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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" N' Q+ Q2 k& j: b( y
GONADOTROPIN
3 |/ d: r" {9 @* x! P) @2 JRICHARD C. KLUGO* AND JOSEPH C. CERNY
9 z; L2 L" ]6 f0 V' P& J0 P1 U: cFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan6 {& t* j* J& H. W' e9 d/ e
ABSTRACT) l" V' E- S0 G7 Z* i
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' q F1 ? P1 G: N$ I5 A
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ R$ `/ X! m0 \+ a1 X
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 ^6 z `& ?# m2 a; v- h% t7 f6 V
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent1 n q; m, [" R" G- R
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 e$ l* U/ i. M" |) Z+ ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 j; _* ~5 p6 h7 M& P s) d# P" Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 c/ q3 l. c. D" g+ n) |6 hoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 Y2 ~: Z- p' v; p" s; ^( Estudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ W: s" u) F* n1 G6 Ugrowth. The response appears to be greater in younger children, which is consistent with previ-" J! v1 f+ v4 m4 w7 _
ously published studies of age-related 5 reductase activity.& d& U) `" O& b: k/ J
Children with microphallus regardless of its etiology will
( s1 F: f4 h' J# ?8 M7 Prequire augmentation or consideration for alteration of exter-1 h/ F5 l' z8 V
nal genitalia. In many instances urethroplasty for hypo-
0 V5 ^ b3 D4 f* o. k$ Yspadias is easier with previous stimulation of phallic growth.
F* T! W8 \4 V% H$ D0 wThe use of testosterone administered parenterally or topically
# h+ N% } D shas produced effective phallic growth. 1- 3 The mechanism of
4 r+ Y8 ^8 d5 b* Y# fresponse has been considered as local or systemic. With this
# \7 u- c) J. o+ X# G7 f: P1 ain mind we studied 5 children with microphallus for response3 h& O$ L& z" ]: f5 f9 I" j6 I" g
to gonadotropin and to topical testosterone independently.
( o' ]7 w7 t3 C0 i& R& H: g( PMATERIALS AND METHODS0 D7 R O: i7 [; ]9 p/ n
Five 46 XY male subjects between 3 and 17 years old were& ~% q4 _: S! h: t- C- @
evaluated for serum testosterone levels and hypothalamic
; [3 N# y: m- ]9 C6 E% L) P7 mfunction. Of these 5 boys 2 were considered to have Kallmann's
Y1 j/ L) M3 S& m, j9 Isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
1 [& j2 v) j- R: j! klamic deficiency. After evaluation of response to luteinizing' J$ ?. v' k8 ~6 x' L) t% @( r; ^4 f& T
hormone-releasing hormone these patients were treated with5 ]6 }+ @: f7 v, G
1,000 units of gonadotropin weekly for 3 weeks. Six weeks: t; @* B9 X! m) i
after completion of gonadotropin therapy 10 per cent topical
, d9 i# x) y: L1 Ztestosterone was applied to the phallus twice daily for 3 weeks.
0 t/ k! I, {( t* G ESerum testosterone, luteinizing hormone and follicle-stimulat-1 Z5 u- D) ~- ?) d+ ]& k; b$ \
ing hormone were monitored before, during and after comple-5 U! e; O( [5 K |
tion of each phase of therapy. Penile stretch length was
6 ]- G$ ]- j7 g h9 sobtained by measuring from the symphysis pubis to the tip of8 s% k0 C, ]- S0 D! n+ J
the glans. Penile circumferential (girth) measurements were* J) }' i! s, s. A
obtained using an orthopedic digital measuring device (see O: X5 O2 L2 I/ T4 i$ @, L
figure).7 V' M8 g/ O9 K9 b8 d5 d
RESULTS, F* h) s& S" b, l" Y, k1 }
Serum testosterone increased moderately to levels between$ K: z) x2 W% Z2 i: [3 g. v, m" V$ F
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
- B& W' l; v, X2 b* E" aterone levels with topical testosterone remained near pre-' h/ _, g# ? i4 \+ _+ x
treatment levels (35 ng./dl.) or were elevated to similar levels! o& y6 D! W! e% t* N
developed after gonadotropin therapy (96 ng./dl.). Higher
- ^" x2 e3 |0 U f! ~. userum levels were noted in older patients (12 and 17 years old),
4 w: l$ e6 K3 d& {% `! Hwhile lower levels persisted in younger patients (4, 8, and 10
$ a. E; m; w9 I: v7 N8 f, |0 {' [9 Myears old) (see table). Despite absence of profound alterations2 }( |4 ]' C- i
of serum testosterone the topical therapy provided a greater e. ^9 e5 u T/ U& S9 @) a4 U
Accepted for publication July 1, 1977. ·# k( {( e; T% @2 q3 L& S7 Z' u
Read at annual meeting of American Urological Association, A2 ~$ C4 e9 v3 Y* @3 U9 y
Chicago, Illinois, April 24-28, 1977.
