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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- M4 T9 t, k4 ~' u) P1 nGONADOTROPIN% Y# \2 k, `% w6 D
RICHARD C. KLUGO* AND JOSEPH C. CERNY
' R7 M7 e1 g8 [3 Z% K- ZFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* F: |9 @$ P% ]7 ^# t$ IABSTRACT0 W8 n* P: c6 ?( _
Five patients were treated with gonadotropin and topical testosterone for micropenis associated* V' _. t# U3 O* X3 p5 v7 F: Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: W- _/ R( i7 a: t. s
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" A* `" {' C7 X2 M/ n& ]
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
2 ?6 P- n2 H- c; z8 g- jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ @0 }5 x) v5 t4 `+ \$ F* Y' q" g; q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average a# H, C# ~! S5 ^/ Z; S
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" f, k0 i4 n9 G9 {& `occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This- Y3 F. l2 E$ R2 {/ O0 p, V* S/ h
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! a" ^& q% Y+ d; d; G
growth. The response appears to be greater in younger children, which is consistent with previ-
1 \6 i, R$ f, y& I8 a4 n' [ously published studies of age-related 5 reductase activity.% G* V* X0 m6 p
Children with microphallus regardless of its etiology will
9 V+ n2 v( F3 P" R1 erequire augmentation or consideration for alteration of exter-
& i! m1 v$ C- j! c1 Z0 x7 jnal genitalia. In many instances urethroplasty for hypo-
" S2 i* B) g& _# c6 V" q. B Kspadias is easier with previous stimulation of phallic growth.5 ?" B$ f% r) b- ]
The use of testosterone administered parenterally or topically
3 |+ {) D9 U& ^* yhas produced effective phallic growth. 1- 3 The mechanism of. N$ D# \- n. n, Y- A( C- _
response has been considered as local or systemic. With this
/ R2 r G5 J: c) r: ^in mind we studied 5 children with microphallus for response; }, X. v+ i4 i# g7 d2 L
to gonadotropin and to topical testosterone independently.
- ?4 R+ r7 l+ l0 _; xMATERIALS AND METHODS
4 b% j1 F3 B8 SFive 46 XY male subjects between 3 and 17 years old were
9 ~# X; C: W* p8 v2 W4 Yevaluated for serum testosterone levels and hypothalamic
. p) C+ ]1 ]8 ^8 p4 k8 f6 zfunction. Of these 5 boys 2 were considered to have Kallmann's
0 _# E0 F' A& g( s) Tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* b3 {0 |. n" b5 {& D# `- o8 U
lamic deficiency. After evaluation of response to luteinizing6 o6 `' Y# r; F0 A- L
hormone-releasing hormone these patients were treated with
" Y1 S' n, d6 s O) m/ n# a1,000 units of gonadotropin weekly for 3 weeks. Six weeks4 ~: _7 C6 |3 r* _, r* o5 S
after completion of gonadotropin therapy 10 per cent topical: I# x$ j9 U( h1 p, s5 D
testosterone was applied to the phallus twice daily for 3 weeks.; X' ^* x1 N6 r* q. a8 s
Serum testosterone, luteinizing hormone and follicle-stimulat-
. [$ R2 P5 F5 y0 @ing hormone were monitored before, during and after comple-' _( h; ^* o& |1 ^) ~- F
tion of each phase of therapy. Penile stretch length was
; s/ T) I6 B" ~6 e, yobtained by measuring from the symphysis pubis to the tip of, @8 K4 n0 b$ |. F" M# ?
the glans. Penile circumferential (girth) measurements were
9 O# {% a! g. g Robtained using an orthopedic digital measuring device (see% F9 c" o T& {
figure).
! H: D, V+ j$ P; |2 j& N% f3 @RESULTS" b/ E N0 t" j1 z6 n- P- ?
Serum testosterone increased moderately to levels between
; u3 A% h5 \" Y" J P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
& \5 _/ F- A4 t) \- P% Q9 I; \# wterone levels with topical testosterone remained near pre-( c) m% ~' Q8 |, E
treatment levels (35 ng./dl.) or were elevated to similar levels
6 P V2 Z; \9 F) X. Z4 {9 a3 W& Cdeveloped after gonadotropin therapy (96 ng./dl.). Higher
& K' k4 X% N& |5 X( ? U& I' ?3 kserum levels were noted in older patients (12 and 17 years old),: r/ e3 }0 W# |/ g6 ^
while lower levels persisted in younger patients (4, 8, and 10' _6 e A* X9 U. O
years old) (see table). Despite absence of profound alterations
! a# z' t$ T- ]& p; v% X8 kof serum testosterone the topical therapy provided a greater
: t1 K& e0 L8 z G" ZAccepted for publication July 1, 1977. ·( u; F S8 }# z0 y, c
Read at annual meeting of American Urological Association, F' {) e" t- p- t, W# W d
Chicago, Illinois, April 24-28, 1977.% O' K0 _4 a" t5 i! {
* Requests for reprints: Division of Urology, Henry Ford Hospital,
- A- K/ a' l, e2799 W. Grand Blvd., Detroit, Michigan 48202.
