: qABSTRACT
( |$ u" S* w4 v3 p* H$ ?% W# ^! OFive patients were treated with gonadotropin and topical testosterone for micropenis associated
: L5 g% Q) b; Z, w2 O0 A! K6 qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& E0 m0 ~& J: |tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
* v# {$ N& J, A) ~; Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 y* _ I* i" p8 N3 ^ tfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* x( R6 v& m; W# f7 Pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, `0 t. N. B" G" {increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ d; _. [8 [( s$ l4 a
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ o( d7 T5 p" [6 \0 i2 K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 D9 K; Y3 F- C; c* j
growth. The response appears to be greater in younger children, which is consistent with previ-3 B/ t' A0 }9 g# b; o
ously published studies of age-related 5 reductase activity.
; v: Z: s# D. X5 Y' A$ B3 `Children with microphallus regardless of its etiology will
$ b( j, }% z4 W/ q6 h+ irequire augmentation or consideration for alteration of exter-' G$ \% M6 D. E2 U% | v3 i
nal genitalia. In many instances urethroplasty for hypo-4 ^/ |. F2 `9 M
spadias is easier with previous stimulation of phallic growth.: V( Z4 c |& w$ o% p0 U( r$ ]
The use of testosterone administered parenterally or topically
2 L; M/ u4 J9 g( {has produced effective phallic growth. 1- 3 The mechanism of
' N' T, ] U8 ~3 a% L$ Presponse has been considered as local or systemic. With this
?" W0 t5 f$ ~" y- l- ^in mind we studied 5 children with microphallus for response' Q. X% D6 }( b! o
to gonadotropin and to topical testosterone independently.
7 n: ~ W3 H! S) G0 f+ YMATERIALS AND METHODS. C( g! A) A0 {3 U) `
Five 46 XY male subjects between 3 and 17 years old were
6 W. v* h/ J4 J/ I1 @: Z; Yevaluated for serum testosterone levels and hypothalamic
8 p3 A' y- y# w! w7 B7 Y. ~function. Of these 5 boys 2 were considered to have Kallmann's7 @ `+ N( k- S& U1 b, o
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 w! r1 V5 _( `0 [2 e' m! e
lamic deficiency. After evaluation of response to luteinizing
, _8 R* x1 d1 ]hormone-releasing hormone these patients were treated with
- c9 s( A" @4 }7 J3 \1 Y4 H7 M1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* S0 C6 Z% j' O9 A, a& Zafter completion of gonadotropin therapy 10 per cent topical. v4 @ z4 l/ T) o9 P- j
testosterone was applied to the phallus twice daily for 3 weeks." n, k6 o+ I" _ [; v2 n1 a" ]
Serum testosterone, luteinizing hormone and follicle-stimulat-
$ o$ u, J( ^/ W% D) V! |% Ying hormone were monitored before, during and after comple-
, Y" @5 a% f5 Otion of each phase of therapy. Penile stretch length was, m0 `4 _7 i6 ]. r* {3 J
obtained by measuring from the symphysis pubis to the tip of! R0 \7 ]( s7 H! ~3 F4 b
the glans. Penile circumferential (girth) measurements were
: _+ q/ u6 F1 Z+ S5 `7 Gobtained using an orthopedic digital measuring device (see2 H- K# ]/ x! a2 k5 n6 E/ T }
figure).$ d4 r. |# E1 S2 A' G
RESULTS0 \( F% {: |1 x5 ^
Serum testosterone increased moderately to levels between
6 C" ?* Z# t, E50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
* X6 S# H; V1 c ~! e [* e U c' Pterone levels with topical testosterone remained near pre-0 Z/ S2 y9 ^. f& A) r$ T9 Q! C: b, h
treatment levels (35 ng./dl.) or were elevated to similar levels) r; R. i3 y& N. s) y, N6 I% K
developed after gonadotropin therapy (96 ng./dl.). Higher
: R6 `/ _) U7 I$ Wserum levels were noted in older patients (12 and 17 years old),2 _3 B) q3 e0 ]
while lower levels persisted in younger patients (4, 8, and 10
- Y+ t" O! t! A# ]/ q$ w! pyears old) (see table). Despite absence of profound alterations8 m) o6 [" m* n1 r$ c3 V
of serum testosterone the topical therapy provided a greater
) y1 s: G9 U1 ~% \/ I3 bAccepted for publication July 1, 1977. ·& g/ F+ X% m1 u! m
Read at annual meeting of American Urological Association,
& y N* W! Y. @1 c1 D: vChicago, Illinois, April 24-28, 1977.