; t: P4 H! A) k. ^, {5 I- ?" ]* Requests for reprints: Division of Urology, Henry Ford Hospital,; E* _$ q6 M: n
2799 W. Grand Blvd., Detroit, Michigan 48202.% u+ @. h( R3 h3 h
improvement in phallic growth compared to gonadotropin.
. O1 n) F! G7 B! EAverage phallic growth with gonadotropin was 14.3 per cent/ p) @1 ]. }- K
increase in length and 5.0 per cent increase of girth. Topical
$ d8 n8 p( p/ x( utestosterone produced a 60.0 per cent increase of phallic length
$ c2 b/ P* U: {& t; M& Q( [0 eand 52.9 per cent increase of girth (circumference). The
5 v, m6 ^: q5 eresponse to topical testosterone was greatest in children be-$ \" P0 Z/ S+ i
tween 4 and 8 years old, with a gradual decrease to age 17
8 |2 p: z. ~! ? ^2 l5 c$ Xyears (see table).- z. w4 u+ N: C G/ T& {
DISCUSSION# ]' } C2 @1 W" F# o; h# H( j
Topical testosterone has been used effectively by other
/ P7 I* {" X; C* k5 Oclinicians but its mode of action remains controversial. Im-' F x" m" l" ~3 S: p
mergut and associates reported an excellent growth response3 V% q, P, X" }! i# d3 j
to topical testosterone with low levels of serum testosterone,
8 {2 ]/ J, k+ e9 h4 nsuggesting a local effect.1 Others have obtained growth re-0 k ^- w0 n& ~" r E
sponse with high. levels of serum testosterone after topical7 Q) B. @7 F, d2 p1 l! e
administration, suggesting a systemic response. 3 The use of' S* \) E6 O4 f& }/ P2 Y+ S
gonadotropin to obtain levels of serum testosterone compara-
6 Y2 c% }5 d. h. W* m5 D. S+ W7 [. yble to levels obtained with topical testosterone would seem to
, Z6 F" m- j: j9 |4 N: b4 i9 ^provide a means to compare the relative effectiveness of# V0 w) Z' F1 Q* b0 C% j/ h
topical testosterone to systemic testosterone effect. It cer-( g i/ L/ i/ v: i* }$ c( T
tainly has been established that gonadotropin as well as par-. G4 _6 d4 i2 I4 z. N E' v/ e
enteral testosterone administration will produce genital. z3 v" Q8 A$ ~6 H% L% {
growth. Our report shows that the growth of the phallus was4 t% p$ F3 g$ _5 c" c- y
significantly greater with topical applications than with go-, ]% A+ e2 [7 _8 ~0 I& ^
nadotropin, particularly in children less than 10 years old.- }5 W2 _/ j; ?3 B+ n7 G6 D
The levels of serum testosterone remained similar or lower
' S* G# p: @ J5 _2 Jthan with gonadotropin during therapy, suggesting that topi-3 ~+ r- r$ C3 B
cal application produces genital growth by its local effect as
7 d- t. S" X, c8 z: L9 D ^2 [well as its systemic effect.