3 ]( b, D, |$ ?4 W' fimprovement in phallic growth compared to gonadotropin.
/ p3 Z4 `$ L: ~Average phallic growth with gonadotropin was 14.3 per cent
- l: ?7 ] `: v8 |4 mincrease in length and 5.0 per cent increase of girth. Topical
* l) R* v9 ^' D+ t' }6 R, h- ^testosterone produced a 60.0 per cent increase of phallic length
3 `, z, Q. I! c" _, v4 e2 ?and 52.9 per cent increase of girth (circumference). The
+ W! k4 H. z1 U% {7 Q- Nresponse to topical testosterone was greatest in children be-3 k& {" K' w( P
tween 4 and 8 years old, with a gradual decrease to age 17
: U1 s5 _1 z9 Y" c1 @ v1 uyears (see table).! t& T L- h( D0 c
DISCUSSION6 ]( H+ H5 u$ {1 {6 R0 X
Topical testosterone has been used effectively by other
/ T4 z0 K* F9 }( B% b9 c% jclinicians but its mode of action remains controversial. Im-
; U v; K6 o7 Y- r$ pmergut and associates reported an excellent growth response
$ H7 v. ~" P8 Q- }* k+ j+ Ito topical testosterone with low levels of serum testosterone,( k, e% \8 C3 H3 `
suggesting a local effect.1 Others have obtained growth re-
. Z& L" j9 j0 [' N; t* p7 ~sponse with high. levels of serum testosterone after topical+ R' D# h# D' m; _) Y* ~2 U
administration, suggesting a systemic response. 3 The use of7 P) G5 {; N- V, G
gonadotropin to obtain levels of serum testosterone compara-1 P/ s5 v2 \$ u: z- r% b3 D- G
ble to levels obtained with topical testosterone would seem to
9 R* N4 t2 a$ d, a- g8 T1 S* _8 E$ |8 eprovide a means to compare the relative effectiveness of
4 Z1 k$ r+ K7 `& Wtopical testosterone to systemic testosterone effect. It cer-
. _1 {: v$ j. y5 j" L# l6 @tainly has been established that gonadotropin as well as par-0 q. p6 V( y2 e, J
enteral testosterone administration will produce genital" D$ t" `9 h" }: m' ^
growth. Our report shows that the growth of the phallus was
* d [. T& l/ Ksignificantly greater with topical applications than with go-
0 I8 u( A. n1 t# @2 Hnadotropin, particularly in children less than 10 years old.
3 n; M$ a E2 f) r1 H( u) E7 zThe levels of serum testosterone remained similar or lower( v) T- D/ P9 o' t Z/ d
than with gonadotropin during therapy, suggesting that topi-' j. N4 v W: N) u1 `
cal application produces genital growth by its local effect as
+ Y. L9 z2 |0 Q0 X+ Iwell as its systemic effect.$ q6 u2 @# w( s' O
Review of our patients and their growth response related to3 ?0 h8 C' H4 ~# V0 e I8 j8 O
age shows a greater growth response at an earlier age. This is
/ H$ r1 p; r" q# U3 L# Econsistent with the findings of Wilson and Walker, who; s3 |$ m' @6 x% Q" M6 g/ Q
reported an increased conversion of testosterone to dihydrotes-$ L! g- m+ Y; C1 T8 g5 s
tosterone in the foreskin of neonates and infants.4 This activ-
6 k% z4 ~8 ]2 Z& N3 city gradually decreases with age until puberty when it ap-. o3 B0 U% n1 X, w# ~
proaches the same level of activity as peripheral skin. It may8 v- J, b5 |/ b" N3 c
well be that absorption of testosterone is less when applied at
U% P* Y! X3 b+ j; ]6 ^& _an earlier age as suggested by lower serum levels in children
% t e/ _7 n% y; Zless than 10 years old. This fact may be explained by the4 c2 Z. Z# M! O/ i% r: Z2 |
