- 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
6 H& ^: \" w$ pGONADOTROPIN
1 T. M* q q1 r8 N1 f1 O; rRICHARD C. KLUGO* AND JOSEPH C. CERNY
E' E% t# w, J0 a% U+ z' HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 ^+ U. F1 i+ k$ W1 j6 Z3 R# T+ I
ABSTRACT
! f4 N; ^, w4 d) `Five patients were treated with gonadotropin and topical testosterone for micropenis associated }- @* v }1 T+ J% R/ L; L
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( e# c# ~, {8 a7 o# Q/ ]7 @& U9 ytropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
~ O! f! i) Ecream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ I f* c& }: U0 m9 I! ]. I
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
3 b8 T% u8 g' r! c) u' jincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average; w- ?5 R1 k+ Y0 C+ q5 I
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
8 R/ t: W8 ?% foccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# c k7 Z% Q' u& u4 J; I. cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% ~$ f% u, O: E& J" m
growth. The response appears to be greater in younger children, which is consistent with previ-
, ?/ A6 T E: ]" ~, Cously published studies of age-related 5 reductase activity.
w; v* m) s" O% EChildren with microphallus regardless of its etiology will" p. o6 O2 w( ]# r8 t
require augmentation or consideration for alteration of exter-
8 M$ |, f' F7 u* Q/ S% L: l! \nal genitalia. In many instances urethroplasty for hypo-) _6 n, n8 k( ^6 _: ]8 ]
spadias is easier with previous stimulation of phallic growth.. ~% B9 L2 t# N) o
The use of testosterone administered parenterally or topically7 y* ]7 j r, e/ H( y
has produced effective phallic growth. 1- 3 The mechanism of
# Z3 i, y, l, R8 ?8 [- K* C# V2 Presponse has been considered as local or systemic. With this' |" p' d! A+ s
in mind we studied 5 children with microphallus for response1 ?# u, d- T+ l( i/ j0 x" ~5 A
to gonadotropin and to topical testosterone independently.: L' K5 {( O4 F6 H$ Y0 M
MATERIALS AND METHODS
0 f1 i8 ~; u I+ DFive 46 XY male subjects between 3 and 17 years old were9 s8 h8 b6 T5 P) M: d3 V
evaluated for serum testosterone levels and hypothalamic
* ]% ~" a6 `4 @# o6 C* ufunction. Of these 5 boys 2 were considered to have Kallmann's: @* B& S# I( G2 }
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 ~2 N# f x: llamic deficiency. After evaluation of response to luteinizing6 l# o% T* ^: |0 Z. ]
hormone-releasing hormone these patients were treated with
: d8 _# a" j" W5 X7 d2 P( M3 y1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 v8 b# J) ]* A6 r L( hafter completion of gonadotropin therapy 10 per cent topical+ i" J9 V6 p& K( U1 d) D* e
testosterone was applied to the phallus twice daily for 3 weeks.
8 F2 y; |4 U0 FSerum testosterone, luteinizing hormone and follicle-stimulat-
5 x1 h/ q) V- c$ ring hormone were monitored before, during and after comple-
/ B, X9 b0 C0 u: Vtion of each phase of therapy. Penile stretch length was
* I- @8 R; }# W+ Y- l, yobtained by measuring from the symphysis pubis to the tip of* E" j. n; h& Z6 y" s
the glans. Penile circumferential (girth) measurements were+ t. J! y( g. [. R
obtained using an orthopedic digital measuring device (see
6 I% ]; q0 H5 u4 t' S9 Vfigure).
; P, [/ B' I( E5 ]( t$ o; I9 O6 [8 JRESULTS2 p( i; \# F) _& m! H, i; g
Serum testosterone increased moderately to levels between
1 b1 D/ ?' @& ?7 ^2 j3 ~1 z4 x# i50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-, T. q8 c# F' B# Q" u
terone levels with topical testosterone remained near pre-. x7 ~& G: J- t. c
treatment levels (35 ng./dl.) or were elevated to similar levels" i8 _" V- _( N
developed after gonadotropin therapy (96 ng./dl.). Higher2 |& Q. }0 F, a0 _" w" ^
serum levels were noted in older patients (12 and 17 years old),
; B+ n3 o; Z+ G9 hwhile lower levels persisted in younger patients (4, 8, and 10. E) u2 s2 r8 |
years old) (see table). Despite absence of profound alterations
{8 L1 w( Y6 I+ P- _% F- D3 |of serum testosterone the topical therapy provided a greater, d8 }) V8 h2 u- _1 w
Accepted for publication July 1, 1977. ·3 s \9 R' Z# I/ r! e; T6 H# y
Read at annual meeting of American Urological Association,) C, r5 P2 W c7 m p" I
Chicago, Illinois, April 24-28, 1977.