0 Y5 Q3 V9 o% C7 k' ^+ v# rReview of our patients and their growth response related to
/ i; }1 }. L" w! ~age shows a greater growth response at an earlier age. This is
: x. k5 P3 F5 `- t% m6 zconsistent with the findings of Wilson and Walker, who
, Q: A/ T+ X. F0 v4 |reported an increased conversion of testosterone to dihydrotes-
- i5 A4 U8 O+ w* jtosterone in the foreskin of neonates and infants.4 This activ-
/ m% f$ e% A5 Dity gradually decreases with age until puberty when it ap-
/ l6 a" u7 `6 Pproaches the same level of activity as peripheral skin. It may$ Z/ r. g5 ?" \" A% E9 ^
well be that absorption of testosterone is less when applied at
2 U# }( a! Z, }1 P( I2 zan earlier age as suggested by lower serum levels in children! U) d9 s: M; I7 J( O0 a
less than 10 years old. This fact may be explained by the& `5 q, w0 X9 D" C5 U3 C
greater ability of phallic skin to convert testosterone to dihy-" e) R3 x4 _- q# O2 t# d- p; d8 d
drotestosterone at this age. Conversely, serum levels in older
" J0 B5 o! M" `/ K8 Cpatients were higher, possibly because of decreased local
9 ~' K9 p- B; Z% D5 d. [) b667$ ?, K, u" B# c- x
668 KLUGO AND CERNY
' w( {0 B3 T: o! [8 \1 lPt. Age
0 i. W) r! P: Y# f1 f& \(yrs.)
0 f; D c- h% P& |& rSerum Testosterone Phallus (cm.) Change Length9 v/ z2 z4 w( V8 [8 O4 U- Q
(ng./dl.) Girth x Length (%)
+ n+ y/ [% B9 [& H% C6 u4- O% T) z$ ?, L
8$ }$ u% ~ f% w) m" {6 k7 H
10
/ A) p* x, M' H) B d12% T- R9 a! X: `' ?
179 v4 _! a1 K) G2 G0 B8 {% ~
Gonadotropin
i* }+ x$ N6 F: i# M71.6 2.0 X 3 16.6; ?* M3 e: Y; y; J4 ^4 e
50.4 4.0 X 5.0 20.0
# D2 c H- K) P- G" W( t4 X22.0 4.5 X 4.0 25.0
8 w: t8 m) p3 P5 W a( F84.6 4.0 X 4.5 11.1- X. B& I6 S8 H$ ~ F
85.9 4.5 X 5.5 9.0
! `8 ~/ }0 K* [5 g( VAv. 14.3# i3 @( B! G' ?1 ?: x
4
* I' T' V7 i: m8
% _/ x7 o+ W {6 z$ I6 l103 Y9 T g z8 g& z) S8 y
129 D: w3 C8 Q& n' ?; T. A0 U6 Y
17
' N& m" ^# |4 E- xTopical testosterone
) Z! g* g u/ n/ Q! `+ ?34.6 4.5 X 6.5 85
$ q3 g. M5 L/ E: ?) I8 ?' ~38.8 6.0 X 8.5 70
6 X6 C0 y! W4 i1 Z3 _- E40.0 6.0 X 6.5 62.5- F/ m f- h1 t5 ?0 t
93.6 6.0 X 7.0 55.5
! F t9 u: _9 j95.0 6.5 X 7.0 27.2
% ~+ Z" @2 l6 W5 t4 |' C; DAv. 60.08 C4 y$ d* I/ V5 P
available testosterone. Again, emphasis should be placed on; X& c& H6 K' `" H- v) @& C
early therapy when lower levels of testosterone appear to8 N; e% ]8 J1 [! ?
