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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, k g9 T, h( t3 f0 j6 }* w
GONADOTROPIN r7 ~* G+ v; s' G0 {
RICHARD C. KLUGO* AND JOSEPH C. CERNY
- V; R3 [% l% C( _3 _1 SFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' x: k5 D% u1 n: ]5 V, l# X
ABSTRACT
1 s" C7 E, \2 Z) ], S( ~: {0 qFive patients were treated with gonadotropin and topical testosterone for micropenis associated' l( t/ d$ G0 Q8 D6 V- t! `
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 g/ D2 J- H* z4 Rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
& M# O0 C. E/ T0 \4 Z& Ncream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 t, ]( t" ?" m, H2 F1 q6 [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 \) j' f% n1 q" B& Z* ^
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 S5 b2 n) ?: Y4 m2 `% T0 ?
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; F1 U* i' v# m- k, E+ moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% }- J7 E* T* s. n8 Fstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 Q7 W T6 d" N. p& B9 ]9 Tgrowth. The response appears to be greater in younger children, which is consistent with previ-
7 m& U$ `$ f/ i+ g; P+ kously published studies of age-related 5 reductase activity.
S( B* ^+ }% M& X8 YChildren with microphallus regardless of its etiology will3 K0 Z' [/ G- l9 O, I$ ?$ z7 z# O9 D
require augmentation or consideration for alteration of exter-' l$ q: v3 s5 Z
nal genitalia. In many instances urethroplasty for hypo-
. x" H! p: G) t/ `spadias is easier with previous stimulation of phallic growth.
3 l# _* a* b& u6 K7 ?6 k, B) }The use of testosterone administered parenterally or topically
0 w- v; m5 |2 O8 i& B+ h, j- L) ohas produced effective phallic growth. 1- 3 The mechanism of- T8 I- Q: p+ l& P- v
response has been considered as local or systemic. With this
Y0 t. I2 {& s/ K4 g% a( ^in mind we studied 5 children with microphallus for response/ k2 G N4 c0 T; K5 X+ w
to gonadotropin and to topical testosterone independently.
7 ?' D$ X- n2 A! Q4 I rMATERIALS AND METHODS, k H' F( ~8 ~' X: b' p
Five 46 XY male subjects between 3 and 17 years old were
" T, ]2 X6 B: Eevaluated for serum testosterone levels and hypothalamic2 m `5 l G$ Z! h4 t
function. Of these 5 boys 2 were considered to have Kallmann's
4 I9 t2 b" l2 w1 s, z3 j% f" Y/ usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' M+ h( ]6 [8 L& h M5 `6 |
lamic deficiency. After evaluation of response to luteinizing
3 R" k: h' E5 U, }hormone-releasing hormone these patients were treated with
1 m' U" K3 @2 x# ^- x: D1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 Y4 b% C1 p3 x" L5 @& b
after completion of gonadotropin therapy 10 per cent topical
3 o$ Q3 t2 D1 K' a7 o: N; ~0 t( Jtestosterone was applied to the phallus twice daily for 3 weeks.
5 Y, _. N- k; n; V* d* ?Serum testosterone, luteinizing hormone and follicle-stimulat-4 M+ {3 L, y( f
ing hormone were monitored before, during and after comple- n6 y5 @7 |& W" }, _7 B0 @
tion of each phase of therapy. Penile stretch length was
1 Q, o% _( l M* Z" Z6 X2 |obtained by measuring from the symphysis pubis to the tip of
, I; L( G! x' h4 A' o+ S- Xthe glans. Penile circumferential (girth) measurements were
3 A- Y7 C) G Zobtained using an orthopedic digital measuring device (see. z5 U! e, {4 b2 c& r2 P
figure).
/ o3 H/ \. z) y2 F9 w3 DRESULTS
7 `* Y' {9 C1 m' G3 m6 F- uSerum testosterone increased moderately to levels between
0 E8 J4 m$ @( Y8 ^50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 G; f }) n4 g: y3 C2 \
terone levels with topical testosterone remained near pre-
1 x$ \# u$ Y& l' r# g9 A- }2 etreatment levels (35 ng./dl.) or were elevated to similar levels D9 w: O4 i+ O, x
developed after gonadotropin therapy (96 ng./dl.). Higher
( O3 p: N3 ~. Q/ @5 a$ wserum levels were noted in older patients (12 and 17 years old),
/ x1 t# d, Z* dwhile lower levels persisted in younger patients (4, 8, and 10
( y1 C) i: G1 Vyears old) (see table). Despite absence of profound alterations
( t, m( X2 G, r" ~of serum testosterone the topical therapy provided a greater% a3 y5 z, P% e+ Q
Accepted for publication July 1, 1977. ·
2 s6 T, D# @% l+ ?9 i* ~( o3 `1 DRead at annual meeting of American Urological Association,5 k1 @& ^+ g' H; D$ Q' ^
Chicago, Illinois, April 24-28, 1977., Z" g% m6 i9 l; `
* Requests for reprints: Division of Urology, Henry Ford Hospital,
( V6 B$ U5 j# S! ~$ V4 c' }2799 W. Grand Blvd., Detroit, Michigan 48202.
