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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 M" q3 H8 J6 k7 _GONADOTROPIN9 r$ f8 L( I" _( ?1 w
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. t a: i4 y* D5 [. H: ~& j: S* dFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan. r/ x) F- T, X
ABSTRACT
" [( ]. ]5 }1 h2 d6 D: oFive patients were treated with gonadotropin and topical testosterone for micropenis associated$ n% B! l1 T% g
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-) a: v+ l5 m% B; E7 j3 L3 [# @2 H
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
D: o: b6 u+ r0 C) Pcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: n4 {3 L# B; E' k6 rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 T, `8 r2 l: yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) a2 |+ @; c( jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 D( p; ^, U+ E/ d4 F5 Y
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ H* m$ }: _# T& m) @1 L
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; L$ b' H+ `! e" f" Agrowth. The response appears to be greater in younger children, which is consistent with previ-
2 n6 ]- ~* Y* I% R! p2 lously published studies of age-related 5 reductase activity.- j6 z( ?7 _& S: l6 A% _
Children with microphallus regardless of its etiology will
+ a1 A1 a( z) i- Y3 o3 t+ D3 D0 Qrequire augmentation or consideration for alteration of exter-
! V$ r4 {. X$ A+ J" t$ |/ g& l% Cnal genitalia. In many instances urethroplasty for hypo-9 p2 H7 U& [! ?
spadias is easier with previous stimulation of phallic growth.$ C* ]3 d! ^' o; Q+ {' {
The use of testosterone administered parenterally or topically
: m0 ?" b( X) G' }) Ahas produced effective phallic growth. 1- 3 The mechanism of1 N: p: Q: x7 g' X" X
response has been considered as local or systemic. With this; T0 @( E/ M0 N; f. y
in mind we studied 5 children with microphallus for response$ y% c$ p$ M& V4 t: }; l
to gonadotropin and to topical testosterone independently.
- C* Y* x/ i# q7 h5 H# g) HMATERIALS AND METHODS- L0 g3 A* C, [# N/ z3 l: [, Y
Five 46 XY male subjects between 3 and 17 years old were
% a3 F& O- v% O9 J4 [4 |evaluated for serum testosterone levels and hypothalamic* D5 ~ O5 y. X
function. Of these 5 boys 2 were considered to have Kallmann's( D, C( D5 A: J
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ d/ J/ N* ~4 b9 a9 v; |! Klamic deficiency. After evaluation of response to luteinizing/ L6 \" [; u: b* N0 Y4 D
hormone-releasing hormone these patients were treated with$ u; K/ l0 I6 d8 E" w# n
1,000 units of gonadotropin weekly for 3 weeks. Six weeks: x3 `" l9 F# S+ Q E
after completion of gonadotropin therapy 10 per cent topical
, l/ x. f! P" S% u% E6 g. f$ etestosterone was applied to the phallus twice daily for 3 weeks.
# [: q$ q* ~% c/ `: A' i% q8 k& mSerum testosterone, luteinizing hormone and follicle-stimulat-$ a" p: [7 z0 a3 L1 j
ing hormone were monitored before, during and after comple-" }$ c" I5 L: }/ F! X) i
tion of each phase of therapy. Penile stretch length was# y$ [$ ~7 |! x# G
obtained by measuring from the symphysis pubis to the tip of1 _% {% l" Q. q( X; ^; J
the glans. Penile circumferential (girth) measurements were
r: i3 |2 A7 o+ n, v+ [obtained using an orthopedic digital measuring device (see
7 B+ }0 J" _' R% \1 w. Dfigure).
T0 h. d5 F/ ^- S9 mRESULTS6 Q! f1 ~% w2 [( V
Serum testosterone increased moderately to levels between9 _! N7 a& O9 o% h: X. l6 L- R* w
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 A# b. v% X a! C( w
terone levels with topical testosterone remained near pre-% R( r/ S- {, O8 n; f# P" T
treatment levels (35 ng./dl.) or were elevated to similar levels
: P$ ?5 ]5 z N Pdeveloped after gonadotropin therapy (96 ng./dl.). Higher
, u( O% ^; j; [' g3 Dserum levels were noted in older patients (12 and 17 years old),$ ~% Y) [0 d3 }; \* J
while lower levels persisted in younger patients (4, 8, and 100 w& e# ^: c7 l y# j
years old) (see table). Despite absence of profound alterations! Q/ I2 v: \+ M, A% `
of serum testosterone the topical therapy provided a greater; Z% d) X& [( E3 }1 ~3 A# o/ F
Accepted for publication July 1, 1977. ·
/ W$ ?% E" B5 S. c' @( RRead at annual meeting of American Urological Association,
" M# |3 c, |; ~2 |- L1 H+ U0 m/ CChicago, Illinois, April 24-28, 1977.
