- 註冊時間
- 2023-5-6
- 精華
- 在線時間
- 小時
- 米币
-
- 最後登錄
- 1970-1-1
|
發表於 2025-1-4 03:09:28
|
顯示全部樓層
RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" `# F$ @0 e) y9 W, D0 MGONADOTROPIN4 w0 m0 T. O; I) i3 T
RICHARD C. KLUGO* AND JOSEPH C. CERNY$ M8 r- r$ ?/ N. P. B
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan% W0 ?0 `! H* N }9 B
ABSTRACT& g* z' z/ m% q/ V
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
. a0 T8 K1 t& s* D* C7 m- R/ Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-4 p2 N, K; U# z' W* P7 \
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# \, y# J& U& O8 b" E! ncream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 Y$ l7 I4 b0 X! Ifor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 e9 [( Z% Y. @) O3 `! g; D3 d
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 { f0 h+ {' R/ zincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ |4 w$ _; H1 J2 k! ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# V* n' |5 H$ Q7 m, K2 m9 S1 G+ ~) T
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
[# ^" g7 ]; j* p q% bgrowth. The response appears to be greater in younger children, which is consistent with previ-$ ^5 q/ ?* G8 U& K ?. z
ously published studies of age-related 5 reductase activity.) |$ w5 N% E. e# |1 A U
Children with microphallus regardless of its etiology will
! E9 Q T) J/ S: r- g& L! `require augmentation or consideration for alteration of exter-/ E0 O5 g8 U9 Z5 Q( D0 ]
nal genitalia. In many instances urethroplasty for hypo-
% Y9 C% S$ t2 y. k, T8 Zspadias is easier with previous stimulation of phallic growth.
" U. w) _ k& c5 ~- x$ ~) sThe use of testosterone administered parenterally or topically1 r: c4 j. w7 V0 }/ R( Z# p/ d3 z( K
has produced effective phallic growth. 1- 3 The mechanism of* K) l* Q7 O; n2 D
response has been considered as local or systemic. With this& {+ m Y% I( b" j0 W
in mind we studied 5 children with microphallus for response
3 z" ~7 |3 A( w/ G$ B5 B4 R, Hto gonadotropin and to topical testosterone independently.
% j' E: `; ?. I yMATERIALS AND METHODS
! @( Q# t2 D* g% \( oFive 46 XY male subjects between 3 and 17 years old were, E- y2 E$ ~' S
evaluated for serum testosterone levels and hypothalamic
% w7 ?1 o: S" {3 b& dfunction. Of these 5 boys 2 were considered to have Kallmann's+ d2 \) C, L. \$ |
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, E5 {+ F3 s3 Y. t
lamic deficiency. After evaluation of response to luteinizing
, Q; \- E" s% F+ m% phormone-releasing hormone these patients were treated with- P* t( p. h' W
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ d3 U* l/ l: t: _; L2 P' m
after completion of gonadotropin therapy 10 per cent topical+ M Z1 w) h7 n+ I
testosterone was applied to the phallus twice daily for 3 weeks.7 }* t) j$ h2 c% A. ]0 `! E
Serum testosterone, luteinizing hormone and follicle-stimulat-. y4 K! i) n6 V$ b! A w8 r
ing hormone were monitored before, during and after comple-- o! P8 f" n' }! t! ]& f' A+ d; @; {
tion of each phase of therapy. Penile stretch length was
! ^. i# g7 }/ {( L8 l* Uobtained by measuring from the symphysis pubis to the tip of
9 j: b6 i% [3 h. L$ d5 \8 Hthe glans. Penile circumferential (girth) measurements were! @6 D) G5 m! B4 {! O
obtained using an orthopedic digital measuring device (see
; q# ^3 h/ C7 z: x5 [5 @figure).
