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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND v5 H Z5 s( n9 B( A! P6 [8 k# g
GONADOTROPIN
; X- o! |0 u( v0 yRICHARD C. KLUGO* AND JOSEPH C. CERNY
! F$ z+ S$ X: j a' \# F, @) UFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan& Z* r0 v& z# D8 e( ~* X) C
ABSTRACT0 @6 m1 Q2 ]% |6 ~
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
2 n! P( O9 t* b2 L( }with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 Q) y8 Y" R6 X& t9 R# m7 {8 I1 D
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 P0 D! ] x7 I0 u& l3 R$ F
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" S0 P9 ~* [- W0 l( Dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent: s5 ?" Q7 p. t2 @: v* P" G
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average' J; u+ g$ `0 T" ?0 ^# u
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 w7 L2 V) d# q$ Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
+ Q/ k& U3 k0 @$ A$ |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 |3 y* n$ S6 q' p; R4 {7 {" {0 Agrowth. The response appears to be greater in younger children, which is consistent with previ-, K' p% l8 K5 n5 ?
ously published studies of age-related 5 reductase activity.9 Z2 ]9 }6 g) N2 I# D" b/ m2 x
Children with microphallus regardless of its etiology will; z! i$ c+ e3 m2 l! a
require augmentation or consideration for alteration of exter-& s) u8 }+ }8 u* k W9 F# F
nal genitalia. In many instances urethroplasty for hypo-
* @$ s! z* i$ h yspadias is easier with previous stimulation of phallic growth.1 _5 v6 V" H% L3 g
The use of testosterone administered parenterally or topically
7 z5 I8 F5 x2 I& ?has produced effective phallic growth. 1- 3 The mechanism of
; i+ Z! q5 l. g; p: ]response has been considered as local or systemic. With this5 m! q [7 c- f1 a5 e3 \8 v
in mind we studied 5 children with microphallus for response
7 t! y8 d, \9 B& R1 R$ G# {1 z. mto gonadotropin and to topical testosterone independently.. j7 A9 N+ C( G6 p
MATERIALS AND METHODS) M2 t8 `0 `+ X8 J0 S* h. A# j7 Y
Five 46 XY male subjects between 3 and 17 years old were/ |5 R# h6 P* Q2 b7 O
evaluated for serum testosterone levels and hypothalamic2 |5 ^" r3 S/ H& D! q5 t
function. Of these 5 boys 2 were considered to have Kallmann's( H. ^, b& G% N9 E; X+ ?5 ]
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-" T. Y# r' I& J9 b7 k
lamic deficiency. After evaluation of response to luteinizing
8 f8 q; c3 P. n7 A) xhormone-releasing hormone these patients were treated with
& ?$ n2 o# z' I6 q' Z @* P3 P2 S1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 d" ^5 Y* C6 A5 nafter completion of gonadotropin therapy 10 per cent topical+ A+ x+ y% \4 \3 r1 a0 \9 n
testosterone was applied to the phallus twice daily for 3 weeks.
& X0 B9 {0 B' {' jSerum testosterone, luteinizing hormone and follicle-stimulat-4 m3 q4 w" Y( x- x+ E
ing hormone were monitored before, during and after comple-
# q( k: s Z" l* ?, F0 M6 ^5 Ntion of each phase of therapy. Penile stretch length was. u3 s5 B$ g! u* f3 {2 o
obtained by measuring from the symphysis pubis to the tip of7 J$ D- |4 K. h, y( _
the glans. Penile circumferential (girth) measurements were
; d0 j: q0 Y4 d6 Gobtained using an orthopedic digital measuring device (see% m# P8 Y7 S; A! Q% q8 l, p j
figure).
! p4 |" j; k5 E4 o( T4 [RESULTS
. u- E/ A, W4 l. v; ESerum testosterone increased moderately to levels between" |; N6 E {1 }, q+ U( v1 {
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 j. V! L% m/ p, x, L6 p% _1 ?" D Bterone levels with topical testosterone remained near pre-5 F. o8 b4 {, j8 S L& V+ T X
treatment levels (35 ng./dl.) or were elevated to similar levels$ x/ z; i4 f3 q5 Z r, i& O
developed after gonadotropin therapy (96 ng./dl.). Higher
$ f4 e- y6 @; T z/ mserum levels were noted in older patients (12 and 17 years old),
! E8 n. l2 e1 X$ O! M4 Y' t: k( T" \: iwhile lower levels persisted in younger patients (4, 8, and 10
, E/ G$ D$ u) n" Z$ ryears old) (see table). Despite absence of profound alterations
" c% V/ z0 Z& Z: o2 ?/ L) K+ xof serum testosterone the topical therapy provided a greater! v/ D* s5 z( `
Accepted for publication July 1, 1977. ·0 \' H Q$ o v) N3 P
Read at annual meeting of American Urological Association, a$ O& M* Q* u/ a
Chicago, Illinois, April 24-28, 1977.