" c" Z2 B. l# r; u8 }* Requests for reprints: Division of Urology, Henry Ford Hospital,% i; G9 ^$ m, p3 \/ t" O/ } t
2799 W. Grand Blvd., Detroit, Michigan 48202.( q9 \, T0 ~9 H, [- G: ^8 }
improvement in phallic growth compared to gonadotropin.
% ^, N" [- V- n( D0 TAverage phallic growth with gonadotropin was 14.3 per cent
) [) K( @% |1 d# d% z z+ X% }increase in length and 5.0 per cent increase of girth. Topical
+ ?' K0 @/ _3 n* n6 M G3 ntestosterone produced a 60.0 per cent increase of phallic length
4 u0 K5 j0 p0 U6 q4 w9 cand 52.9 per cent increase of girth (circumference). The
: n5 S. L6 c8 d' \response to topical testosterone was greatest in children be-) S/ W4 `# m: y( O' J
tween 4 and 8 years old, with a gradual decrease to age 17
- b0 l: H* P7 j* ]& @years (see table).
* R8 ~4 O9 @+ C+ j' \6 cDISCUSSION
! r7 m% O- e% U: T! M! ^- GTopical testosterone has been used effectively by other, v! L3 @) |3 n1 O9 g& f
clinicians but its mode of action remains controversial. Im-
& e6 _3 y, r8 W& U2 p1 a7 e, p/ ^mergut and associates reported an excellent growth response% H+ z& g0 y0 X" T f2 ~
to topical testosterone with low levels of serum testosterone,
k E% V, A/ h, qsuggesting a local effect.1 Others have obtained growth re-2 W0 s( u: g7 w5 r+ W, U% L
sponse with high. levels of serum testosterone after topical
: Q4 W4 E9 z$ L! c/ g; B( |9 M: Kadministration, suggesting a systemic response. 3 The use of
: u2 B, {, _7 g1 P1 U4 ugonadotropin to obtain levels of serum testosterone compara-
3 m- h0 ?, R" z8 N: b E) uble to levels obtained with topical testosterone would seem to# o3 f- b5 F3 h# v
provide a means to compare the relative effectiveness of
5 U& a0 G6 ~( l" M( ^* Ftopical testosterone to systemic testosterone effect. It cer-" j& g# Y8 T) V ^$ P
tainly has been established that gonadotropin as well as par-
7 }8 ~. f9 _9 S# m: j6 _; Yenteral testosterone administration will produce genital2 B, l" `+ a1 a+ c" K' ?# H
growth. Our report shows that the growth of the phallus was F9 h1 {8 Q9 t0 M
significantly greater with topical applications than with go-
! l. L6 p5 a+ Bnadotropin, particularly in children less than 10 years old.
# X( M+ Q g2 D- p ^0 vThe levels of serum testosterone remained similar or lower6 p% v! l) b( x+ I+ \
than with gonadotropin during therapy, suggesting that topi-& m5 t% s8 ^* P# m1 o1 ?- W
cal application produces genital growth by its local effect as; `! L+ z% c E$ |% Q5 v7 n
well as its systemic effect.
* \2 o2 s. W9 ]" Y0 ^/ [Review of our patients and their growth response related to9 i' Q& N6 s |
age shows a greater growth response at an earlier age. This is5 x3 B3 S6 ~6 k3 i* f4 ^3 C) C
consistent with the findings of Wilson and Walker, who
, @4 k2 l1 `) w) T7 q! m7 I6 n/ Zreported an increased conversion of testosterone to dihydrotes-
. d; l' r* X- v4 Atosterone in the foreskin of neonates and infants.4 This activ-& }" M# W& N6 `) M. A% C9 V( a* K
ity gradually decreases with age until puberty when it ap-
$ a( r- x8 n% i5 `proaches the same level of activity as peripheral skin. It may8 O# r6 l; X' G
well be that absorption of testosterone is less when applied at
- `+ q! x6 c- Q* b2 I) xan earlier age as suggested by lower serum levels in children
" n: `1 q9 v5 E# Tless than 10 years old. This fact may be explained by the
9 D/ P1 b1 n% J/ l& Lgreater ability of phallic skin to convert testosterone to dihy-
' i) W" } u" j8 z: Ndrotestosterone at this age. Conversely, serum levels in older
2 {5 h8 E1 S: E) j: b( O/ [* ppatients were higher, possibly because of decreased local5 n' U8 n" i: O, y$ ^