U0 [3 \1 ~: H4 w$ H: c# s% N0 MRESULTS! r% m7 p- D1 e5 |
Serum testosterone increased moderately to levels between6 I) D& L' F' ^$ t& L
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 n, V# i J& @terone levels with topical testosterone remained near pre-
- v: h4 [7 c1 h0 h# _* B3 F9 [treatment levels (35 ng./dl.) or were elevated to similar levels8 Q: ~+ Y. S5 [: i
developed after gonadotropin therapy (96 ng./dl.). Higher! v* Q" C2 x6 i8 o2 w/ e
serum levels were noted in older patients (12 and 17 years old),. z2 O4 o& B$ h* h
while lower levels persisted in younger patients (4, 8, and 10
% z6 [8 o+ v; e eyears old) (see table). Despite absence of profound alterations
8 c! F9 Z- l1 p- D+ bof serum testosterone the topical therapy provided a greater! f7 n, [0 S% ^6 E" u
Accepted for publication July 1, 1977. ·
% | }. M: ]: q. \& Q$ MRead at annual meeting of American Urological Association,
4 Y- v( V2 W1 L3 F" QChicago, Illinois, April 24-28, 1977.8 z- f6 R8 M3 C( Q* y
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 N+ P7 O6 g9 ]. d3 p% R2799 W. Grand Blvd., Detroit, Michigan 48202.3 j j- r9 S- A. r# c& A& h6 {" n
improvement in phallic growth compared to gonadotropin.( b# J& Q) [/ T1 k* `7 R
Average phallic growth with gonadotropin was 14.3 per cent
9 A3 @! v6 s: e% N6 l" x) ~& wincrease in length and 5.0 per cent increase of girth. Topical
! y" N! G% }* L( p+ T9 ptestosterone produced a 60.0 per cent increase of phallic length
2 ]" E5 a" J* a: K& A8 Jand 52.9 per cent increase of girth (circumference). The3 q5 J) `. p% R5 f8 h2 h& d
response to topical testosterone was greatest in children be-
/ W6 h3 P# v4 B8 M3 Jtween 4 and 8 years old, with a gradual decrease to age 17" P8 c1 ~ z; p/ N% V
years (see table).3 a- D. \4 _) J5 W/ c3 A# i
DISCUSSION& ^" Q. R3 I! c2 c' ~$ C! x
Topical testosterone has been used effectively by other
5 g: V) i- n7 K! \( g8 Q: N! yclinicians but its mode of action remains controversial. Im-. k: N7 I8 E) k: v- T; Z
mergut and associates reported an excellent growth response
* x5 J8 Z$ N0 wto topical testosterone with low levels of serum testosterone,
! w0 W% M5 @, e8 f6 |- _3 fsuggesting a local effect.1 Others have obtained growth re-) E/ r, {1 p) p
sponse with high. levels of serum testosterone after topical" n" H. E5 E' W* C; Z
administration, suggesting a systemic response. 3 The use of) Y7 y R( c; t. _
gonadotropin to obtain levels of serum testosterone compara-8 z7 ^! l& a) \$ `& }0 b1 j- w
ble to levels obtained with topical testosterone would seem to
8 d, k0 r& e% B- n8 F' A+ C) }provide a means to compare the relative effectiveness of
& {0 ]/ d& {- c) x! Ntopical testosterone to systemic testosterone effect. It cer-7 b) P/ ~; ^. T0 p" k
tainly has been established that gonadotropin as well as par-% n! O* Y/ G; S/ B7 d
enteral testosterone administration will produce genital( r* X: P& T6 v' L& z; D$ @ o5 w
growth. Our report shows that the growth of the phallus was# @0 E, Y _3 u1 {
significantly greater with topical applications than with go-$ ~& J9 O( r+ a6 L4 R- n
nadotropin, particularly in children less than 10 years old.
3 J4 h2 G4 w9 O4 l3 dThe levels of serum testosterone remained similar or lower# e V$ b$ B- c2 n' @+ K$ S% P1 Z7 ^
than with gonadotropin during therapy, suggesting that topi-" ]. V* V2 x0 L1 c* B' c& K
cal application produces genital growth by its local effect as
# z# l" @/ \& N- Ywell as its systemic effect.8 U9 {' }1 [' C- \- B1 U
Review of our patients and their growth response related to. h5 G) M7 }5 I- G/ C- I
age shows a greater growth response at an earlier age. This is
6 ^2 k7 F, O+ }+ l; j( \, v' Mconsistent with the findings of Wilson and Walker, who
) j. X; ?7 h: ]; Preported an increased conversion of testosterone to dihydrotes-. C6 _/ ^: G5 M' V