% w X! y, r" h+ ~. `% p7 O* Requests for reprints: Division of Urology, Henry Ford Hospital,3 Q0 p I: `6 o
2799 W. Grand Blvd., Detroit, Michigan 48202.% D2 T ] Z# f4 l f
improvement in phallic growth compared to gonadotropin.+ H3 w3 C5 i% p. O% S( ^
Average phallic growth with gonadotropin was 14.3 per cent
" g. ~1 }' B9 u$ p, t, z+ s' _increase in length and 5.0 per cent increase of girth. Topical
) b" y) X4 n! e! s+ jtestosterone produced a 60.0 per cent increase of phallic length
q. \% I7 F+ l' l- a+ Rand 52.9 per cent increase of girth (circumference). The
5 L4 e# h5 D7 N8 n5 }response to topical testosterone was greatest in children be-
# \# p+ P9 R/ B0 ]* s) V) ttween 4 and 8 years old, with a gradual decrease to age 17( [* S# Z, g3 p( ~ c+ q/ [
years (see table).
- ?3 J$ [( F1 V9 k/ @DISCUSSION
& n; j/ ]' i" d1 bTopical testosterone has been used effectively by other
7 n, O) g9 W& _! q6 m8 v: n/ Bclinicians but its mode of action remains controversial. Im-
, m' l: ^7 j% j8 L0 Z5 k7 e) Imergut and associates reported an excellent growth response
8 K. O n9 s, O0 L7 q2 l7 d; Lto topical testosterone with low levels of serum testosterone,
# m, l5 c+ a' H4 asuggesting a local effect.1 Others have obtained growth re-
* V* `8 n) j5 b$ c) T, dsponse with high. levels of serum testosterone after topical8 }7 Q6 }+ p9 X2 b
administration, suggesting a systemic response. 3 The use of
! N& r! G6 Q3 I* S0 Z8 G) j' U; Q1 Ugonadotropin to obtain levels of serum testosterone compara-8 J, W: b' \4 t! f
ble to levels obtained with topical testosterone would seem to
! | d4 s% X" Z+ Lprovide a means to compare the relative effectiveness of/ C% I9 m# I" P9 u5 I/ J
topical testosterone to systemic testosterone effect. It cer-
; T; i' T5 W! o: c! X$ T; l* etainly has been established that gonadotropin as well as par-' d/ o/ R5 M- i
enteral testosterone administration will produce genital. N, H& i6 f8 Y6 n9 i z1 l7 {' J; H
growth. Our report shows that the growth of the phallus was7 V$ Z: [& v9 C
significantly greater with topical applications than with go-5 T$ X3 l4 H: E% S. P/ ~( h
nadotropin, particularly in children less than 10 years old.) o- O6 |9 R2 C% n$ @7 ?" j1 p8 k
The levels of serum testosterone remained similar or lower; t2 F# o+ Q/ d0 S$ r7 l; A5 Y
than with gonadotropin during therapy, suggesting that topi-0 ?+ M5 y" I7 E+ h
cal application produces genital growth by its local effect as8 k1 T1 K# A) o
well as its systemic effect.