667: l. u2 e! Y2 d- g+ j8 k5 j$ \
668 KLUGO AND CERNY5 V) {3 s& R3 J
Pt. Age( b; l% A- j2 @% \! H
(yrs.)" V! {) \! x4 q. @8 B9 N7 D
Serum Testosterone Phallus (cm.) Change Length
6 Z0 U0 g: x. e5 Y+ a' B(ng./dl.) Girth x Length (%)( n, M; k. r# ?" N# Y- ?
4
) {7 Z" w4 a, w) t88 ]3 u; u9 r7 e7 p% i4 p
10% o' G& ~+ m" d
12' k$ Y7 {3 q8 G, f
17
5 J8 O- u3 x& {) a0 p T1 @4 sGonadotropin2 F2 Q# e/ ~+ c$ Y/ B ?) |, h' z% }' p
71.6 2.0 X 3 16.6: _: Z4 Z' w& \$ x' c( G9 p- R( |
50.4 4.0 X 5.0 20.01 s% a: ~$ H) n/ p6 G( \8 Y/ ^! e
22.0 4.5 X 4.0 25.0
1 G, R- M+ F O% D0 |9 a9 F5 ]84.6 4.0 X 4.5 11.18 {4 ^) p/ G# d; i: n: J7 b2 N
85.9 4.5 X 5.5 9.0
/ q3 o5 P7 K& K4 B/ P7 z$ J5 tAv. 14.3. _" n- x: a% ~, x1 h. V
4
9 T6 B% Q3 }) y$ e' D. V; E; P8, G; `9 U# ^; @' ~ P1 j; x0 f' [
10, y6 \ t6 j- u
12
8 J y; {; R- S. H) P: A17
$ j# M# L. o5 w& BTopical testosterone
: r6 Y" }4 l( ^8 ?34.6 4.5 X 6.5 85
' i4 ^ p1 M3 _2 s; g38.8 6.0 X 8.5 70; J+ d9 Y/ v# \, f( Z9 C
40.0 6.0 X 6.5 62.5
# l- @! [# e2 J' q8 w }! W$ @% N0 I, {93.6 6.0 X 7.0 55.5; ]+ b& t/ [" {
95.0 6.5 X 7.0 27.25 I! p; i4 A8 h! G2 R+ q
Av. 60.0( _! j, _# B- D9 |& ~
available testosterone. Again, emphasis should be placed on! x+ ^# b0 R8 {9 |
early therapy when lower levels of testosterone appear to
2 X5 z, F2 j e6 i! uprovide the best responses. The earlier therapy is instituted/ G$ S- d& U. l/ W4 d( }
the more likely there will be an excellent response with low5 z4 L1 ~) ^% N0 j ]9 O
serum levels. Response occurs throughout adolescence as4 W' }# X$ O, O/ E( ^
noted in nomograms of phallic growth. 7 The actual response( u7 _ ]/ f/ o# g- I2 Y2 _2 V$ A. Q
to a given serum level of testosterone is much greater at birth
! J& b2 ]5 i% v o' i2 q. L/ jand gradually decreases as boys reach puberty. This is most
+ J' e4 _7 `& |+ |# o3 c5 M4 Q klikely related to the conversion of testosterone to dihydrotes-6 ?' p3 b1 ~. u
tosterone and correlates well with the studies of testosterone5 s8 r. o# @8 z1 A0 @2 z8 |! |( A
conversion in foreskin at various ages.
4 o# o5 \" E* l) g& d8 f1 Q! YThe question arises regarding early treatment as to whether2 S" P+ O" w% b
one might sacrifice ultimate potential growth as with acceler-
+ i& S5 O$ T& W) z. wated bone growth. The situation appears quite the reverse
/ ^3 P$ N' Q7 u1 ]with phallic response. If the early growth period is not used2 ?9 T8 `9 [$ K+ p* C4 U
when 5a reductase activity is greatest then potential growth
$ u: X: [/ _/ n3 ymay be lost. We have not observed any regression of growth/ d+ o! g, u0 r J5 r9 Q6 h% Q
attained with topical or gonadotropin therapy. It may well
, t! {& u* I) M: y, q+ |* U% qbe that some patients will show little or no response to any" ?. g2 }- [- @3 v% h- y/ L( x
form of therapy. This would suggest a defect in the ability to
3 X6 r- g, {; Pconvert testosterone to dihydrotestosterone and indicate that$ p) U; Y4 I( w. P9 o5 S+ B" J3 a
phallic and peripheral skin, and subcutaneous tissue should
4 U V4 S* k1 ^be compared for 5a reductase activity.
9 o6 F. C I' j8 Q! L: e! SA, loop enlarges to measure penile girth in millimeters. B,
. _2 Z+ R1 Y" Z% L' @$ q* M hexample of penile girth computed easily and accurately.
