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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
2 M$ O! N6 z+ J; ]GONADOTROPIN! {: g3 H( w% D: d$ x
RICHARD C. KLUGO* AND JOSEPH C. CERNY( \# @- |. T1 ~6 N
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
d* `1 V6 Y. n: E- @4 {0 cABSTRACT
( r. R" u2 m+ z; gFive patients were treated with gonadotropin and topical testosterone for micropenis associated
' F( Y" ~& l, F- `# t1 lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-; u' {. N {* T) H- L l& ?
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. ~) h% C5 R5 o6 l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 [, Z2 ]- k l0 n" W. G
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent% d1 i, N. W) p. J% B
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average- h# D1 M5 i7 g3 Y: c+ T
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 a, X# U# V+ b/ t8 poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This1 o0 |7 j3 s, }& J, Y1 H. s9 c
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; `, T: Q8 _4 k9 U' }* [+ F% M
growth. The response appears to be greater in younger children, which is consistent with previ-/ m% g% M( J# r
ously published studies of age-related 5 reductase activity.
2 o I) X' F, b/ g; b+ t3 Z3 @4 NChildren with microphallus regardless of its etiology will* n ?! }8 n# c9 T7 r$ Y3 q( ]! n
require augmentation or consideration for alteration of exter-3 ]9 H5 @1 M* P* ^. ?* y
nal genitalia. In many instances urethroplasty for hypo-
" d7 e5 ^& w: ^( F0 Pspadias is easier with previous stimulation of phallic growth. [9 p9 h3 R& j5 Q/ j, J
The use of testosterone administered parenterally or topically) A% p( a5 M1 ]- \- t" ^. n) r/ K
has produced effective phallic growth. 1- 3 The mechanism of
% I! {- g/ k- I1 C1 `$ Uresponse has been considered as local or systemic. With this
, U- ]+ S5 J$ Lin mind we studied 5 children with microphallus for response
7 H* n, `3 f+ Y S8 D5 [. uto gonadotropin and to topical testosterone independently.
7 m* w! @' [. X; r8 I+ Q0 LMATERIALS AND METHODS6 D" E* a1 l$ |
Five 46 XY male subjects between 3 and 17 years old were9 T1 _0 t1 y, {! f
evaluated for serum testosterone levels and hypothalamic# u) X+ h$ \! Y" v( s
function. Of these 5 boys 2 were considered to have Kallmann's W" Z) H7 j9 h& P
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, Y( g5 F% s9 h& a' N6 s
lamic deficiency. After evaluation of response to luteinizing0 E' H9 K6 H0 g+ O" j6 B5 k5 P
hormone-releasing hormone these patients were treated with
* F$ f. F( M/ o! o1,000 units of gonadotropin weekly for 3 weeks. Six weeks* a1 X6 a$ c! K& `6 O! ]" Q# {" i8 b
after completion of gonadotropin therapy 10 per cent topical, u9 `2 F+ Y8 s b, `- U4 m& _
testosterone was applied to the phallus twice daily for 3 weeks.( |) |! Q. k1 }- P
Serum testosterone, luteinizing hormone and follicle-stimulat-) P, U ] `' ~1 i; ]% }
ing hormone were monitored before, during and after comple-
B0 r6 \! v# x( Y3 {* ition of each phase of therapy. Penile stretch length was
( y6 I" h" N; a( T2 R6 oobtained by measuring from the symphysis pubis to the tip of
v% k5 _# ~$ e. f7 G+ _the glans. Penile circumferential (girth) measurements were" v. r* D! Y$ } G$ z y5 X; n* h
obtained using an orthopedic digital measuring device (see' D/ ]# `: `/ \/ z+ l; U& u
figure).
" {8 y K& Y4 Q. n. V3 o. r( ]RESULTS: D- L, c. }6 g$ J- {7 N+ k
Serum testosterone increased moderately to levels between
% B" D+ p- \; X' g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 y+ s' B! s) U' K' Sterone levels with topical testosterone remained near pre-8 S5 b4 \1 r& w9 C( p' N- J! f
treatment levels (35 ng./dl.) or were elevated to similar levels
" ~9 n; m2 G, N+ i/ Ndeveloped after gonadotropin therapy (96 ng./dl.). Higher+ p1 c8 c" v6 f9 a& D h
serum levels were noted in older patients (12 and 17 years old),6 g, q* }2 y) t$ f* u
while lower levels persisted in younger patients (4, 8, and 105 q, |' Q+ ] o9 j! e
years old) (see table). Despite absence of profound alterations6 Z* I j6 C. T0 P9 r
of serum testosterone the topical therapy provided a greater
o' S" d" w* F: Y/ H3 t4 GAccepted for publication July 1, 1977. ·
4 x4 t2 d( B; GRead at annual meeting of American Urological Association,
( I) ^2 G J1 r- ZChicago, Illinois, April 24-28, 1977.# w, W r4 A/ @; y2 ]
* Requests for reprints: Division of Urology, Henry Ford Hospital,
: C( ^. O" E. D2 j1 M2799 W. Grand Blvd., Detroit, Michigan 48202.