; c- _1 q" t, f" U5 nimprovement in phallic growth compared to gonadotropin.
9 `- X' O. s* M8 M. `6 R7 fAverage phallic growth with gonadotropin was 14.3 per cent
2 `9 T3 f9 m: _9 E! Fincrease in length and 5.0 per cent increase of girth. Topical+ i% v2 ], Q0 h9 c/ t
testosterone produced a 60.0 per cent increase of phallic length& j% r% M* ~, ^9 O$ A! S
and 52.9 per cent increase of girth (circumference). The) m$ D+ T* U( t1 J1 g! B- u
response to topical testosterone was greatest in children be-+ u. E3 E! K4 B4 d+ ^0 E' `4 n
tween 4 and 8 years old, with a gradual decrease to age 17
6 f& ^; W8 D' B j s* Vyears (see table).
4 } N4 o/ r1 ?" I% MDISCUSSION: `9 @5 ]7 l L% U5 p
Topical testosterone has been used effectively by other
7 v7 d, \; h) O- u* qclinicians but its mode of action remains controversial. Im-- n+ L2 w+ ]2 ~8 a6 @) {
mergut and associates reported an excellent growth response
5 M2 }9 Y$ K3 q1 A+ c5 Hto topical testosterone with low levels of serum testosterone,
|& K4 a+ ?$ B' ?5 k$ ~1 Hsuggesting a local effect.1 Others have obtained growth re-# _2 ~, q: Q& z$ J0 d9 k
sponse with high. levels of serum testosterone after topical5 I5 g$ c5 X+ v$ |9 f2 K. n- ?
administration, suggesting a systemic response. 3 The use of
- y/ b0 R" B F8 z1 i- pgonadotropin to obtain levels of serum testosterone compara-# g& h& ~! l6 y1 ~" ? x) Z
ble to levels obtained with topical testosterone would seem to
7 l( V8 \& e- a, H" p1 U2 ?) Cprovide a means to compare the relative effectiveness of
" N5 r5 T( c, r7 Btopical testosterone to systemic testosterone effect. It cer-
y; z6 i. x Z6 ptainly has been established that gonadotropin as well as par-
d7 \$ A7 [" z, H/ Ienteral testosterone administration will produce genital
, v$ \8 f3 I# u) Igrowth. Our report shows that the growth of the phallus was* _) c0 P: M( p4 W
significantly greater with topical applications than with go-
' k9 _) Y5 n( @7 A. C6 z5 e. \nadotropin, particularly in children less than 10 years old.9 U, k ]1 b! }4 l5 v% s
The levels of serum testosterone remained similar or lower
. J2 D/ U P! C# F% r. z6 Kthan with gonadotropin during therapy, suggesting that topi-, }& U$ }( c. T7 Y4 g% l/ j
cal application produces genital growth by its local effect as8 s5 o' |. m) o- {
well as its systemic effect.
3 H% V7 _! m& o. P, c; fReview of our patients and their growth response related to
7 R& r; N; ^6 \: V; ^* aage shows a greater growth response at an earlier age. This is, N# C) N3 p8 J6 X& z
consistent with the findings of Wilson and Walker, who
4 i! K0 U' p5 |: x1 @reported an increased conversion of testosterone to dihydrotes-
' T! y! c' [( Rtosterone in the foreskin of neonates and infants.4 This activ-
" R5 |/ [- \& v& bity gradually decreases with age until puberty when it ap-, n1 z3 t+ T' i8 U( u
proaches the same level of activity as peripheral skin. It may8 w/ @& Q4 M' {8 g
well be that absorption of testosterone is less when applied at
: i# S7 l. Z; K6 }# o$ ^3 Ean earlier age as suggested by lower serum levels in children
$ q+ h0 u% e8 zless than 10 years old. This fact may be explained by the
' y J0 e; r! Qgreater ability of phallic skin to convert testosterone to dihy-. U. O1 a l' D( E
drotestosterone at this age. Conversely, serum levels in older6 N9 |; b/ u. ~; g" @6 q) ?
patients were higher, possibly because of decreased local1 a1 c% T# e- J& \3 ?4 A
667
. H" r+ p$ j1 O/ ^2 f0 m0 h) z668 KLUGO AND CERNY! @& A) h' j: r+ e W: w2 |
Pt. Age
7 l1 F- w5 {5 a& [' c4 T D1 j' Q(yrs.)
