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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& T# R4 |# G! B8 ]0 e% Z
GONADOTROPIN
" x# e1 ~- X* e+ U- `8 `( CRICHARD C. KLUGO* AND JOSEPH C. CERNY- B2 N# D4 O, ^& Z$ Z- L) r
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 f7 m" z; @; y% t5 n: hABSTRACT5 R8 g& z, N) d( w# S
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
% _, c+ k- H% S9 D8 D4 ?. [3 cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-8 o) Q( _3 M& M1 `. h: ?% R
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 {9 e [0 V6 z Tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ F1 @1 y( G$ R j, M
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ e% d. T" e, c: I/ E2 Z# O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; H8 {, C) W3 v" z& L* fincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ `3 a) }6 ?- |& z
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, T3 |* M6 r& _9 g4 istudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 G3 o3 @( c+ l: w N5 G/ B! \8 v2 b
growth. The response appears to be greater in younger children, which is consistent with previ-4 ]& e O3 z# R. Z: p
ously published studies of age-related 5 reductase activity.
/ b( ~# A* C9 j: q6 s, EChildren with microphallus regardless of its etiology will
7 S& j; ^& @3 s- {4 Irequire augmentation or consideration for alteration of exter-* p" z5 R; P% X, d# p
nal genitalia. In many instances urethroplasty for hypo-$ R) F6 f* |& G8 J
spadias is easier with previous stimulation of phallic growth.
0 W4 p! Z; f8 ?2 n; \The use of testosterone administered parenterally or topically
! u3 T. y0 T* G9 f" d, Chas produced effective phallic growth. 1- 3 The mechanism of
6 t9 P5 ~, \* p/ T& jresponse has been considered as local or systemic. With this
h. N; t. q4 P0 `' `+ `in mind we studied 5 children with microphallus for response( ^. V7 u _+ o: [* Z% y0 s
to gonadotropin and to topical testosterone independently.: e; l& S8 @" E# v
MATERIALS AND METHODS
& Q+ }) O4 T3 O& s, Y8 BFive 46 XY male subjects between 3 and 17 years old were* B* b' V# L$ {+ [7 ]( s
evaluated for serum testosterone levels and hypothalamic
1 f* P1 C d/ f. Dfunction. Of these 5 boys 2 were considered to have Kallmann's# t# Y" _! S- ^4 N& F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' S7 z# e, H. c. V! m
lamic deficiency. After evaluation of response to luteinizing
" M! y# W4 n- g. Yhormone-releasing hormone these patients were treated with# Y3 w( R K" {
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ T+ P, i9 }1 _+ W/ l" r0 |) o# |
after completion of gonadotropin therapy 10 per cent topical# }1 ?6 E) [+ y4 Q/ J9 x
testosterone was applied to the phallus twice daily for 3 weeks./ z, ]( u# f# n( O4 ^) b
Serum testosterone, luteinizing hormone and follicle-stimulat-0 J6 q) n* z. m( g
ing hormone were monitored before, during and after comple-
) f4 ~$ H y' T5 ^( wtion of each phase of therapy. Penile stretch length was
' Y8 i- C8 [* {# m: C& H" Robtained by measuring from the symphysis pubis to the tip of
* {* K4 i5 R- A: w, jthe glans. Penile circumferential (girth) measurements were- K; W' ?6 [, J$ h6 U) L! X+ U& B# Q
obtained using an orthopedic digital measuring device (see; n& G/ h* a& a8 u; P
figure).
# a" h7 e# ]9 u& j% B$ V4 \, w% _( @1 dRESULTS
9 T1 E# r. j2 D7 w4 T; ^Serum testosterone increased moderately to levels between
2 Y% a* ?- c; S8 \7 Z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-' H4 o x( U$ p8 C
terone levels with topical testosterone remained near pre-
6 }- ~- ?. ^0 A6 w4 ytreatment levels (35 ng./dl.) or were elevated to similar levels
5 ~2 o8 V8 n1 @; W' Zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
) @1 X( I: D- vserum levels were noted in older patients (12 and 17 years old),
* Y5 ^2 k' ~3 M6 gwhile lower levels persisted in younger patients (4, 8, and 10
4 p6 X% r4 C, J+ I: Pyears old) (see table). Despite absence of profound alterations/ Y u$ D- s4 J+ S
of serum testosterone the topical therapy provided a greater
. m) i6 }) S0 _; N4 b( {Accepted for publication July 1, 1977. ·, I' Z% B, z% F. q$ Y; W4 w8 j
Read at annual meeting of American Urological Association,
% }9 J$ x) E F+ g# yChicago, Illinois, April 24-28, 1977.