( o+ d A, K: ?improvement in phallic growth compared to gonadotropin.$ ?6 z/ ?! X% ~2 s s
Average phallic growth with gonadotropin was 14.3 per cent2 L# F) o3 n; N2 g( W
increase in length and 5.0 per cent increase of girth. Topical' A( P& ?3 u2 I& a% h
testosterone produced a 60.0 per cent increase of phallic length
. F( v& P$ D5 x. u2 land 52.9 per cent increase of girth (circumference). The
6 O" B- ~1 q3 O: L9 iresponse to topical testosterone was greatest in children be-2 b! v$ }1 f ^! t" l( \1 \
tween 4 and 8 years old, with a gradual decrease to age 17
# I0 ?9 b& y- Y/ r+ lyears (see table).+ Q' g/ m! D' m
DISCUSSION
G1 ?* P* x9 c/ m* iTopical testosterone has been used effectively by other
$ b! J( O' m$ d& U8 k1 ?% E4 K! O- D$ Lclinicians but its mode of action remains controversial. Im-" Q0 ?/ U+ E1 o6 ]6 T1 I, Z
mergut and associates reported an excellent growth response' \6 K4 r3 F( f. e
to topical testosterone with low levels of serum testosterone,4 w b0 W9 R' _" n# }! \
suggesting a local effect.1 Others have obtained growth re-. A1 w+ z, P7 ^9 [ g5 r
sponse with high. levels of serum testosterone after topical4 M) I2 }! @* n6 i
administration, suggesting a systemic response. 3 The use of( ^4 T5 U. R/ I' ^# a
gonadotropin to obtain levels of serum testosterone compara-
0 u4 m: W; z- sble to levels obtained with topical testosterone would seem to
) y2 M* \- k& Z" S# T: P- Yprovide a means to compare the relative effectiveness of& g* _, w; v* i8 `% Y$ X) B/ ]
topical testosterone to systemic testosterone effect. It cer-3 ]' W- n2 J: w# v6 m
tainly has been established that gonadotropin as well as par-
, n1 C. O6 e% henteral testosterone administration will produce genital$ u. w+ s/ C/ [: z2 }
growth. Our report shows that the growth of the phallus was
% ~7 j G/ m( T- `4 ksignificantly greater with topical applications than with go-
: V1 r: T; L+ u) ^/ R- I$ }nadotropin, particularly in children less than 10 years old.2 {" t8 D( u" d; x
The levels of serum testosterone remained similar or lower. m3 F. p6 o' I: v/ v( i' W! h
than with gonadotropin during therapy, suggesting that topi-) X: R+ a4 V* K3 Z
cal application produces genital growth by its local effect as
1 L; T& Y5 }* u u. A: k4 iwell as its systemic effect.# A8 z# Z/ }- [) ~/ B0 D
Review of our patients and their growth response related to% F" q( ]9 }1 k3 v5 i' U
age shows a greater growth response at an earlier age. This is
! n7 }( M1 q7 qconsistent with the findings of Wilson and Walker, who
8 z h6 q/ V7 k: ?8 ~4 A1 C, vreported an increased conversion of testosterone to dihydrotes-
: e0 t- `$ }4 H; Q) k8 I9 Jtosterone in the foreskin of neonates and infants.4 This activ-
$ ]; t0 |% _1 j& eity gradually decreases with age until puberty when it ap-: ?0 W0 r6 V. d1 F0 w. [; w
proaches the same level of activity as peripheral skin. It may
$ t/ y2 a x8 n; h7 T, Rwell be that absorption of testosterone is less when applied at% n1 U6 \& O$ g- R
an earlier age as suggested by lower serum levels in children% l& `$ g2 S/ b
less than 10 years old. This fact may be explained by the* p! ^0 Y- }* r) ~' ?: I0 b
greater ability of phallic skin to convert testosterone to dihy-
3 L& U* e. q, d K% Y* Idrotestosterone at this age. Conversely, serum levels in older% P8 o7 ]! N( A* M( n: D
patients were higher, possibly because of decreased local! H; s- G+ m6 h
667
, {/ ]3 M6 ]/ \* Z8 _+ \4 |7 P668 KLUGO AND CERNY
& F4 ]' n0 o$ Y( m- y8 JPt. Age0 p( j7 y* b! d: L% k
(yrs.)) _ V) f6 A5 W0 [4 k, F, S
Serum Testosterone Phallus (cm.) Change Length5 u/ P$ B. F% n% I" R
(ng./dl.) Girth x Length (%)- R+ ~. j+ N; |. R0 y
4# n9 E5 I; ]) l- ]4 v/ q
8
8 I: u- ?7 k) @; l/ {+ r J100 ~5 ]/ t! Q- t% o5 W: a2 A
12
( H6 h, e- M) R2 P1 k6 Q8 v1 n17
. v! }4 k8 r$ A6 r# X: ?Gonadotropin9 p( O0 f2 I. g' J
71.6 2.0 X 3 16.6
( K3 z& p% `$ T; `# |4 s50.4 4.0 X 5.0 20.0
- ~% N: b* [% P5 k6 F4 F% r$ s22.0 4.5 X 4.0 25.0! _1 Q T4 c8 s+ ?