) o H/ h' d: x, r1 P; u* k* l* Requests for reprints: Division of Urology, Henry Ford Hospital,9 y4 X# z6 D5 z' O c0 T
2799 W. Grand Blvd., Detroit, Michigan 48202.0 P3 N" f% O! i( i3 L7 u% _
improvement in phallic growth compared to gonadotropin., L9 }& x2 ~" q( X+ u
Average phallic growth with gonadotropin was 14.3 per cent/ C, i* B9 X6 O4 f- T5 [
increase in length and 5.0 per cent increase of girth. Topical
, Z: o& o- {# ]& N# L5 otestosterone produced a 60.0 per cent increase of phallic length
3 M- ?2 m1 N3 rand 52.9 per cent increase of girth (circumference). The
+ h/ u# A5 M/ K4 Jresponse to topical testosterone was greatest in children be-
+ P7 v" y R& Q& L- @- ~/ L( Stween 4 and 8 years old, with a gradual decrease to age 17+ o- O4 X( X* ~- s* e) @% U
years (see table).& t( H4 X8 @* d; v
DISCUSSION2 _. `- H0 k* L; R' a
Topical testosterone has been used effectively by other
' B; f+ }! `% Z3 Z, q0 `/ }% ]5 E' vclinicians but its mode of action remains controversial. Im-
. G- n# k& b3 r, \# umergut and associates reported an excellent growth response
, i7 \; S! C1 {( Kto topical testosterone with low levels of serum testosterone,
c9 A3 {9 O8 r, \) Y- esuggesting a local effect.1 Others have obtained growth re-
3 o4 l9 Y0 K' S* isponse with high. levels of serum testosterone after topical/ [* x$ X3 h5 n( l8 l0 Q
administration, suggesting a systemic response. 3 The use of
" A3 l+ D6 ?/ h3 Dgonadotropin to obtain levels of serum testosterone compara-+ f! s" O' G6 ]/ x q; ]! s; V
ble to levels obtained with topical testosterone would seem to
" b/ ~; X3 L' s0 j1 Fprovide a means to compare the relative effectiveness of6 S# B4 w$ ~. z1 V" h8 F& l2 x
topical testosterone to systemic testosterone effect. It cer-! d9 Z$ C- K. L8 i! i
tainly has been established that gonadotropin as well as par-4 c( j& d& j& w( F
enteral testosterone administration will produce genital
; _2 y/ @7 U" a- ?2 c% K7 H* t8 sgrowth. Our report shows that the growth of the phallus was, b# Z4 p; t( p6 k3 w
significantly greater with topical applications than with go-
' R+ Z6 p4 r$ N _ q5 g) _nadotropin, particularly in children less than 10 years old.
+ N4 b9 j8 @1 |# u/ }5 i/ z0 bThe levels of serum testosterone remained similar or lower$ X( g7 z, m: h4 J, N) P% S- C
than with gonadotropin during therapy, suggesting that topi-
4 v1 u# ]/ u% ^cal application produces genital growth by its local effect as
# D1 U2 q3 R4 f; ^" n2 Q1 \well as its systemic effect.
6 H% W* \/ v% k9 z1 cReview of our patients and their growth response related to
# A4 u: U( R# x' X% v. K; {age shows a greater growth response at an earlier age. This is& \. O( Y) B) \: ~* i
consistent with the findings of Wilson and Walker, who1 |' s( G0 d7 Y
reported an increased conversion of testosterone to dihydrotes-$ e5 y8 }2 n1 b
tosterone in the foreskin of neonates and infants.4 This activ-' ~* r7 C) l9 n5 \' ?5 \8 l
ity gradually decreases with age until puberty when it ap-
6 f# T7 K: v: Q3 F# i# p9 p& pproaches the same level of activity as peripheral skin. It may% Y4 R" c0 Y3 X0 F% H& u
well be that absorption of testosterone is less when applied at0 I9 r* E& V- Q
an earlier age as suggested by lower serum levels in children
9 }# \3 I% @! o( |' I% Oless than 10 years old. This fact may be explained by the
. E. Q5 @3 |. g; zgreater ability of phallic skin to convert testosterone to dihy-) W* `- ~2 U; W- q1 G" s/ v" m
drotestosterone at this age. Conversely, serum levels in older
5 M3 [& f9 u7 H% ?# gpatients were higher, possibly because of decreased local0 y# c% D% {4 q# d
667% I* X! b/ T! x3 V
668 KLUGO AND CERNY
, ~6 P; l6 l1 ?8 h# x1 z- A1 BPt. Age8 \" V. f }! z# \+ L* [
(yrs.)