9 H' d! y. N! b% u( |2 S5 {6 t* Requests for reprints: Division of Urology, Henry Ford Hospital,
" x( Z- i, k. y2799 W. Grand Blvd., Detroit, Michigan 48202.
. w M( \+ r( W$ G3 S' t! Simprovement in phallic growth compared to gonadotropin.
1 S! B( Q; A# J% M6 d3 hAverage phallic growth with gonadotropin was 14.3 per cent
9 M! E4 i8 ^/ ]$ ^" g0 [1 q- Bincrease in length and 5.0 per cent increase of girth. Topical
7 W3 ]7 c' M" X- W7 M" rtestosterone produced a 60.0 per cent increase of phallic length( ?7 y, ]: U0 _/ u* f, d
and 52.9 per cent increase of girth (circumference). The( [# E! J( T* @ |
response to topical testosterone was greatest in children be-" A& H5 E1 R' B4 Q+ Q3 K, g2 v! y
tween 4 and 8 years old, with a gradual decrease to age 17
" @6 w! \! y% E) G' S2 C1 ayears (see table).
5 }; k, h* h5 A9 L ^2 eDISCUSSION. c3 y5 V" y' d
Topical testosterone has been used effectively by other' p2 P4 w$ T! D" Y8 q/ T3 n
clinicians but its mode of action remains controversial. Im-
/ J7 l" \# w" I8 n4 @9 O9 kmergut and associates reported an excellent growth response- W% S6 A" F: ?4 J* F9 }: G% L" j
to topical testosterone with low levels of serum testosterone,, \. X) P% ?* |# W7 g/ R
suggesting a local effect.1 Others have obtained growth re-- h1 }7 {3 o, }) {/ W1 ^1 T
sponse with high. levels of serum testosterone after topical
1 c9 U+ y* S7 x5 ?administration, suggesting a systemic response. 3 The use of
1 Y) n" P6 R. l; w- Z( Ggonadotropin to obtain levels of serum testosterone compara-6 a; j/ i, S' W
ble to levels obtained with topical testosterone would seem to
0 q- w G" O- C; \provide a means to compare the relative effectiveness of5 L9 h: {# h$ S' R! ]' E$ E; Q
topical testosterone to systemic testosterone effect. It cer-
; K6 ^! d# X8 [) F8 H1 @ h3 qtainly has been established that gonadotropin as well as par-
: x5 i5 `9 P8 {enteral testosterone administration will produce genital8 Q8 K2 i$ [0 Z8 j# a/ b* N
growth. Our report shows that the growth of the phallus was, |6 N: ?) e2 ?; d: T
significantly greater with topical applications than with go-
; F" d# P- A& a1 l' V( H5 W! knadotropin, particularly in children less than 10 years old.) g' o+ M% ~' ^0 H
The levels of serum testosterone remained similar or lower! y( S2 E4 E1 j# }# W
than with gonadotropin during therapy, suggesting that topi-0 Y7 E6 f. j& |5 f! _4 I
cal application produces genital growth by its local effect as
X1 S7 s0 @" h5 c; qwell as its systemic effect.3 p, I7 l' ]% R' ` S3 u9 |
Review of our patients and their growth response related to, @ n' A l @
age shows a greater growth response at an earlier age. This is
6 B4 x" L- Q( b0 I( w3 Z4 b: Uconsistent with the findings of Wilson and Walker, who1 N' O6 J# ^: a' q, \4 ]
reported an increased conversion of testosterone to dihydrotes-; L6 X- G7 [3 ^* S" T1 ~! l0 k3 i
tosterone in the foreskin of neonates and infants.4 This activ-3 H6 c- X, H8 [6 x1 u* ?0 T+ ]- D) [$ M
ity gradually decreases with age until puberty when it ap-
/ f( Y, e; H+ x" T2 ^- kproaches the same level of activity as peripheral skin. It may* W2 H! V4 }5 |+ l5 l3 u
well be that absorption of testosterone is less when applied at
7 R2 @" h: X1 o) y7 Z5 y& S5 h6 [' @an earlier age as suggested by lower serum levels in children6 n7 L3 J+ L' X% N/ Y
less than 10 years old. This fact may be explained by the0 s5 W/ K- U6 {0 h
greater ability of phallic skin to convert testosterone to dihy-
8 h; K7 H0 c- t m) Sdrotestosterone at this age. Conversely, serum levels in older5 p# [" v; J- b$ g
patients were higher, possibly because of decreased local0 ~; [! P7 U6 r$ Q/ W' h! `& e+ s
667
) Y! F% a$ Y/ _5 x5 z7 Q/ ^668 KLUGO AND CERNY
5 L) E6 D( i4 u) h$ {Pt. Age
$ l f/ b8 ^- `# z( L(yrs.)