84.6 4.0 X 4.5 11.10 o7 \" k0 E: R$ x) P5 A% j+ _/ `
85.9 4.5 X 5.5 9.0
3 }7 ?3 J; n) o, g- y3 C& kAv. 14.3! F- Q V6 C. j9 ~% T8 O/ c. ~
4
' I; I/ b8 f, j: V8
2 s' e9 H2 v& h4 }# f& C" Q# ~10
4 y3 E% A s: r7 a& | c2 A12
% v! Q; }/ g3 G; `17' {2 G/ r1 p+ F
Topical testosterone& u4 M; g) z4 j! m- Y; U6 H
34.6 4.5 X 6.5 858 O h4 r1 H2 E% b* ~( s4 m7 d
38.8 6.0 X 8.5 70
+ [7 F& ?" X4 f40.0 6.0 X 6.5 62.59 m+ w I5 L, x1 ` R9 E
93.6 6.0 X 7.0 55.59 K; O* J+ ~! y, H2 E, N. D3 `* ^! x
95.0 6.5 X 7.0 27.21 v! w) y8 I( Q
Av. 60.0
" ^1 S* N$ S5 H( d0 E5 uavailable testosterone. Again, emphasis should be placed on- P7 t6 ^& f: E# ]
early therapy when lower levels of testosterone appear to2 v. J4 y* g7 M5 Y$ ^( W3 \8 {
provide the best responses. The earlier therapy is instituted" c8 Z& `& z1 v0 r
the more likely there will be an excellent response with low
1 I W) F9 m' p! O' S7 p/ wserum levels. Response occurs throughout adolescence as
3 D% ]1 m# ~( s @5 Ynoted in nomograms of phallic growth. 7 The actual response
3 `* n# h& i/ ^5 p4 o/ j$ H2 Cto a given serum level of testosterone is much greater at birth6 T; q; d* l3 h% L1 H8 v$ c; N8 X+ ?
and gradually decreases as boys reach puberty. This is most: ^9 C0 r& z( d) Q* n
likely related to the conversion of testosterone to dihydrotes-
8 U X& C; F+ J$ \( u' a) J/ j% \tosterone and correlates well with the studies of testosterone& v+ P2 \6 k7 Q8 E" E+ ~
conversion in foreskin at various ages.
& j; k1 Q$ y/ hThe question arises regarding early treatment as to whether
! l$ @, l* D, O, B; hone might sacrifice ultimate potential growth as with acceler-/ h( ?7 F9 [. k; U0 T
ated bone growth. The situation appears quite the reverse
9 K% y E' a0 j# Y( nwith phallic response. If the early growth period is not used
c, q. k, q Y$ `5 iwhen 5a reductase activity is greatest then potential growth% x# M2 R1 C5 u9 U. U8 @) M; ]" [
may be lost. We have not observed any regression of growth: H- v% Z9 n, T
attained with topical or gonadotropin therapy. It may well
) U& _% `$ d) @3 Q( G1 J! ibe that some patients will show little or no response to any+ ?: f d) D' O" ?& P1 \
form of therapy. This would suggest a defect in the ability to
8 Q# o( U7 l2 @' p; Z4 a: b$ X; g Lconvert testosterone to dihydrotestosterone and indicate that
7 f5 M3 @3 C9 W U$ Yphallic and peripheral skin, and subcutaneous tissue should
4 `% s7 a# o# p$ g) `6 Kbe compared for 5a reductase activity.
