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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' J5 d9 H0 j" s0 j
GONADOTROPIN
9 w+ j( p6 D0 e' c' ?/ f. K% q! ?RICHARD C. KLUGO* AND JOSEPH C. CERNY
# A. \, q) D/ ]1 AFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; C6 B) y7 l& L6 d$ tABSTRACT
[8 \1 F4 U' h8 K3 b/ s6 @Five patients were treated with gonadotropin and topical testosterone for micropenis associated% E r7 D, |& P! \9 ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' x) P( m, L: L' Qtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
C/ F3 ?- a2 c9 M, F/ K! Lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 o+ s2 D4 w# F5 q% |: u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 L; Y* W$ i3 S* O5 n
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& d& R. R; x7 b* \& I
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% {1 v3 T* R( z% f/ O" O: ~
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- Z7 m8 {+ A% M6 O$ P: @* D- z* u+ fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% Z% D2 ?' [- U8 k$ b, Ggrowth. The response appears to be greater in younger children, which is consistent with previ-1 _4 U r9 q* r! a
ously published studies of age-related 5 reductase activity.
' z; V3 @: c& H) z6 oChildren with microphallus regardless of its etiology will
% |% ?; B& X" u4 b; t [ krequire augmentation or consideration for alteration of exter-9 Y/ G0 C7 I% n% b& S" ^ n
nal genitalia. In many instances urethroplasty for hypo-
3 o& u( l2 d2 @; I' k; n ospadias is easier with previous stimulation of phallic growth.# Z6 s, |; a( `' n/ a. t) ?
The use of testosterone administered parenterally or topically
) h1 E( ]2 U3 ?, T% ]4 _has produced effective phallic growth. 1- 3 The mechanism of
. }7 X! j* k3 C3 e2 U2 g2 Hresponse has been considered as local or systemic. With this5 ~' O7 U! T$ B
in mind we studied 5 children with microphallus for response8 D7 f# i$ ~. Q5 ^7 A
to gonadotropin and to topical testosterone independently.
; [% r( _& o2 {- L; G+ k0 LMATERIALS AND METHODS
2 c9 T9 i0 l% q8 k* mFive 46 XY male subjects between 3 and 17 years old were1 c" r& i! q8 _; X$ h
evaluated for serum testosterone levels and hypothalamic
G$ k, [1 ~$ b* Efunction. Of these 5 boys 2 were considered to have Kallmann's( s$ e& N P8 N8 Q( a, A
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) T% e. F, F, \
lamic deficiency. After evaluation of response to luteinizing2 P3 Z' R [; W
hormone-releasing hormone these patients were treated with7 {. @4 U% w2 q0 k9 C6 L
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, ^7 P; e4 a$ Y: l' n7 V: Pafter completion of gonadotropin therapy 10 per cent topical
* P" y, Z* l* X: q1 z9 G9 vtestosterone was applied to the phallus twice daily for 3 weeks.( K h+ h; G4 x3 l
Serum testosterone, luteinizing hormone and follicle-stimulat-; _: G: V1 l( v+ E, Z2 j
ing hormone were monitored before, during and after comple-
" _$ _* u v9 y" m ~ S* K. Y, W. ction of each phase of therapy. Penile stretch length was7 V0 _6 B) H: G% e' v& [
obtained by measuring from the symphysis pubis to the tip of0 N9 H: B" b9 C$ w ?
the glans. Penile circumferential (girth) measurements were; z+ z- s6 _ @3 d; s: w
obtained using an orthopedic digital measuring device (see
) h5 H# R$ j0 y4 x5 P* Nfigure).+ e# t% s: R* n7 ?; {- O; ]
RESULTS
9 s" a" {0 S. F8 s8 K1 u# Y* mSerum testosterone increased moderately to levels between' W& D s/ B6 s+ {! `9 S% q
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-) |) E& ` T7 p4 H
terone levels with topical testosterone remained near pre-
6 c: R) j, }) q7 H$ y+ l1 Htreatment levels (35 ng./dl.) or were elevated to similar levels# p3 N3 N; d8 u: ^
developed after gonadotropin therapy (96 ng./dl.). Higher
' `; R+ e( R. L; Wserum levels were noted in older patients (12 and 17 years old),
% l( e! `+ y% a+ }) \0 [) K0 Bwhile lower levels persisted in younger patients (4, 8, and 10
( ]5 M: \7 i$ y$ p ^2 y; ayears old) (see table). Despite absence of profound alterations4 f( X9 W/ X- `
of serum testosterone the topical therapy provided a greater3 p, z; C' B5 U. l7 H3 u
Accepted for publication July 1, 1977. ·
& s! [1 z9 q$ {, `; l! aRead at annual meeting of American Urological Association, D) J/ ~+ D% ]1 }; ~: T* |
Chicago, Illinois, April 24-28, 1977.$ Z5 N/ r2 `( `1 ^: `# }; [& H
* Requests for reprints: Division of Urology, Henry Ford Hospital,0 D) h; I/ p( l! W% s, s
2799 W. Grand Blvd., Detroit, Michigan 48202.
" x" G. C0 R* z% U o& Jimprovement in phallic growth compared to gonadotropin.