( x% ?: G A' p+ a. ySerum Testosterone Phallus (cm.) Change Length
. b2 X" q- W! E; ^3 k) `(ng./dl.) Girth x Length (%). n$ T* y% k7 n7 b
4( P* J8 }0 o( q% R' K
8
^# ~" ~- S) R9 Z10) ?3 R+ @. D- J8 V! u
12
; ~/ \0 `# L, y6 i' S& C2 O17/ ]/ m9 b5 }0 w
Gonadotropin0 K' v. N- _& p0 C! o1 m A$ q
71.6 2.0 X 3 16.6# n. v( @+ O2 T' f
50.4 4.0 X 5.0 20.0
- A6 }1 @3 S2 v, \( B3 L! |7 Y22.0 4.5 X 4.0 25.0. ^, k, F' q, D" j4 O1 P
84.6 4.0 X 4.5 11.1- ^1 u R7 ^' F+ o1 G8 `; _
85.9 4.5 X 5.5 9.0/ p1 ~ O4 [. N. f; y9 C3 y' u
Av. 14.3
6 k' M% `& |- r' W! i# ~4
/ W0 {6 \! W h8 e5 i( c: V& K# s8
: D$ r0 M( m5 ]3 _6 J10
8 r0 i0 O* U8 G a \' i12
. _0 c4 ^# v; J; @, }17( }9 v8 R% \- g" k' G' D4 o9 B
Topical testosterone$ M/ W2 k2 p! Y) h+ i5 t
34.6 4.5 X 6.5 85
( Z; Z! i/ S7 c/ K38.8 6.0 X 8.5 706 [ j/ \. f( `9 n9 W" C% g6 u$ w) r
40.0 6.0 X 6.5 62.5: z3 g/ e) b! p$ {
93.6 6.0 X 7.0 55.5' P& o, s3 E B0 v# ~
95.0 6.5 X 7.0 27.2
" ~! A- B8 _4 e9 mAv. 60.0
0 q+ ^: @. u: ]6 Q3 o8 Iavailable testosterone. Again, emphasis should be placed on) j( L$ ]( r: U. X3 ~6 V+ N
early therapy when lower levels of testosterone appear to
2 D5 d% T& C. Wprovide the best responses. The earlier therapy is instituted( g6 E) H8 h) ~' _/ Z
the more likely there will be an excellent response with low5 x! a/ s5 Q% P3 G& Y
serum levels. Response occurs throughout adolescence as
8 O" i8 A) w P& Ynoted in nomograms of phallic growth. 7 The actual response# c9 H4 [: ]2 ]" h/ N9 V
to a given serum level of testosterone is much greater at birth
7 w( y- I* [# r, z( }and gradually decreases as boys reach puberty. This is most$ t2 A5 D5 I; j/ k
likely related to the conversion of testosterone to dihydrotes-
5 C5 ~- l8 @0 n5 Z1 Htosterone and correlates well with the studies of testosterone
. H: d* I2 t9 y* iconversion in foreskin at various ages.6 x8 J; B* ^9 `( L& ~3 s" Y
The question arises regarding early treatment as to whether
0 v% z5 x( J( J3 B% {, bone might sacrifice ultimate potential growth as with acceler-
7 Y9 T- y- x$ d; @ated bone growth. The situation appears quite the reverse
# i, w+ a% F: m5 v" Uwith phallic response. If the early growth period is not used1 K6 f7 h: o" h) E0 o1 o3 r
when 5a reductase activity is greatest then potential growth2 C( c% F1 g) c0 c# O
may be lost. We have not observed any regression of growth- m9 g$ i8 o8 ?9 }+ y
attained with topical or gonadotropin therapy. It may well' X- P* q4 a3 L a$ X
be that some patients will show little or no response to any& P4 `% K" ?. R: Y; j3 s- R$ s
form of therapy. This would suggest a defect in the ability to2 O) D( C6 b) n5 h8 }* K& u7 H% S
convert testosterone to dihydrotestosterone and indicate that
+ f7 O" v: W( xphallic and peripheral skin, and subcutaneous tissue should
$ k6 O. T. |% c( t6 l' |6 `# H! Dbe compared for 5a reductase activity.( a; }3 d4 @3 j) p+ _3 y