! M: P3 `8 V' j" p% ~! m; `Review of our patients and their growth response related to) r2 ` Y; S0 _4 b4 R* c, m
age shows a greater growth response at an earlier age. This is
: n) N) J$ I) z( P5 {! L7 L$ lconsistent with the findings of Wilson and Walker, who; y+ O; w2 W1 w0 Q
reported an increased conversion of testosterone to dihydrotes-
8 L+ H; [: A4 e0 P* Mtosterone in the foreskin of neonates and infants.4 This activ-" `$ x+ L. G7 y& v
ity gradually decreases with age until puberty when it ap-
# a9 ]; w) e% T& C/ {0 vproaches the same level of activity as peripheral skin. It may4 l0 _8 S3 m; }" K
well be that absorption of testosterone is less when applied at4 v. Z, |; Z1 X8 @
an earlier age as suggested by lower serum levels in children
. M' x; e9 n$ _ w+ ~7 W" x0 nless than 10 years old. This fact may be explained by the
& K4 T5 Q7 m& S: i& c0 ]: `1 Igreater ability of phallic skin to convert testosterone to dihy-
+ x; f2 j7 R: Z4 m! E3 }3 o: {drotestosterone at this age. Conversely, serum levels in older& W$ e" T1 \: D, G4 S1 Y# ]7 S
patients were higher, possibly because of decreased local
. I* f3 @& r2 C) `2 e6 k7 b8 h) Y667
8 e) T1 p u! h9 T# C Y668 KLUGO AND CERNY
2 z' Z* o# w+ n$ r" F5 A6 M9 nPt. Age% b" K( D/ M4 e- l0 I6 q- E. v
(yrs.)) c) T X6 m* `7 d
Serum Testosterone Phallus (cm.) Change Length
: V, g J! h# l6 M(ng./dl.) Girth x Length (%)
9 f$ s7 ?/ C- s# B0 h0 c4
( E6 x1 A0 e& y: O6 F, S: N8
/ z/ v. n5 T; X( i. R& V! i4 {# Q10
: h- a5 y2 g. h12
' |$ Q3 C' [/ L6 N' Z17
5 P/ \! g2 N! I6 P: K1 O; J4 KGonadotropin$ o. b. {- f# W4 m+ D- Z% d2 S
71.6 2.0 X 3 16.6
: P% U$ t+ i1 P7 u/ _( U$ G8 {7 i50.4 4.0 X 5.0 20.0
3 [, n! J, k6 Q' c2 X22.0 4.5 X 4.0 25.0
% N0 H" j" n; f3 R3 o$ t+ I1 I4 L- W3 _84.6 4.0 X 4.5 11.10 b! K) b d& W9 _0 Q! a4 \
85.9 4.5 X 5.5 9.0
# d+ N' z5 V' N; IAv. 14.3: C/ R! F1 Z* ^* N& L) @
43 z3 |" T& e! @; N
8
/ a) S, |5 N2 v10
2 I" [. i, h+ C* `9 O12% m. n; [6 J0 N7 D; k3 O3 `
17
x# y, V M/ j0 {4 _Topical testosterone
" q2 o a" R# ?& q& c, h34.6 4.5 X 6.5 853 M) k- r8 n6 ?* E9 X1 v( [, U6 A
38.8 6.0 X 8.5 70
6 s/ @# N( R2 P- Z40.0 6.0 X 6.5 62.52 q, g8 \9 ^6 Y' h9 t2 z& j
93.6 6.0 X 7.0 55.5% M$ d6 b. `1 C9 N: h
95.0 6.5 X 7.0 27.2
9 u* |5 P. L4 _Av. 60.0
5 y7 W" k+ d5 C$ J, U$ `available testosterone. Again, emphasis should be placed on
( k. n, R0 ]9 w% _8 O% H' X eearly therapy when lower levels of testosterone appear to
8 I& s8 b) L0 G) eprovide the best responses. The earlier therapy is instituted6 {% O, E- m+ t
the more likely there will be an excellent response with low% B! n" q) F2 E4 v
serum levels. Response occurs throughout adolescence as
4 l) l* Q S; i/ snoted in nomograms of phallic growth. 7 The actual response
) f4 e [3 {3 y2 S# H- Kto a given serum level of testosterone is much greater at birth+ X+ p/ B; } t9 }% h' ]
and gradually decreases as boys reach puberty. This is most7 L" i/ B2 Q: I9 b
likely related to the conversion of testosterone to dihydrotes-
. P0 i9 C; g8 l- ] U& Mtosterone and correlates well with the studies of testosterone' J8 }* I) i' _* v& l7 O: f
conversion in foreskin at various ages.3 i ]2 u) ^/ t3 B' H, I; S
The question arises regarding early treatment as to whether
$ c3 E# F) M" M0 {/ sone might sacrifice ultimate potential growth as with acceler-
1 L8 a5 s$ y# Z5 t4 {2 hated bone growth. The situation appears quite the reverse
" f/ y* t3 B% q/ ^/ ]( J4 Ewith phallic response. If the early growth period is not used9 B) M \! T% k
when 5a reductase activity is greatest then potential growth: N y2 e: W: D% D( M* Q1 _3 U* W
may be lost. We have not observed any regression of growth
* N% Y2 s- a' {attained with topical or gonadotropin therapy. It may well
0 i$ K/ x- p- i9 ^be that some patients will show little or no response to any
C+ U% {: I+ @% rform of therapy. This would suggest a defect in the ability to( b. a5 j- Q, F( c
convert testosterone to dihydrotestosterone and indicate that1 l" ~8 y( B+ ^9 _) p* E0 r
phallic and peripheral skin, and subcutaneous tissue should! P1 A" i- X! a: D' H
be compared for 5a reductase activity.