1 @0 ?! O6 V% t5 d7 M& U7 qAverage phallic growth with gonadotropin was 14.3 per cent
3 Y' @$ Y+ h7 B) q4 }1 }' I: c, Gincrease in length and 5.0 per cent increase of girth. Topical
6 W$ c" n8 P4 btestosterone produced a 60.0 per cent increase of phallic length% o. ^$ c" ^- d5 b$ z' n! X/ o- L
and 52.9 per cent increase of girth (circumference). The( z# I" O+ L8 U2 C/ M: G+ t5 s* S/ |
response to topical testosterone was greatest in children be-8 _7 ?+ a6 V& \' {
tween 4 and 8 years old, with a gradual decrease to age 17* B/ u, H$ {3 j: z0 o. r
years (see table).
" \& F2 L! M% z$ a5 sDISCUSSION
% s0 l! W% j7 s' z2 f: G5 xTopical testosterone has been used effectively by other+ g0 C( F# c% z$ U
clinicians but its mode of action remains controversial. Im-
3 |- p# |5 h7 b. S( W& a. V+ _$ H1 Pmergut and associates reported an excellent growth response7 F1 l8 d6 U9 R4 \% G0 j
to topical testosterone with low levels of serum testosterone,' ], q9 N! x/ H" `: S3 x$ q# `
suggesting a local effect.1 Others have obtained growth re-+ R8 J9 a0 Z' d) H3 H* B4 O
sponse with high. levels of serum testosterone after topical0 D+ D: z- W! K
administration, suggesting a systemic response. 3 The use of
2 M1 X x1 v8 D7 t: e3 `/ Ggonadotropin to obtain levels of serum testosterone compara-
' A# e0 L- |5 } Q' X {ble to levels obtained with topical testosterone would seem to
1 S Y6 }0 q) j3 m, J' \provide a means to compare the relative effectiveness of
" g r4 \0 v* J# P9 v, gtopical testosterone to systemic testosterone effect. It cer-
+ o4 F8 E( Z! b4 G% y; Wtainly has been established that gonadotropin as well as par-
* s' [' D4 u5 v# y! ]! Uenteral testosterone administration will produce genital
0 G3 E9 ~/ c" w/ N: tgrowth. Our report shows that the growth of the phallus was
) ~; c1 r. F8 ^. V* I7 |significantly greater with topical applications than with go-5 M0 v, O+ g' _$ P
nadotropin, particularly in children less than 10 years old.
! d3 `( j9 x E0 K: t8 n0 E4 }The levels of serum testosterone remained similar or lower' { S6 M9 H; E
than with gonadotropin during therapy, suggesting that topi-
. J0 v3 @7 ? x0 `/ B `) `cal application produces genital growth by its local effect as, [- [4 L: ]* [4 ?" X
well as its systemic effect.- t2 ^) J8 W& t) G; ` i: V. _1 e
Review of our patients and their growth response related to
2 ]9 [9 S; [+ t% Eage shows a greater growth response at an earlier age. This is3 G7 `- ~9 ]/ k4 b3 d8 O
consistent with the findings of Wilson and Walker, who) \5 b* x, L& \; o
reported an increased conversion of testosterone to dihydrotes-) f/ D9 R, ^! p- \
tosterone in the foreskin of neonates and infants.4 This activ-
6 e% p0 _1 E4 R z* m& v2 [* hity gradually decreases with age until puberty when it ap-( ?# K) h4 Y) j6 T3 u
proaches the same level of activity as peripheral skin. It may3 E1 g1 l1 x* o. @: S: ^
well be that absorption of testosterone is less when applied at
' T1 Z2 ]& R% K- Xan earlier age as suggested by lower serum levels in children
' f% U# y. l+ i- h _0 r; Mless than 10 years old. This fact may be explained by the. T1 p: b0 ?! ]' X# Z
greater ability of phallic skin to convert testosterone to dihy-
# z- N6 C( p# z& I# W7 R# Mdrotestosterone at this age. Conversely, serum levels in older k) N0 ~" s- j3 ]! Q- `( s( N
patients were higher, possibly because of decreased local0 C! w: p& ]/ u, E0 ~3 l6 k, y