% e! X0 [3 ], J. e& R5 a9 Z9 y+ y* Requests for reprints: Division of Urology, Henry Ford Hospital,- B" D, z6 Q2 i# A
2799 W. Grand Blvd., Detroit, Michigan 48202.0 _. ~; T6 P2 I+ P5 ]2 p9 n3 a
improvement in phallic growth compared to gonadotropin.! u+ x/ h6 s& D+ ^
Average phallic growth with gonadotropin was 14.3 per cent
0 X4 u- e! Y2 F" }) O" Q; yincrease in length and 5.0 per cent increase of girth. Topical0 p3 p1 t, i7 N; c- X
testosterone produced a 60.0 per cent increase of phallic length+ O0 ~( \8 Z' [9 F# D) \# A2 |
and 52.9 per cent increase of girth (circumference). The
1 s) u. x' [1 e yresponse to topical testosterone was greatest in children be-
* Q# {7 K) C$ Ftween 4 and 8 years old, with a gradual decrease to age 17% }% @' C' @1 }
years (see table).
; I9 d% Z+ B" C1 h8 s/ TDISCUSSION- w7 \$ B4 f9 q' Z; ]
Topical testosterone has been used effectively by other
$ e8 m( D7 B9 o; i% }clinicians but its mode of action remains controversial. Im-
# Q+ r( Q1 H) g: j$ Bmergut and associates reported an excellent growth response
" s l _ r% m. z4 M _: Qto topical testosterone with low levels of serum testosterone," r3 W. ~. P( a2 e" ~) a' T- s
suggesting a local effect.1 Others have obtained growth re-
9 H$ k# Q- T5 T% W6 p* \sponse with high. levels of serum testosterone after topical
2 D) L$ m/ N- M7 S. l7 ? Zadministration, suggesting a systemic response. 3 The use of
0 F. F! x. t; a! _: F2 |& M6 [; vgonadotropin to obtain levels of serum testosterone compara-0 |; f- P: D) u6 j/ L8 @ j
ble to levels obtained with topical testosterone would seem to
6 h/ i! h# D' b: Yprovide a means to compare the relative effectiveness of
1 Q6 u9 x. K/ c8 t8 Dtopical testosterone to systemic testosterone effect. It cer-
}" x$ T" W: O* Q" x& C0 u2 ~tainly has been established that gonadotropin as well as par-9 q. m- ~4 v8 A5 A m2 D& h0 {2 p
enteral testosterone administration will produce genital
) F) t @) _' C' h4 }: ]growth. Our report shows that the growth of the phallus was
8 `9 E: ?2 ?4 U* v9 `) H0 A0 Osignificantly greater with topical applications than with go-# W3 m. u5 y% A, [, T; m! X( H
nadotropin, particularly in children less than 10 years old.% h9 q. N0 ~% l$ y* g) B% A
The levels of serum testosterone remained similar or lower" d8 q5 E H: a5 Y
than with gonadotropin during therapy, suggesting that topi-; p4 q q$ w6 U- n
cal application produces genital growth by its local effect as \. O; m4 f- X6 C* m$ H6 r7 k. A
well as its systemic effect.