& B+ \; [* a2 i1 i3 m) V! DSerum Testosterone Phallus (cm.) Change Length" D$ D8 {5 Q5 m/ E
(ng./dl.) Girth x Length (%)/ |1 G0 q& D: |
4
3 c( ?" X" J# F A6 b& {' z+ {" i4 n89 o! h& N, q) M
10
1 y% N$ n F# Z( o- Z12" ]1 v# a. y; z8 n- k1 @) ~8 |
17
2 U1 @/ y- f3 h. A: h. q* R) YGonadotropin
# U1 B* m2 `5 L71.6 2.0 X 3 16.6
7 r9 P- v) j5 u50.4 4.0 X 5.0 20.0
$ _; W! R U r22.0 4.5 X 4.0 25.0
, O! e+ w, ]+ f& ]84.6 4.0 X 4.5 11.1
& w9 k l7 j2 e- l9 }( t# V85.9 4.5 X 5.5 9.0
3 g m1 E# ^2 z& d! G, e) T, QAv. 14.3
# W R! k8 x' B8 u* `4
$ t+ H' k( P" F8
9 e- X$ T. _7 z2 W) d4 k# w2 S* z10# j8 r# ]- b, O
12( p& r/ Q" F" O R
17/ {- l& [0 ~$ {0 n- y
Topical testosterone
3 s6 L0 C, z: z3 U0 C34.6 4.5 X 6.5 85- ~3 X S3 V6 z+ ?) L W a' Y/ o/ K; ?; G
38.8 6.0 X 8.5 70: D+ }$ n6 k/ c/ W% _/ x8 h
40.0 6.0 X 6.5 62.5
9 N7 }* Q6 z0 h5 Y; Q93.6 6.0 X 7.0 55.5
9 h% a& W& k% p6 ]9 V95.0 6.5 X 7.0 27.24 x8 j( {; ~& j6 @3 e1 t; r `
Av. 60.0
6 G# u& z" I8 p, p, ~0 B8 M9 wavailable testosterone. Again, emphasis should be placed on
4 y' z; s0 t+ m. A# _+ K# [early therapy when lower levels of testosterone appear to9 t: m# g# P9 `* v0 R
provide the best responses. The earlier therapy is instituted7 ?. v* j- h* M* Q- N
the more likely there will be an excellent response with low
% S u0 d1 `" W) j5 x, l, gserum levels. Response occurs throughout adolescence as( o% _0 r g r3 t8 \# f
noted in nomograms of phallic growth. 7 The actual response
$ F7 }. f* t4 m' Mto a given serum level of testosterone is much greater at birth
. ^) [* b6 ~0 B+ E; jand gradually decreases as boys reach puberty. This is most
9 r! L# Q5 F$ ]1 e5 k2 i* k- ]9 plikely related to the conversion of testosterone to dihydrotes-
. S4 ^- q6 M! Utosterone and correlates well with the studies of testosterone( X' @" ~: [2 g! ]
conversion in foreskin at various ages.
# Z9 E( g9 y% H& _1 M, D2 _% Z" m yThe question arises regarding early treatment as to whether1 P$ G3 L( g5 E, e
one might sacrifice ultimate potential growth as with acceler-( d8 Z0 J! {! H" w
ated bone growth. The situation appears quite the reverse: T6 u" a0 Q( _3 H5 A
with phallic response. If the early growth period is not used3 h9 a; |3 M5 i# u7 K& Y3 h, C; u
when 5a reductase activity is greatest then potential growth& z* {+ N5 e$ A4 Z! v, a6 n
may be lost. We have not observed any regression of growth
- `4 Z/ c, M# zattained with topical or gonadotropin therapy. It may well
1 G; C, ?) @; f4 B( D, qbe that some patients will show little or no response to any) Q/ F# H4 f, w; A
form of therapy. This would suggest a defect in the ability to
7 _$ s) l* g- r3 bconvert testosterone to dihydrotestosterone and indicate that
! @9 m5 n4 b7 I1 ~: Jphallic and peripheral skin, and subcutaneous tissue should
6 p; \) X4 D" _. A4 T, @be compared for 5a reductase activity.; f& d% J7 b* U: p, X4 ~
A, loop enlarges to measure penile girth in millimeters. B,
. t+ J5 k% _" k2 s( G& B! kexample of penile girth computed easily and accurately.