667; \! K% I7 |- c5 C
668 KLUGO AND CERNY) P7 X1 p7 c; E/ u4 L5 j& Y
Pt. Age2 G7 C' n. M. A' Y& O/ k
(yrs.)6 g% p2 S5 r0 ]( @
Serum Testosterone Phallus (cm.) Change Length
! O/ a5 Z" X* k% l0 _$ i) h(ng./dl.) Girth x Length (%)
- q% B8 g0 l& g0 \& ?& z7 z47 o$ m+ c2 G1 B. T4 p& C& ^2 {
8
0 J4 n% k# j. V- d10* ~9 d( X! ]' D; G. e! H& Y/ V
12" W) N; j, h4 B3 Z* m
179 h8 T$ g1 l K; C( I( t& \
Gonadotropin
/ ~# {5 | u8 a2 h/ |5 ~71.6 2.0 X 3 16.6
' k$ U1 P+ x" w50.4 4.0 X 5.0 20.0
- }* \- l5 V8 r+ r. @22.0 4.5 X 4.0 25.0
( @9 q0 m- z; X2 `" i" e/ K* A( U0 C84.6 4.0 X 4.5 11.1
1 X4 [" ]! O/ l+ {: W5 ], V85.9 4.5 X 5.5 9.0
7 b, W, h4 s7 K9 a2 GAv. 14.30 F: T1 K9 `9 @. P3 T
44 D, H2 O) @5 Q
8
! ^& s! `6 |! y8 g+ h, P6 A( d108 u; m( s- I* F- ?8 P* V
12 w Y: H; C9 P4 {; k
17" ]7 {2 N$ E$ R- _; ], F' P; E! o. E
Topical testosterone
2 ~3 f" q+ S, ~; v& b34.6 4.5 X 6.5 85
3 P+ Q1 e2 X4 S: x! M. r# _38.8 6.0 X 8.5 70. J3 q( h4 E; y9 o1 ?
40.0 6.0 X 6.5 62.5/ A, f4 L4 x( n% y
93.6 6.0 X 7.0 55.5/ l' Z+ A6 }/ a$ W7 m! R" e \4 k
95.0 6.5 X 7.0 27.2* `8 Z' t+ A) ~. C3 `
Av. 60.0
, y0 {6 g* O/ t( E( t/ u& Yavailable testosterone. Again, emphasis should be placed on' k: ?) w7 x2 u2 p4 \# Y
early therapy when lower levels of testosterone appear to1 t) V- V* ?+ a& {8 w
provide the best responses. The earlier therapy is instituted
/ \: X/ G% P/ E( f& q7 l5 b- {the more likely there will be an excellent response with low
; H0 }3 @$ D3 u- Jserum levels. Response occurs throughout adolescence as" U t. c0 h# P( P: r. O
noted in nomograms of phallic growth. 7 The actual response7 A( W; [) q w
to a given serum level of testosterone is much greater at birth/ @ d! H& |/ ] i
and gradually decreases as boys reach puberty. This is most Z- \8 x! p/ u1 K' R
likely related to the conversion of testosterone to dihydrotes-
5 y6 `+ a9 d5 s5 wtosterone and correlates well with the studies of testosterone
+ F" U0 Y6 c# y# |5 L3 M- Q5 mconversion in foreskin at various ages.; }& Q1 e; g2 {4 Y, H, H
The question arises regarding early treatment as to whether. D) _; h! M* G. C% C0 [
one might sacrifice ultimate potential growth as with acceler-, Z( W, J A4 w5 K B
ated bone growth. The situation appears quite the reverse
3 [+ S/ c0 Q4 W) x# Nwith phallic response. If the early growth period is not used* r* V: d+ ] Z6 ^0 {0 T- c+ U& L y
when 5a reductase activity is greatest then potential growth
! i7 C i4 u `. mmay be lost. We have not observed any regression of growth5 j2 ~( U1 z s7 H8 h0 S
attained with topical or gonadotropin therapy. It may well$ l2 q0 _- f' P
be that some patients will show little or no response to any2 Q! q( y# ^* b3 Y! \
form of therapy. This would suggest a defect in the ability to6 V5 a# w5 R9 W
convert testosterone to dihydrotestosterone and indicate that8 _5 o6 [1 g4 `0 ]
phallic and peripheral skin, and subcutaneous tissue should* c+ ~; \9 b7 G, Z
be compared for 5a reductase activity.8 D' }/ ?; u4 J! h5 x: E3 v. n+ u
A, loop enlarges to measure penile girth in millimeters. B,
2 L( ~5 b% u( h: s7 Eexample of penile girth computed easily and accurately.7 _& x! b9 M, a5 W
conversion of testosterone to dihydrotestosterone. It is in this
8 n! q& w" h: v% Molder group that others have noted high levels of serum1 k; b2 t y* [* a+ ~
testosterone with topical application. It would also appear
6 F8 a# V% N& p7 q, f' T) `that phallic response during puberty is related directly to the, E G' g1 |+ w" L