tosterone in the foreskin of neonates and infants.4 This activ-
/ p( \. K+ }' i& S, [ity gradually decreases with age until puberty when it ap-
3 o- S6 ^& u( d. _7 d9 tproaches the same level of activity as peripheral skin. It may
) S% M1 E; J9 r; J. s; _8 z/ gwell be that absorption of testosterone is less when applied at2 O' z1 y% z: I
an earlier age as suggested by lower serum levels in children
+ n# L$ f% ~, s$ B( ?' C& r& tless than 10 years old. This fact may be explained by the
- f& p, @0 G, h/ A! ^ vgreater ability of phallic skin to convert testosterone to dihy-
K8 r" m& H$ g: ? y& n; p/ @drotestosterone at this age. Conversely, serum levels in older/ r6 A; {+ T5 T! @9 n) W$ M; h& Y6 N7 V
patients were higher, possibly because of decreased local7 H5 i6 G; F; X4 G5 W
667
6 k& _' p' t! Q1 v" X% X668 KLUGO AND CERNY% X' }$ x0 R8 x5 n
Pt. Age
( u) W( s6 g$ P( W8 P(yrs.)5 o' O* D0 C- E
Serum Testosterone Phallus (cm.) Change Length% m' \9 w0 A, x& Q9 G* ~( g( Q
(ng./dl.) Girth x Length (%)
! l+ Y* q0 J( e9 y" L6 N* {3 a46 t: w8 U5 U/ R, _3 G1 \5 N
8
% X% o' H6 X9 m1 U+ O/ h, `, z10 f3 }4 _ Z7 t p2 o
12
; ~' \, F0 W9 D, p! A! B17
. X/ _4 i6 V* A w& cGonadotropin2 R. }. m( P ^4 G3 G
71.6 2.0 X 3 16.6
6 ?% u% |% T- ?2 e3 e I0 E" i- _50.4 4.0 X 5.0 20.0, c4 Q, v6 |" B' ^, k4 G8 Y
22.0 4.5 X 4.0 25.0
8 r5 x: Y W V; w' D84.6 4.0 X 4.5 11.1& c9 H0 o" \& |6 h
85.9 4.5 X 5.5 9.0" G0 a \8 T) A. p* ]; m9 r
Av. 14.3
% Z. w, f4 j4 P4. ]( A" E O4 ]1 o, l
8- f7 X. q; N u3 | a4 t# Q$ ~% p3 y
10' ?% n7 q# W( D
12" B- ?/ y6 \* K/ ]8 m
17
3 J( }5 Q t8 g8 yTopical testosterone( b g* {0 N- x* W* V2 Q& m: k
34.6 4.5 X 6.5 85
5 ^& M$ p, Z- D; b- P& p ~! K38.8 6.0 X 8.5 70
& V# w* o! N8 W2 B4 y40.0 6.0 X 6.5 62.5
3 d; l. q7 \& h- B3 M. j7 ]93.6 6.0 X 7.0 55.5
) z$ Q: v/ g1 ^ `$ c6 k" I( K95.0 6.5 X 7.0 27.2
9 f9 B Y X" @2 JAv. 60.09 F- n$ ~ C$ v4 p. Y/ B0 R
available testosterone. Again, emphasis should be placed on
$ A: b+ _- {/ z% S" p. p9 Aearly therapy when lower levels of testosterone appear to7 Y7 r1 E% ^( ?! A \+ b8 o
provide the best responses. The earlier therapy is instituted
/ f* w& s& j4 A0 d! U Q1 Othe more likely there will be an excellent response with low/ ~. ^1 s3 B9 L+ ]4 ?1 B
serum levels. Response occurs throughout adolescence as! c6 L9 M! _ N( F8 P# W
noted in nomograms of phallic growth. 7 The actual response6 P- M# _, e) K% a9 k& q
to a given serum level of testosterone is much greater at birth5 J: M+ m5 k. I7 U& c; d
and gradually decreases as boys reach puberty. This is most
2 Q4 z% k0 ?0 N* F* j4 N% _( ulikely related to the conversion of testosterone to dihydrotes-" ?& X- q! H; T2 h. _# I. L1 k
tosterone and correlates well with the studies of testosterone# R4 W+ f5 {0 K: w
conversion in foreskin at various ages.6 w& }: a, c3 Q
The question arises regarding early treatment as to whether
$ s% V- }3 S8 D7 R/ K, }one might sacrifice ultimate potential growth as with acceler-
$ m' s8 M$ |3 Wated bone growth. The situation appears quite the reverse7 r8 t6 m. ?* p8 q
with phallic response. If the early growth period is not used
5 a. `( D6 d/ t% Q# xwhen 5a reductase activity is greatest then potential growth
2 v9 U: m' Z1 A& S$ @, gmay be lost. We have not observed any regression of growth* x5 |/ B. c6 V4 m$ y: o: b+ o
attained with topical or gonadotropin therapy. It may well
1 `4 ]# S/ v$ [/ o, Kbe that some patients will show little or no response to any
/ e& P5 m2 C6 {! uform of therapy. This would suggest a defect in the ability to9 m6 b S2 i A# f) R6 I- G8 ]$ z* x
convert testosterone to dihydrotestosterone and indicate that
2 @8 X0 w! B) pphallic and peripheral skin, and subcutaneous tissue should! x6 s6 C$ ^6 k& F: p
be compared for 5a reductase activity.