7 l9 t; ~) h' G, _conversion of testosterone to dihydrotestosterone. It is in this; p. B/ w/ U; t& A; G
older group that others have noted high levels of serum% x& B1 I% f9 i$ d
testosterone with topical application. It would also appear4 P8 q [; l/ |( I
that phallic response during puberty is related directly to the
- X9 O4 T! V$ O$ `! E0 jserum testosterone level. There also is other evidence of local: M/ k( i$ i# M
response to testosterone with hair growth and with spermato-
2 H/ |: [1 K6 S4 H" E6 N1 Igenesis. 5• 6
" i2 I, A& h$ r3 F7 t* z7 IAdministration of larger doses of gonadotropin or systemic
5 e2 ~! h2 Y( ]% R2 P/ O) _* a& atestosterone, as well as topical applications that produce
5 z( g7 y8 Q# Ghigher levels of serum testosterone (150 to 900 ng./dl.), will: m, u8 t3 |: H) M9 V9 q' y
also produce phallic growth but risks accelerated skeletal
% ^% O3 |; i9 N! S0 Lmaturation even after stopping treatment. It would appear
1 v+ g( `6 @. U+ g4 t" J/ Uthat this may be avoided by topical applications of testosterone# g u" B; m/ t
and monitoring of serum testosterone. Even with this control
6 I# t. Z' B0 T3 f! cthe duration of our therapy did not exceed 3 weeks at any1 {1 {8 T; u, S7 p7 {3 E
time. It is apparent that the prepuberal male subject may+ I8 e: \3 {! {+ X8 e! V
suffer accelerated bone growth with testosterone levels near2 Q8 ]' {. }/ L/ n) m# ]' R
200 ng./dl. When skeletal maturation is complete the level of
, ]( z: U6 b6 K- h' X' I% _) wserum testosterone can be maintained in the 700 to 1,300 ng./
: ?/ W' Z' _# v4 T# Ndl. range to stimulate phallic growth and secondary sexual3 O8 Y1 S: i& Y7 E# G; K& l
changes. Therefore, after skeletal maturation parenteral tes-
3 O! T. y, H$ Wtosterone may be used to advantage. Before skeletal matura-
8 a8 p- A' b# V7 v7 wtion care must be taken to avoid maintaining levels of serum
) H2 E+ a( ?: a5 Gtestosterone more than 100 ng./dl. Low-dose gonadotropin+ @4 n$ d! Z# s8 R+ q6 Y' f% j
depends upon intrinsic testicular activity and may require
% m% [ n3 p2 Q4 }) k) M pprolonged administration for any response.5 Y& Q2 R: r+ ~, t9 V
Alternately, topical testosterone does not depend upon tes-, }) [7 a$ A+ q/ x3 \5 y
ticular function and may provide a more constant level of# b5 ?5 m& W$ P$ C, K
REFERENCES) n$ T% @7 a" R: t* _; Y
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: b- x$ @: Q% [% E- b2 a# T# dR.: The local application of testosterone cream to the prepub-7 K$ u* @. J4 h: V$ q( @
ertal phallus. J. Urol., 105: 905, 1971." v& }. @# ]7 V4 i
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ q. T- L" X" M, _- S2 r; ktreatment for micropenis during early childhood. J. Pediat.,8 Z: h* E7 V2 F p% g& [5 k" E
83: 247, 1973.
) j+ ^7 X3 R8 z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% ~ g6 H8 f1 C7 E; ione therapy for penile growth. Urology, 6: 708, 1975.6 e. M6 x4 x, B# E
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' E3 }/ x5 d9 L2 \( D- ]
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- {* D/ k9 ?% I; q: j
skin slices of man. J. Clin. Invest., 48: 371, 1969.: O3 G' ?: ~" O8 D; _% w" y+ r) p
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth' O* q3 P. n8 o& k$ i/ }( H
by topical application of androgens. J.A.M.A., 191: 521, 1965.
9 p [6 @% H6 A$ q6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local F: M0 [ c+ ]% y. Z. [
androgenic effect of interstitial cell tumor of the testis. J.! ~* }" Y3 c. k" `9 O- i% G
Urol., 104: 774, 1970.
' i) l9 E: ^& o1 J7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 k c6 R; ]/ ] J" p3 wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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