serum testosterone level. There also is other evidence of local3 O/ h5 d5 X" ?8 }) H! L8 R& O0 }
response to testosterone with hair growth and with spermato-, t+ y2 i- N' ?4 ^+ S v
genesis. 5• 6* M z7 C' h4 w
Administration of larger doses of gonadotropin or systemic" |4 e# I. i/ p# p: U& h$ X
testosterone, as well as topical applications that produce& W' G6 [) ?1 i) e
higher levels of serum testosterone (150 to 900 ng./dl.), will( U6 _! K& O9 j v9 ~. B& {
also produce phallic growth but risks accelerated skeletal2 b' O2 M+ a: ~% h. T9 Z( B. p7 \
maturation even after stopping treatment. It would appear9 `* w9 V5 V& I; n
that this may be avoided by topical applications of testosterone# l' A. `% |) }, j. D8 g
and monitoring of serum testosterone. Even with this control+ j/ W$ B3 j+ J. b
the duration of our therapy did not exceed 3 weeks at any
4 v; |) J* @1 \6 j9 H2 Ctime. It is apparent that the prepuberal male subject may
' D, C4 T. p+ t4 G% [, k0 f# Bsuffer accelerated bone growth with testosterone levels near
3 e& T- h0 y" [, t0 Y200 ng./dl. When skeletal maturation is complete the level of4 ~0 N J [! }) y, F1 d7 G) J
serum testosterone can be maintained in the 700 to 1,300 ng./
' n) T+ e5 m# J) zdl. range to stimulate phallic growth and secondary sexual
& g; w! ^6 H& D3 z( e" pchanges. Therefore, after skeletal maturation parenteral tes-) v3 B9 h8 e3 T& Q
tosterone may be used to advantage. Before skeletal matura-
y" k; s5 {9 O, r! Z/ @tion care must be taken to avoid maintaining levels of serum) d% o9 `: w: s: @
testosterone more than 100 ng./dl. Low-dose gonadotropin
$ N0 @; M- F3 {3 C& {6 ]' `depends upon intrinsic testicular activity and may require
7 R4 T+ R$ A$ g1 vprolonged administration for any response.
7 h. Q( ]9 v3 H* P l* A, xAlternately, topical testosterone does not depend upon tes-( V6 A" f1 H0 I2 J0 I
ticular function and may provide a more constant level of5 V' o3 x" d8 U7 x8 z. k
REFERENCES, C$ j) J2 `; P( o% K) P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 F5 ~! C) D9 ]0 v9 N
R.: The local application of testosterone cream to the prepub-
5 U0 g- y$ G9 ?* Sertal phallus. J. Urol., 105: 905, 1971.5 f' i, J' X4 U# f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 \9 t+ q$ P# d' s* L; G5 q9 ^
treatment for micropenis during early childhood. J. Pediat.,
2 B, L( }$ n, w2 m b! `, j83: 247, 1973.
- ` Z) l/ J) ]+ V5 N1 b' l" K/ M3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( K5 }& J9 }8 {) }, R8 X6 _one therapy for penile growth. Urology, 6: 708, 1975.
' Z; J2 J+ y% w3 ?4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- h# @: n) q4 n" l
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
2 }! B# s. U8 Rskin slices of man. J. Clin. Invest., 48: 371, 1969.0 q$ x; W# a0 N( J0 J: d
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
" e6 Q4 ^- y! m c$ N0 o4 g4 Uby topical application of androgens. J.A.M.A., 191: 521, 1965.
5 X; o! I- p/ r; h+ _' f1 t6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: j* T" @6 P# {( r* t- V4 m8 X
androgenic effect of interstitial cell tumor of the testis. J.
i4 ^2 X. B9 c# `1 a) ~; z* JUrol., 104: 774, 1970. d: E& o% L( G! g; F
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 B5 [% e P' J# g! _8 @; Ytion in the male genitalia from birth to maturity. J. Urol., 48: |
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