greater ability of phallic skin to convert testosterone to dihy-
" h4 O% _2 |# [3 D. t/ N% ~drotestosterone at this age. Conversely, serum levels in older
- y7 E! h4 b# r0 B. [; mpatients were higher, possibly because of decreased local
( M( W% y/ K* b3 f" i6 L667$ S {, \3 p8 ]$ ]/ F* S
668 KLUGO AND CERNY* G* `: p7 E. V1 a/ x
Pt. Age: H3 E- l3 O/ q7 x- j
(yrs.)9 T' x% }$ s( P+ x
Serum Testosterone Phallus (cm.) Change Length1 A6 A# E- u4 w' F6 _& Z3 `
(ng./dl.) Girth x Length (%)
) H. _2 a- a3 O4
. R) J9 |. y l- p8, S2 w( ?- U, {4 z' S
10
" S. s' d8 @ r/ J% C5 V% }12
( d4 p" q4 b4 y% i1 ?6 m9 r17/ }5 n- f( C( ^4 ^) E
Gonadotropin
$ b8 J- m4 Q3 o3 \ w& u71.6 2.0 X 3 16.61 s7 _3 T2 E) l( W* J
50.4 4.0 X 5.0 20.0
% ~( \+ J1 }+ A22.0 4.5 X 4.0 25.0- a, o1 g" t$ q3 Y7 l
84.6 4.0 X 4.5 11.1 {3 g+ X/ ]: e
85.9 4.5 X 5.5 9.01 Y5 U6 ?7 N+ u5 G# U
Av. 14.3
) I/ f1 S) g' ^* v4; C: ]1 S5 F! ?5 k$ E
8: X) u$ r% v- @( w' g" B. P6 S7 ~/ X- A
10
3 F$ }; S i# d6 ^% ^' t0 ?2 F12
, n; I R' ?! y% F: a% D17; S/ \5 C* o' ~' n+ [$ B
Topical testosterone
6 D1 \7 Z' M. Q- ~& @0 C6 u3 v) U34.6 4.5 X 6.5 85
- n$ \& @% e2 A38.8 6.0 X 8.5 70+ m4 Y( J3 g: x! c \! P- k8 w6 |$ ]: X
40.0 6.0 X 6.5 62.5
! g( d* m, j1 B& p' M6 @93.6 6.0 X 7.0 55.5
# b n! P. I+ j3 S95.0 6.5 X 7.0 27.2
6 q" X8 v8 Z- u$ `Av. 60.07 `( m9 V7 D0 b2 d" _" T
available testosterone. Again, emphasis should be placed on( N5 e5 S) k4 p
early therapy when lower levels of testosterone appear to
: \$ n S9 U; ^5 K+ f0 zprovide the best responses. The earlier therapy is instituted
& `" G) j# W2 ~2 mthe more likely there will be an excellent response with low
4 @! S9 N' l( Kserum levels. Response occurs throughout adolescence as
4 @, o% X4 {; e2 d0 tnoted in nomograms of phallic growth. 7 The actual response
# c8 }8 |- o2 b1 v9 p3 Lto a given serum level of testosterone is much greater at birth
6 F8 }) J. ?# t5 f: s: Q, Nand gradually decreases as boys reach puberty. This is most
4 z1 s. L9 D0 j& K0 f* glikely related to the conversion of testosterone to dihydrotes-2 m0 Z/ h* Z! d- e2 U
tosterone and correlates well with the studies of testosterone" w, R/ H% A% i( M3 d+ k; K- L# v
conversion in foreskin at various ages.' I. h" t b2 i; F
The question arises regarding early treatment as to whether
: v) m, |) E2 x1 A/ jone might sacrifice ultimate potential growth as with acceler-$ H8 }$ r! N) e
ated bone growth. The situation appears quite the reverse ^* s* a- p0 \% O8 A
with phallic response. If the early growth period is not used
c$ D! z9 f5 k3 Cwhen 5a reductase activity is greatest then potential growth
+ h. Y5 G* H3 [: q( t; dmay be lost. We have not observed any regression of growth
) S, f8 y5 ^* N- {; oattained with topical or gonadotropin therapy. It may well1 }) n) D( F2 p4 {
be that some patients will show little or no response to any
. B4 a: b; s: V5 G8 S1 f# Mform of therapy. This would suggest a defect in the ability to3 g# \% @: h9 U( U
convert testosterone to dihydrotestosterone and indicate that- [3 I U- {3 M
phallic and peripheral skin, and subcutaneous tissue should0 D& B' D0 z2 G* I
be compared for 5a reductase activity.