! V. @8 X/ |2 d0 `' B( Q+ IA, loop enlarges to measure penile girth in millimeters. B,1 Y# g5 V" H- f
example of penile girth computed easily and accurately.! V. a3 L' @( W8 ^" D
conversion of testosterone to dihydrotestosterone. It is in this; K- g {- z4 t" T# R, T# M
older group that others have noted high levels of serum: {/ O" Q' f) l: @8 f8 U( s3 |
testosterone with topical application. It would also appear
$ o: ?; B8 D! @( t" ithat phallic response during puberty is related directly to the
8 T6 c7 R) a! F8 j8 l {8 u6 ?serum testosterone level. There also is other evidence of local
7 P3 N! W& L6 B, Presponse to testosterone with hair growth and with spermato-
1 f% d& e$ m5 Y5 K7 R3 [genesis. 5• 6/ g: m7 r$ y$ ]
Administration of larger doses of gonadotropin or systemic- Y+ S: s: H' F
testosterone, as well as topical applications that produce" A: T; U# J# ]+ e# x
higher levels of serum testosterone (150 to 900 ng./dl.), will- L/ v7 M; n2 z9 W! T o8 B& B
also produce phallic growth but risks accelerated skeletal! p7 A; g5 @' y
maturation even after stopping treatment. It would appear
+ R6 E" W1 p2 ?; x/ e" S) Zthat this may be avoided by topical applications of testosterone
, G. B: g f9 zand monitoring of serum testosterone. Even with this control/ A2 ~& Y/ d6 ^( Y" X% N
the duration of our therapy did not exceed 3 weeks at any8 p1 g3 h/ @& b& X3 Y# l
time. It is apparent that the prepuberal male subject may
) T r! q1 T. y" y; L, Z& x$ Ssuffer accelerated bone growth with testosterone levels near
* Q0 A) l( J! A ?200 ng./dl. When skeletal maturation is complete the level of( I5 p# s; G" q& o' k6 T; |
serum testosterone can be maintained in the 700 to 1,300 ng./
! Z; S N9 L9 O. Mdl. range to stimulate phallic growth and secondary sexual' i- c% C: l) _! u, r+ r
changes. Therefore, after skeletal maturation parenteral tes-
" V. C5 Y# y& C- c* otosterone may be used to advantage. Before skeletal matura-" U3 |; C( `) Y( V+ P
tion care must be taken to avoid maintaining levels of serum
6 P' l1 j8 W5 P7 Atestosterone more than 100 ng./dl. Low-dose gonadotropin. A. o+ B2 p# G* c& p
depends upon intrinsic testicular activity and may require
$ s; K8 Z! ~& H7 U$ ?prolonged administration for any response.
7 x1 y5 _( t/ ^' H& ZAlternately, topical testosterone does not depend upon tes-- Y6 k* M8 u6 b- O2 |2 \3 H! r% S
ticular function and may provide a more constant level of0 ?" X# G5 A! x9 ]( |
REFERENCES( ]1 b# r) O0 V; c2 A: J/ w4 l2 t9 ]
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, v8 [* u5 q: b( f; eR.: The local application of testosterone cream to the prepub-
4 P7 h0 D) f- sertal phallus. J. Urol., 105: 905, 1971.! L4 J d/ g4 X; H) a3 M
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
2 Q2 t. R g! t/ U5 ftreatment for micropenis during early childhood. J. Pediat.,: [2 s! J2 |6 u% p: D
83: 247, 1973.
9 L F8 b6 V- p, X3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( H u# b6 ] v# g+ Z
one therapy for penile growth. Urology, 6: 708, 1975.7 l2 g" J& @8 y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( M# ^% C" ~! a7 ^& ~4 C9 X, u2 gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 Z; C3 q) b V2 e; }1 r8 Hskin slices of man. J. Clin. Invest., 48: 371, 1969.
. y" i* u% R: k* L" O9 n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth; ]. m0 f9 r$ z# y% G7 v/ P4 X+ h
by topical application of androgens. J.A.M.A., 191: 521, 1965./ u! B0 T# a [; y. S1 y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ t& o& x Z7 Q+ e
androgenic effect of interstitial cell tumor of the testis. J.
; y8 {5 z+ ^) c+ K& k1 \9 Z$ }Urol., 104: 774, 1970.- B4 ~3 S2 }' U; Z1 Q: M- Q4 E
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! \* B# z7 y+ b2 N* Y; b
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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