) n! {- o- G2 Y3 l8 V. i; |/ Q+ kA, loop enlarges to measure penile girth in millimeters. B,: u% T/ U l6 ]" I- I
example of penile girth computed easily and accurately.
( o8 o/ Z$ n* i+ |# P cconversion of testosterone to dihydrotestosterone. It is in this
2 U& b$ i% g( y$ aolder group that others have noted high levels of serum
w- h1 |. p9 f5 w4 `2 b* h2 gtestosterone with topical application. It would also appear
3 P" y: I& B: X! jthat phallic response during puberty is related directly to the% N" x( ?; C& A- c1 x0 A2 W
serum testosterone level. There also is other evidence of local
4 h8 ]9 {# F9 g2 K# Aresponse to testosterone with hair growth and with spermato-
: l# T, A; R% D7 Ggenesis. 5• 6
8 }6 V1 B8 \( A4 d$ H7 U) EAdministration of larger doses of gonadotropin or systemic4 E% t; W7 i8 q0 S; F. n) ~: D& H
testosterone, as well as topical applications that produce- P! \, ]* \% X: G
higher levels of serum testosterone (150 to 900 ng./dl.), will
0 X% U$ t# J; _$ e9 N: I4 Galso produce phallic growth but risks accelerated skeletal: q, ]/ D& c/ z! [/ R
maturation even after stopping treatment. It would appear
9 s8 \/ a! q& K6 w; N, M& U7 qthat this may be avoided by topical applications of testosterone
- N3 s2 {: c6 u; B, f2 Q) f: wand monitoring of serum testosterone. Even with this control
5 _' m" f) o' m! _! V. M. Fthe duration of our therapy did not exceed 3 weeks at any i5 N9 y. R: {3 B2 q
time. It is apparent that the prepuberal male subject may1 u. Z$ {7 w0 d- r; G5 Z
suffer accelerated bone growth with testosterone levels near- U2 v3 g, b" c3 `: o+ p
200 ng./dl. When skeletal maturation is complete the level of
5 w& R0 ~" V$ n y& h3 G t/ rserum testosterone can be maintained in the 700 to 1,300 ng./' Z" `3 v- E+ Q2 A
dl. range to stimulate phallic growth and secondary sexual0 H5 p, c1 Z( J" _( r: o' I
changes. Therefore, after skeletal maturation parenteral tes-1 I$ I# f. d& \4 Q2 i1 e: G. l
tosterone may be used to advantage. Before skeletal matura-& ~ n: e3 z Z. u& c& j
tion care must be taken to avoid maintaining levels of serum Q/ ]9 u0 n1 z& f% ^
testosterone more than 100 ng./dl. Low-dose gonadotropin
, c9 k+ W3 N2 N9 |5 W2 S+ Sdepends upon intrinsic testicular activity and may require
9 z" j4 N, V7 ~& c* pprolonged administration for any response.
6 s( f: S, t$ x Y- a) @, d0 U: nAlternately, topical testosterone does not depend upon tes-
0 [: r' n, ]- k; B8 E3 Tticular function and may provide a more constant level of
& j5 I% k% c7 q! y7 j& ]& xREFERENCES/ R) M% `9 U& t V' \1 R- @5 N( P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! i" [: A5 G$ T0 g9 V9 ]
R.: The local application of testosterone cream to the prepub-
( T8 y2 u+ G' N8 d: \/ Eertal phallus. J. Urol., 105: 905, 1971.
4 k9 K4 G& N' ~2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 }4 C1 g: i7 t% s
treatment for micropenis during early childhood. J. Pediat.,$ Z8 E% `, M6 Z; t+ ]. k( W! A" ?" W
83: 247, 1973.
& A: c# b ^. N3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% Z; l/ I! b: Sone therapy for penile growth. Urology, 6: 708, 1975., z# s( ~8 y4 B! _$ `4 K
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" Y/ a; P% {9 o' ^: F. c* Kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by _5 A" f% Z3 @$ r
skin slices of man. J. Clin. Invest., 48: 371, 1969.; a4 O3 @ T+ E6 Y4 x
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 J2 f1 C# l2 Mby topical application of androgens. J.A.M.A., 191: 521, 1965.$ h3 D' T \: I5 k
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
! U! e' Y: B! O$ U/ vandrogenic effect of interstitial cell tumor of the testis. J.5 u6 Q2 O0 l8 H3 ]( u2 p
Urol., 104: 774, 1970.
0 [. D4 U0 u+ p }+ U7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-2 F+ ]: N" T$ ^& l, X
tion in the male genitalia from birth to maturity. J. Urol., 48: |
|