4 I& c+ \! E5 ?# b* iA, loop enlarges to measure penile girth in millimeters. B,6 }3 u1 |0 J! u Q1 i% N4 x. F
example of penile girth computed easily and accurately.# n% \5 d* }% R7 H- w' b! b7 N
conversion of testosterone to dihydrotestosterone. It is in this
) X; P' L |! s% v/ T) d! yolder group that others have noted high levels of serum
3 D, h Z! I! V+ _ a1 g% ktestosterone with topical application. It would also appear! r) s$ H* f) x5 U( W K* g: @
that phallic response during puberty is related directly to the6 W+ T6 W0 s1 Q& Q
serum testosterone level. There also is other evidence of local
- b; W2 ?( o; N" tresponse to testosterone with hair growth and with spermato-$ j$ m; t/ V/ Z$ H8 z+ L
genesis. 5• 6( \! s4 b4 o6 `3 ?2 ^* G: V/ P Z. N
Administration of larger doses of gonadotropin or systemic' Q1 D3 F! b+ I* n7 S
testosterone, as well as topical applications that produce! N3 m1 W# m5 I0 W. i# A% ?
higher levels of serum testosterone (150 to 900 ng./dl.), will8 J& a; @5 I' p) q# }
also produce phallic growth but risks accelerated skeletal6 Z4 D. [. q' g
maturation even after stopping treatment. It would appear
% Y8 O8 A( q4 U7 P1 I8 sthat this may be avoided by topical applications of testosterone3 h, Y% X; Q/ t d8 a* @0 C
and monitoring of serum testosterone. Even with this control
' B* N0 ?9 s, Rthe duration of our therapy did not exceed 3 weeks at any
8 k, m B0 {- Btime. It is apparent that the prepuberal male subject may+ Y- Y2 Q( F k) n
suffer accelerated bone growth with testosterone levels near
. b. B w9 ^9 G' t$ C200 ng./dl. When skeletal maturation is complete the level of
# m% N2 T/ @; j+ V' fserum testosterone can be maintained in the 700 to 1,300 ng./
6 `! b, g8 c& E d k8 Edl. range to stimulate phallic growth and secondary sexual
7 y# i& k2 ?2 e3 Lchanges. Therefore, after skeletal maturation parenteral tes- ~& i- m" f" d$ i
tosterone may be used to advantage. Before skeletal matura-
$ E% M% |5 u" ytion care must be taken to avoid maintaining levels of serum. [' ]+ V+ s" ?1 w9 D
testosterone more than 100 ng./dl. Low-dose gonadotropin5 A% S, j7 s) e; C7 i5 w- m
depends upon intrinsic testicular activity and may require
" N8 `; E/ c5 J/ ~prolonged administration for any response.; K$ B: Y( {8 K6 P0 P
Alternately, topical testosterone does not depend upon tes-* \+ o8 I; U6 D' ]: i4 r
ticular function and may provide a more constant level of& p Z9 u8 Y5 W1 Y1 ]
REFERENCES7 U* z& @9 V+ e3 ]+ o( {: a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
* U' r) [, ~7 a' \$ V' BR.: The local application of testosterone cream to the prepub-
) B+ p+ y8 E: i0 rertal phallus. J. Urol., 105: 905, 1971.9 h- w) G& W, ?
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 N7 o9 b' s/ m! Q
treatment for micropenis during early childhood. J. Pediat.,
& o0 G# N( d- G: T1 {83: 247, 1973.
' H# |% v7 J; N6 V- r3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
/ G( i9 \, ^) @( e- xone therapy for penile growth. Urology, 6: 708, 1975.1 U X* }" Q2 I( d/ x3 L
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 ] Z2 e# W0 w" Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
+ P' C( H6 j; T* w, A3 k* n2 kskin slices of man. J. Clin. Invest., 48: 371, 1969.
. W$ r. H4 [: K& o: y2 M+ i: b" F) R9 c5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ h. e8 v! Z" R: |7 m2 d1 S) ^
by topical application of androgens. J.A.M.A., 191: 521, 1965.
! ]! n& Q) J/ O! F+ b* [6 L+ Q6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 i a' b. |) `2 Mandrogenic effect of interstitial cell tumor of the testis. J.* T' L6 u. c- b4 A- H! D) v+ `
Urol., 104: 774, 1970.( p% v2 k A* ~% Y- Y! o+ e
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; F% v+ j% u% O) r% `7 w7 P& ]/ i$ rtion in the male genitalia from birth to maturity. J. Urol., 48: |
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