; ^. ? F" |& b! Y' h) n! ~$ x2 mReview of our patients and their growth response related to7 l g2 S8 F6 Q, s
age shows a greater growth response at an earlier age. This is
4 K3 R! g7 U! o \0 o! Aconsistent with the findings of Wilson and Walker, who+ ?5 C/ y( K" k8 H/ K! a
reported an increased conversion of testosterone to dihydrotes-8 C! \4 Y: S" [2 r# F j
tosterone in the foreskin of neonates and infants.4 This activ-9 v$ a- V: }- \, i9 Y
ity gradually decreases with age until puberty when it ap-
* P/ Q3 R7 t! f5 u: b- R) i' vproaches the same level of activity as peripheral skin. It may) X9 r. M$ K6 ]$ F
well be that absorption of testosterone is less when applied at
) i0 \1 x, m1 }; K; l+ l: man earlier age as suggested by lower serum levels in children
* `7 D0 r) ~5 ]: j9 iless than 10 years old. This fact may be explained by the/ c6 i" `. L3 v+ h
greater ability of phallic skin to convert testosterone to dihy-
+ Q: I! i2 x* Vdrotestosterone at this age. Conversely, serum levels in older) T- U+ Y" R$ r$ s) F7 _1 x5 B5 s
patients were higher, possibly because of decreased local
7 N$ W$ w: \# n8 l3 o667, }, r# z. z, e" b
668 KLUGO AND CERNY, W; I/ W, K# ?- n, }1 A) a
Pt. Age% x/ H7 t: H/ @: y
(yrs.)4 P% R+ z5 _( B- O* y4 E( V A$ o# d
Serum Testosterone Phallus (cm.) Change Length3 V: j! |, N$ ~' g
(ng./dl.) Girth x Length (%)
) W! @5 M% s9 @5 `( a47 B& A8 H! |* r; B- o
85 R* W& Q- e* T# k6 K! }
10% }3 [0 S7 W$ ?4 ?' o# Z1 J
12
, A5 o @& D) T8 S17- K8 c! U2 h% i. H2 D
Gonadotropin$ O. Y5 l8 m2 w0 T4 x+ ]
71.6 2.0 X 3 16.6
* k" `7 L1 S' t2 y" s50.4 4.0 X 5.0 20.0! Z' F5 ?3 u6 O7 ~& k6 c$ e* V8 f
22.0 4.5 X 4.0 25.0
" L3 Q, C f R; `& C7 F84.6 4.0 X 4.5 11.1! {) ]2 s* ]- D* {9 t
85.9 4.5 X 5.5 9.0
$ G, `0 U: n( ]" q& a, F7 aAv. 14.33 [1 C; n% l( C
4& V% W+ Q8 j# M: _+ G# Y" p
8
4 g. N/ T0 H, n6 s$ `6 g: @9 i1 d10
4 x9 D( o9 H3 Z& `# n1 T7 k12
, y- F: y) R r1 P17) m/ V: g& X6 x7 j1 L4 J
Topical testosterone3 _5 c \ y6 A5 e* T6 ^; \" p& y
34.6 4.5 X 6.5 85
% l9 ?, F" J$ M! @, y4 ?# `38.8 6.0 X 8.5 70
4 P* N, Q* U/ F( Q- q: f: g40.0 6.0 X 6.5 62.5; I, q o& |" }0 p
93.6 6.0 X 7.0 55.5! \+ n) i: F$ `6 k5 L+ o. M
95.0 6.5 X 7.0 27.27 x: a) u4 s, G6 @+ P/ W4 g2 i) l
Av. 60.0
/ {' {- V+ ] R# E( `2 qavailable testosterone. Again, emphasis should be placed on
+ B! i( w P j/ D: }# \early therapy when lower levels of testosterone appear to
" l" z# w( Q4 b% P& s- Cprovide the best responses. The earlier therapy is instituted
5 l) p$ S$ o* w- Fthe more likely there will be an excellent response with low
7 I8 b6 r$ j1 `6 a+ Xserum levels. Response occurs throughout adolescence as# z, u/ p, c. Z( I
noted in nomograms of phallic growth. 7 The actual response. i+ L& O$ w6 {
to a given serum level of testosterone is much greater at birth
4 x; m" I+ r; h7 x* b" Xand gradually decreases as boys reach puberty. This is most: U# J. k" c' p$ C
likely related to the conversion of testosterone to dihydrotes-
5 X7 ]8 ?4 |7 ?# N# g* mtosterone and correlates well with the studies of testosterone
6 ]: o) U. d3 _9 vconversion in foreskin at various ages.