+ Q9 S2 d# M& v3 z7 ISerum Testosterone Phallus (cm.) Change Length: `7 J, e* k L# A; y
(ng./dl.) Girth x Length (%): H6 a1 A+ v$ `* y5 Q
44 t' p! s4 w8 M; G2 S, d4 O2 Z
8! r/ A b8 U' z( m
105 z" O1 L' J6 D2 s1 F" t0 M
12' ^7 k. q- s: [8 ~3 [
172 l% C e: Y8 K0 \3 H
Gonadotropin1 @% Q; W3 M% U9 N
71.6 2.0 X 3 16.6
2 O; K/ i5 U' @7 S1 t9 q50.4 4.0 X 5.0 20.0' ?! G6 C6 P7 x4 V* G9 Q
22.0 4.5 X 4.0 25.0
( D8 Q7 e& u9 ^: m K* L84.6 4.0 X 4.5 11.1$ `+ d; f5 I' h, V9 X- a
85.9 4.5 X 5.5 9.03 i7 ]9 d3 ]- g$ U
Av. 14.3% V- L$ w' l* J L4 R& I
4
0 v* b8 B& J5 k" Y* U% t. N$ X8
# N3 d: O& q$ g8 O10
8 d' r) [. g8 X$ Y" m. h7 u* k12
% w) H- @- ]5 W8 R% b17
' Y9 k9 i! r4 q' M: x7 C5 O4 kTopical testosterone
; e2 T* @$ |0 X9 v34.6 4.5 X 6.5 85
. f+ y4 Y5 |# q. ~! T1 S' H38.8 6.0 X 8.5 70+ }) c8 k8 _& O$ s- u2 @% m8 S
40.0 6.0 X 6.5 62.52 B5 W7 m+ E; X" f9 C& v
93.6 6.0 X 7.0 55.5
- N* E& m" H" p. u7 y2 [95.0 6.5 X 7.0 27.2! H. B- e5 _" \2 [
Av. 60.03 j6 y# z# J+ j7 @3 r0 Q
available testosterone. Again, emphasis should be placed on
& Y m% w' G9 l( F8 }) {early therapy when lower levels of testosterone appear to
& ^: d1 S/ N& _provide the best responses. The earlier therapy is instituted
- Y! O# [3 T* ?# g( l1 Rthe more likely there will be an excellent response with low
# R; i+ |1 H/ D5 u# u+ mserum levels. Response occurs throughout adolescence as8 U; f( s( q, y" D$ D
noted in nomograms of phallic growth. 7 The actual response- Z; N( b: r& t
to a given serum level of testosterone is much greater at birth' m5 M/ c2 M2 [+ v# p
and gradually decreases as boys reach puberty. This is most, |6 ?# W( H; U1 B% s: b
likely related to the conversion of testosterone to dihydrotes-
6 q/ R6 y# C& @$ {tosterone and correlates well with the studies of testosterone" D4 [% \6 y6 o) i' A2 z
conversion in foreskin at various ages.
0 l8 P+ b7 i1 v$ g- fThe question arises regarding early treatment as to whether
- t8 A, B& w3 o2 R' vone might sacrifice ultimate potential growth as with acceler-" x' Z" q( X7 |# ^; A9 _& H* s5 d
ated bone growth. The situation appears quite the reverse
" T7 c. e+ f! T# r; ]3 ]with phallic response. If the early growth period is not used
& K; k; u% h# ]) d7 @when 5a reductase activity is greatest then potential growth. F) J+ z" [" n3 t J
may be lost. We have not observed any regression of growth& s! @5 V$ t9 g3 }7 H; S9 j
attained with topical or gonadotropin therapy. It may well* W; _$ w f1 j
be that some patients will show little or no response to any
: | V% c+ [9 U. K9 G; U3 sform of therapy. This would suggest a defect in the ability to7 b3 W8 \; J' A3 J) H) T
convert testosterone to dihydrotestosterone and indicate that8 G6 y; S) v; L3 k+ U
phallic and peripheral skin, and subcutaneous tissue should2 A+ e+ y. m3 @5 G
be compared for 5a reductase activity.