A, loop enlarges to measure penile girth in millimeters. B,
7 N$ p( H! n) L. A! x4 uexample of penile girth computed easily and accurately.
& c) ]7 \: \, `8 p( K1 cconversion of testosterone to dihydrotestosterone. It is in this
7 k5 F5 O; K5 M7 e1 P" ~2 holder group that others have noted high levels of serum
9 k7 e I* }( i* A. l8 o9 qtestosterone with topical application. It would also appear( _0 q, d& a, z; h# q6 C' }
that phallic response during puberty is related directly to the
. [5 u5 d/ p5 I# c! ^+ C6 kserum testosterone level. There also is other evidence of local
5 h; ]5 y4 u) S) T+ @2 sresponse to testosterone with hair growth and with spermato-
/ E+ U9 P; E7 B* R) c: D; F4 Qgenesis. 5• 6$ H% k! n- {% M% R" b b- J
Administration of larger doses of gonadotropin or systemic
, |. i$ `! \- C* Etestosterone, as well as topical applications that produce, L7 q; i9 I/ C2 q W( S# B+ \
higher levels of serum testosterone (150 to 900 ng./dl.), will4 P! U; e d% K H: v, Z
also produce phallic growth but risks accelerated skeletal
8 w$ h) y. t7 a* l1 ?8 i5 y" ?maturation even after stopping treatment. It would appear
3 _# c9 \. S5 [& _5 G/ {that this may be avoided by topical applications of testosterone( w/ L* }! A7 N- L5 F: f1 t
and monitoring of serum testosterone. Even with this control7 v) A; \( r; I- R
the duration of our therapy did not exceed 3 weeks at any) ^# Q: L K- f
time. It is apparent that the prepuberal male subject may
G6 I- K+ \; `1 E, o; J, |; Wsuffer accelerated bone growth with testosterone levels near
0 i( p; O- z: M& H$ Q, J5 I7 b" H" `200 ng./dl. When skeletal maturation is complete the level of
2 O( Q4 W7 X/ b3 b7 @9 M6 _& W$ |serum testosterone can be maintained in the 700 to 1,300 ng./
' U" L* H. b* w, G7 A+ Fdl. range to stimulate phallic growth and secondary sexual
( P- O( H* C0 _- d% u; k; |changes. Therefore, after skeletal maturation parenteral tes-
0 a2 a b+ U" x3 Itosterone may be used to advantage. Before skeletal matura-/ e) s3 u* _, G4 @# F
tion care must be taken to avoid maintaining levels of serum4 {& [; `' N4 u" J2 [: o6 V
testosterone more than 100 ng./dl. Low-dose gonadotropin
; h( i4 w W. sdepends upon intrinsic testicular activity and may require
7 g! b3 X# T+ c$ X- `: ~prolonged administration for any response.
$ _$ i' U S* t) Z+ f. GAlternately, topical testosterone does not depend upon tes-
1 F- J. D8 m, Y. Z5 X% oticular function and may provide a more constant level of
3 d9 f0 r5 h- P5 ]3 wREFERENCES! o3 R2 L! S6 i2 x3 w; H! F& b: P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 D$ |2 q& U& HR.: The local application of testosterone cream to the prepub-' l3 E( G2 f: c1 C. J' m3 L& ?% z+ |
ertal phallus. J. Urol., 105: 905, 1971.% P3 q1 C) F1 B9 F
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 Z' T0 Y: V# m, r1 q( S0 u O4 k1 Etreatment for micropenis during early childhood. J. Pediat.,* |6 z# s* c# w3 t5 D# y! Y
83: 247, 1973.
7 j) S+ V( @2 q0 I3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" z. ?; ]9 O' p- T, eone therapy for penile growth. Urology, 6: 708, 1975.
1 t9 }$ g5 W9 M8 C4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& n# G) A; {4 W: O. l& d9 G1 dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, k1 L0 U( B# e5 u6 ?skin slices of man. J. Clin. Invest., 48: 371, 1969.+ E( S- S w+ m7 F0 L8 D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: r9 K6 D, U; n
by topical application of androgens. J.A.M.A., 191: 521, 1965.5 ?9 ]$ q3 L4 p* h, N5 x$ K
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
& d' j/ Z/ U, W3 u" vandrogenic effect of interstitial cell tumor of the testis. J.! C/ T5 |; c$ L
Urol., 104: 774, 1970.! `7 K, B# E1 c8 E7 E( w/ x; D5 }- u3 J
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ H$ S0 {$ @3 ^+ X- Mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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