* @( o$ C( c; Z1 K1 {conversion of testosterone to dihydrotestosterone. It is in this" v% m/ A O w* O/ {4 v- h
older group that others have noted high levels of serum, p J: P7 ]3 V& z/ s
testosterone with topical application. It would also appear
1 @' n2 ~1 P- vthat phallic response during puberty is related directly to the
" x7 M# W3 o5 Dserum testosterone level. There also is other evidence of local' c7 I( z a4 y) O
response to testosterone with hair growth and with spermato-
& T3 q+ |+ J7 h2 T; V0 Qgenesis. 5• 6 E$ t. x+ x' R9 D3 a7 v
Administration of larger doses of gonadotropin or systemic2 ]+ t O4 @' R" k2 S. H5 o
testosterone, as well as topical applications that produce, P5 T( m3 }. V i% E8 x" y
higher levels of serum testosterone (150 to 900 ng./dl.), will) s K5 v8 L5 q' ~8 M
also produce phallic growth but risks accelerated skeletal- {- ?: N5 I0 V& W
maturation even after stopping treatment. It would appear
9 x5 |& ^' ]2 {1 M+ _/ gthat this may be avoided by topical applications of testosterone2 B7 @4 C( x1 [$ W/ j
and monitoring of serum testosterone. Even with this control
, n7 u' z& g& q1 tthe duration of our therapy did not exceed 3 weeks at any8 x% m ~! i# h5 X# V; M4 ]
time. It is apparent that the prepuberal male subject may) o: J# Y- M0 v N' W! ]
suffer accelerated bone growth with testosterone levels near
" d3 p1 L' h' L- n200 ng./dl. When skeletal maturation is complete the level of$ [* N9 v# u; S
serum testosterone can be maintained in the 700 to 1,300 ng./: i: O5 w6 [3 l) M0 u4 ~
dl. range to stimulate phallic growth and secondary sexual
' L8 d- q+ R0 S/ m, \( o1 \- b' ~changes. Therefore, after skeletal maturation parenteral tes-
. W. U; D# ]! d& ktosterone may be used to advantage. Before skeletal matura-
( R% o4 z$ N. A9 w: Xtion care must be taken to avoid maintaining levels of serum$ q: i) x3 ^; G9 u2 \; h
testosterone more than 100 ng./dl. Low-dose gonadotropin
6 M5 s2 J: L! Y5 @depends upon intrinsic testicular activity and may require
# r. I* C* j7 k. Q6 t7 eprolonged administration for any response.
4 y: r: [! |9 w3 NAlternately, topical testosterone does not depend upon tes-
$ t5 c# D$ W8 m; _4 e! U" _! uticular function and may provide a more constant level of4 o2 M5 @$ k1 g; ~) x/ j" Y( z
REFERENCES- S7 Y Z6 l8 A# S, s. `. m0 ~5 a
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,' o5 ?' F6 c. y a
R.: The local application of testosterone cream to the prepub-4 x/ b. h+ J4 I( H1 p
ertal phallus. J. Urol., 105: 905, 1971.% Z) B. x3 V' W6 ^) l, G' F
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% }! }3 I3 I) ]0 y
treatment for micropenis during early childhood. J. Pediat.,/ g' U. t& g" J4 f, @! |
83: 247, 1973.8 ^. h4 @0 }2 z4 G/ T
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 F; c6 K: `* }- F
one therapy for penile growth. Urology, 6: 708, 1975.
+ z8 P$ ~4 B+ }" ]6 \1 B8 U4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone* e3 x. a9 D# m0 r/ J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* o% U8 w; e, z/ Q$ O
skin slices of man. J. Clin. Invest., 48: 371, 1969.5 M& o$ B7 s3 l0 x4 z
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 k* A4 U# T% i0 W. c: Tby topical application of androgens. J.A.M.A., 191: 521, 1965.
1 L5 `2 w6 n: U5 W! s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
' l8 {1 K& e+ g, s; \& |' }androgenic effect of interstitial cell tumor of the testis. J.2 |% o' |7 {9 k: P5 t
Urol., 104: 774, 1970.- Y5 ]. w4 l% H8 G
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
# g- k( \3 H/ S2 L+ j: E) I' Otion in the male genitalia from birth to maturity. J. Urol., 48: |
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