" d5 C! j7 h% B% o8 b0 qA, loop enlarges to measure penile girth in millimeters. B,$ v8 B" {# h/ r
example of penile girth computed easily and accurately.
4 _# C W% d& j+ W6 F! |' Z; r, Nconversion of testosterone to dihydrotestosterone. It is in this
# O( s$ O* J5 C1 h. `- B1 M( wolder group that others have noted high levels of serum$ Y9 B7 p+ Z) [
testosterone with topical application. It would also appear
. V& c" E1 C" a! z$ b5 F; \0 tthat phallic response during puberty is related directly to the
( {& B( m& L6 `# Zserum testosterone level. There also is other evidence of local1 d7 S& o O+ Z4 d6 S
response to testosterone with hair growth and with spermato-
5 a' | c. g3 s% Q) y) ? Agenesis. 5• 6
4 A: d1 y9 Z0 e3 t0 c7 t+ [& RAdministration of larger doses of gonadotropin or systemic
- [( p4 t$ s! j. a5 `5 Ztestosterone, as well as topical applications that produce
/ w; l& h! T2 E3 t0 X% m4 jhigher levels of serum testosterone (150 to 900 ng./dl.), will; V. t7 i2 u3 R7 x
also produce phallic growth but risks accelerated skeletal/ S& U9 ^+ r |* t
maturation even after stopping treatment. It would appear
2 _7 V x) T( |; [- Rthat this may be avoided by topical applications of testosterone, s- F) s: ~, a2 n8 t
and monitoring of serum testosterone. Even with this control8 z6 U. j: K3 l* K3 G9 O/ B
the duration of our therapy did not exceed 3 weeks at any
: G* `" g4 b9 q! L& q- i% t( p7 Dtime. It is apparent that the prepuberal male subject may
9 }2 w+ \* U% `suffer accelerated bone growth with testosterone levels near' g5 ]% |8 Z, p# c- |" d1 H' \. k1 {
200 ng./dl. When skeletal maturation is complete the level of w0 C8 f$ D0 C) T8 E- |! F
serum testosterone can be maintained in the 700 to 1,300 ng./
7 [% o8 j' k# M @dl. range to stimulate phallic growth and secondary sexual5 G* N% n" c# x, I/ p
changes. Therefore, after skeletal maturation parenteral tes-* ^# E& J }6 J+ ?' Q$ v
tosterone may be used to advantage. Before skeletal matura-) H: q6 t& Y/ O, V2 I$ j
tion care must be taken to avoid maintaining levels of serum! E# `2 D; j3 z' e6 S
testosterone more than 100 ng./dl. Low-dose gonadotropin
! I7 }: a- R: s4 y: x6 xdepends upon intrinsic testicular activity and may require
, a# s% }% x5 R4 ~prolonged administration for any response., c. {2 ~% |- U/ [$ d1 [- I
Alternately, topical testosterone does not depend upon tes-
* ]. |; v3 x! M/ |6 mticular function and may provide a more constant level of- m5 a% N; X/ |# Q5 r* x6 h& W3 @' `
REFERENCES
9 c/ l8 v# `* e" b8 [1 b* V3 q0 h: Z1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; V+ n8 @. R6 zR.: The local application of testosterone cream to the prepub-( ~' R" I1 j- k1 _" m+ w
ertal phallus. J. Urol., 105: 905, 1971.
; h, a) f5 `2 H5 b( E/ I# X2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 ?$ Q* ]* h" m% F. Q7 \treatment for micropenis during early childhood. J. Pediat.,$ T$ _; D1 h8 X L; \
83: 247, 1973.$ j S8 ~, W b
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 c& P0 a9 Z& f% q* T! s: y4 f I
one therapy for penile growth. Urology, 6: 708, 1975.
$ h/ {: h: q$ K0 y4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& l5 w3 G( j7 y/ c6 x- i
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- v" H" F; v' N1 Z9 p+ P. o
skin slices of man. J. Clin. Invest., 48: 371, 1969.
; W$ @! N. ]" X$ r6 U' `, E7 ~9 j* O5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 a7 J1 t; ]- T# p6 }* ^by topical application of androgens. J.A.M.A., 191: 521, 1965.9 @: D# S" W7 F' C; m* }
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 x/ H& m+ P5 i( @
androgenic effect of interstitial cell tumor of the testis. J.7 V* H. C' @' ]: P$ v0 z9 A
Urol., 104: 774, 1970.
/ E2 H) s9 o1 B/ j+ H7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& w' p6 F0 B9 W/ \, ?" otion in the male genitalia from birth to maturity. J. Urol., 48: |
|