1 s9 y$ c4 e5 uThe question arises regarding early treatment as to whether
; t; Y* R. V& S5 Oone might sacrifice ultimate potential growth as with acceler-
3 r; i# }4 K, n* vated bone growth. The situation appears quite the reverse6 ^0 p8 k( Z. F" A. y7 z
with phallic response. If the early growth period is not used
. H5 x8 k8 n0 v' t) o( `" k7 v! Qwhen 5a reductase activity is greatest then potential growth. f# K' Q, |6 `. @, p9 d
may be lost. We have not observed any regression of growth
) q# {# M) M- O- fattained with topical or gonadotropin therapy. It may well
3 P# }& Q9 t) j R' \" y5 Pbe that some patients will show little or no response to any: T- u( R v5 R: y1 Y
form of therapy. This would suggest a defect in the ability to5 G& W9 U, m" [6 w6 U3 L( Q( f
convert testosterone to dihydrotestosterone and indicate that
. ~: v, m/ S0 h- Q m- ?( J- L% J2 `phallic and peripheral skin, and subcutaneous tissue should4 z2 k* }; w9 n- E+ k
be compared for 5a reductase activity.9 p5 Q0 R" \# p# g- d9 P k% N
A, loop enlarges to measure penile girth in millimeters. B,# a- l s/ O$ e D
example of penile girth computed easily and accurately.' c, Q3 O4 M. `0 \4 P
conversion of testosterone to dihydrotestosterone. It is in this
3 S- T/ U/ Y H0 D/ m |older group that others have noted high levels of serum! K9 ^) g3 J/ X: X; ]2 D
testosterone with topical application. It would also appear
3 Y1 N$ Z4 L- rthat phallic response during puberty is related directly to the4 T; S2 ^1 u9 h$ L' J) z
serum testosterone level. There also is other evidence of local
+ Z6 \( w, w% f' X2 Dresponse to testosterone with hair growth and with spermato-0 |# Y0 J3 u; h( v
genesis. 5• 68 S+ @, p7 }3 u4 E1 i: o! y
Administration of larger doses of gonadotropin or systemic
5 h" L! I: K) N5 Y% z; ntestosterone, as well as topical applications that produce
6 }6 N" Y5 x& @2 P3 K9 {8 ~higher levels of serum testosterone (150 to 900 ng./dl.), will! E* I7 Y# r2 ^3 G- H& |/ B* B
also produce phallic growth but risks accelerated skeletal
$ f$ ]/ a) n. G6 xmaturation even after stopping treatment. It would appear* g6 t$ @- W5 R/ w; B
that this may be avoided by topical applications of testosterone
1 A" |9 ?/ U5 b2 G/ n$ }8 x' Kand monitoring of serum testosterone. Even with this control
3 ~0 ~0 `; d' j2 qthe duration of our therapy did not exceed 3 weeks at any
0 C6 C/ y/ J2 q- Y8 N3 Mtime. It is apparent that the prepuberal male subject may1 c8 G0 |' ~8 \) A0 j3 R8 |( W
suffer accelerated bone growth with testosterone levels near! F) E7 i. a" y2 \7 D$ g7 \; V7 w
200 ng./dl. When skeletal maturation is complete the level of$ }: U# i7 L8 e# T
serum testosterone can be maintained in the 700 to 1,300 ng./% V/ L1 T8 \5 b$ R& k. s# ]& I
dl. range to stimulate phallic growth and secondary sexual8 ?& K: O0 p& L2 k
changes. Therefore, after skeletal maturation parenteral tes-
" v8 F9 Z0 D4 S. ?0 A3 f+ etosterone may be used to advantage. Before skeletal matura-" {' x C5 S8 n8 \. u# \
tion care must be taken to avoid maintaining levels of serum
- H$ L# c; g9 Qtestosterone more than 100 ng./dl. Low-dose gonadotropin
; Q0 J" |) h1 cdepends upon intrinsic testicular activity and may require" w" D* t o! e$ Q
prolonged administration for any response.2 P- H! `( M- z9 |! m0 r
Alternately, topical testosterone does not depend upon tes-+ i4 E j9 K7 V/ ?' Y7 w; A4 U
ticular function and may provide a more constant level of3 L" ?! ]9 k4 w& g4 Y' m5 Q
REFERENCES
5 L1 y# D, e! v' C# _. N1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; k; W! L9 v) t E/ T1 H8 x
R.: The local application of testosterone cream to the prepub-
- u# q7 h9 u8 o1 X, Eertal phallus. J. Urol., 105: 905, 1971./ _& ?% Z( Q) Y% p8 L& j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) A" H4 T0 x0 xtreatment for micropenis during early childhood. J. Pediat.,' F' v" r; ]0 f/ J, \5 Y
83: 247, 1973.
- |1 ]# A1 v1 D3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' h. D8 A! v1 v6 |2 Z% _0 t1 ^
one therapy for penile growth. Urology, 6: 708, 1975.6 p# _* o7 [1 L5 c
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone6 s* o9 n/ W R; Y$ ?$ _6 [0 d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
; {6 H' S7 u! Z5 Pskin slices of man. J. Clin. Invest., 48: 371, 1969.
5 R: J5 o$ H) `: O0 e5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 l8 r( O \1 [+ `5 X3 o5 i# f
by topical application of androgens. J.A.M.A., 191: 521, 1965.% S& d2 b' e+ v& e5 |) q7 u
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: d/ Z& g5 d# d6 {1 X4 k+ m$ w
androgenic effect of interstitial cell tumor of the testis. J.
2 J5 I9 H( m8 z8 L& ~" ^Urol., 104: 774, 1970.
1 [: u I( U- l: a6 a$ B7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 B% r0 m5 [' r
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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