0 n P6 D% D5 lA, loop enlarges to measure penile girth in millimeters. B,
2 @ z5 v6 ? W6 e0 Fexample of penile girth computed easily and accurately.) ]2 |+ w5 |7 h$ f0 N, G
conversion of testosterone to dihydrotestosterone. It is in this% P4 j2 @ W, {/ M2 c0 W
older group that others have noted high levels of serum
5 b& w9 C- T/ U; Ntestosterone with topical application. It would also appear
9 ` Q+ ~9 h) g, t5 G$ Lthat phallic response during puberty is related directly to the
. a% ?, d: b4 h: kserum testosterone level. There also is other evidence of local. q# t ]9 q2 ?7 m' a; M9 a5 \& B
response to testosterone with hair growth and with spermato-
: c; v5 ]( ^! _% k% z, bgenesis. 5• 6
- U* A- t$ ~/ N8 i0 v' [3 ~Administration of larger doses of gonadotropin or systemic
1 z1 C7 L; s0 t' z" M; stestosterone, as well as topical applications that produce
7 h" r, _- |, Y% L9 Jhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 c& V# p9 ^6 u# w$ Nalso produce phallic growth but risks accelerated skeletal7 S1 M) [& C" [4 E
maturation even after stopping treatment. It would appear
5 @3 d- o3 b& U2 K" Athat this may be avoided by topical applications of testosterone
h! Z- o2 v0 B9 m, \and monitoring of serum testosterone. Even with this control( [) S: o) I* S! g" i4 `! z/ I w
the duration of our therapy did not exceed 3 weeks at any
) v; E, Y# g+ f" P3 `6 Xtime. It is apparent that the prepuberal male subject may" ~9 H' L+ s0 w2 W
suffer accelerated bone growth with testosterone levels near
3 s3 W0 \9 E5 P/ n; U# o200 ng./dl. When skeletal maturation is complete the level of( R" A; T" g5 U7 M2 L
serum testosterone can be maintained in the 700 to 1,300 ng./
% s+ _% E9 ]9 I5 edl. range to stimulate phallic growth and secondary sexual2 C7 E' M9 U0 E( ~
changes. Therefore, after skeletal maturation parenteral tes-
- o, R) s& W8 g* L% }7 a/ a4 Q/ \7 Otosterone may be used to advantage. Before skeletal matura-- J6 f) n4 X8 u6 M6 K
tion care must be taken to avoid maintaining levels of serum
' \% v! {# l2 M' D2 r9 p; a, rtestosterone more than 100 ng./dl. Low-dose gonadotropin7 I; a& J8 H% b( I( G" }7 i
depends upon intrinsic testicular activity and may require7 ^1 |2 D! k; d2 K. R) @
prolonged administration for any response., m9 R, D) D1 ?' m' h8 y; a
Alternately, topical testosterone does not depend upon tes-% H" D+ l8 `* E6 q! F4 z
ticular function and may provide a more constant level of. Q- x" O% @0 O8 G% U+ k+ z
REFERENCES
8 j# h; d" v6 I- c ~5 a' _4 W1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ u0 ?" E e+ N3 {# r) T4 I. u+ `
R.: The local application of testosterone cream to the prepub-
% y+ o# v9 g1 F6 r9 Sertal phallus. J. Urol., 105: 905, 1971.3 ~6 y2 \' O# o; l* i, P# m
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# ]4 Z* m9 ^) V& W& I: r+ t- e
treatment for micropenis during early childhood. J. Pediat.,
$ a- \' B" K( K+ ~% K4 ^83: 247, 1973.
8 y: C, u" _! U' t3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ j) @3 N; E( P9 N' k
one therapy for penile growth. Urology, 6: 708, 1975.
! l% \- S0 J k6 c. M" Z: @4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 x, t8 J9 u1 v- G" S7 E
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. K+ I" _* I8 K7 {
skin slices of man. J. Clin. Invest., 48: 371, 1969.
# c, Z# Q# f2 _/ F+ H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: c# C Y) r: l1 ~
by topical application of androgens. J.A.M.A., 191: 521, 1965.
& _& U2 `( R$ O6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
0 M' T& C4 X0 G! T1 z& p- |androgenic effect of interstitial cell tumor of the testis. J.5 I. d7 ~* {$ c( m, O# Q
Urol., 104: 774, 1970.
5 u3 M! l; ^# n. H* A- @5 h7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ t0 S8 j; e5 H2 x3 N$ T V" Q
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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