provide the best responses. The earlier therapy is instituted# |5 Q4 F. j* Z2 F3 m8 w8 k
the more likely there will be an excellent response with low
% e" L- ?# m- Jserum levels. Response occurs throughout adolescence as
% t9 d/ M* w; r8 x% [. H8 I5 _noted in nomograms of phallic growth. 7 The actual response, t& ?' q0 o) `
to a given serum level of testosterone is much greater at birth
+ O: i4 x$ |2 H) jand gradually decreases as boys reach puberty. This is most
E+ f( x* y+ G4 d4 Vlikely related to the conversion of testosterone to dihydrotes-% m x% p* A! x* A
tosterone and correlates well with the studies of testosterone
- B7 c7 I5 g# x( r- ~0 O, \conversion in foreskin at various ages.: X/ {" Y! \& B. ~4 L | f3 S
The question arises regarding early treatment as to whether
. a# M: X& {2 I; }one might sacrifice ultimate potential growth as with acceler-8 ?; {2 ^+ {; Z6 B+ n9 H' y* s
ated bone growth. The situation appears quite the reverse
6 ]5 | S/ U! Y1 h: _: \with phallic response. If the early growth period is not used
- e* i% [0 X$ v, zwhen 5a reductase activity is greatest then potential growth
$ D7 d ^4 c& ^9 u& Lmay be lost. We have not observed any regression of growth. V0 Q0 V/ M/ }4 g5 T0 Q3 G
attained with topical or gonadotropin therapy. It may well* f% e8 H) h* p: v3 U: f
be that some patients will show little or no response to any
/ f2 i8 G. o. c1 H3 i- yform of therapy. This would suggest a defect in the ability to
7 o, A& h2 A1 R) f% n# S) h2 Iconvert testosterone to dihydrotestosterone and indicate that, W& q3 g, |) W! U
phallic and peripheral skin, and subcutaneous tissue should8 w a& a& Y. v2 v1 i
be compared for 5a reductase activity.
8 O# O. x- ~9 S( v9 O0 D/ P2 bA, loop enlarges to measure penile girth in millimeters. B,: w5 X: @0 C& Z! n$ v' Q
example of penile girth computed easily and accurately.! M) Y Q6 N1 ]' t! U e$ S
conversion of testosterone to dihydrotestosterone. It is in this
8 ?! F' _' S$ C! iolder group that others have noted high levels of serum8 f# i& q' [2 R( D$ L4 M
testosterone with topical application. It would also appear- I% p1 H+ e- m ~6 l! z8 d# ^
that phallic response during puberty is related directly to the
! G1 m: @6 w0 s" y: O% Y" \serum testosterone level. There also is other evidence of local n6 C/ {1 R$ _! @6 A2 c! F
response to testosterone with hair growth and with spermato-
: g) R8 ~+ t3 @4 w) n( `& Cgenesis. 5• 6
+ D# h1 {- ]% V- h9 MAdministration of larger doses of gonadotropin or systemic
' h1 y9 L0 I( z9 `testosterone, as well as topical applications that produce$ C: i% F5 c5 r5 @
higher levels of serum testosterone (150 to 900 ng./dl.), will v6 \* |% N. ^& d
also produce phallic growth but risks accelerated skeletal
$ k" I' O. n4 L0 ?maturation even after stopping treatment. It would appear
% [8 a- ~% L. ithat this may be avoided by topical applications of testosterone/ e2 E5 ?/ \$ {) Z0 ^
and monitoring of serum testosterone. Even with this control: T0 J" Z- A7 w1 C, c5 t I
the duration of our therapy did not exceed 3 weeks at any
# V& d5 A# z3 \5 Vtime. It is apparent that the prepuberal male subject may8 A% t5 J/ Q' b4 d1 i
suffer accelerated bone growth with testosterone levels near
. k3 S6 w. E+ [9 c% h200 ng./dl. When skeletal maturation is complete the level of
& y p- A0 R* I5 E) u3 kserum testosterone can be maintained in the 700 to 1,300 ng./ P/ M) Y1 S2 E8 u
dl. range to stimulate phallic growth and secondary sexual3 _/ T6 r( V& I. c/ h
changes. Therefore, after skeletal maturation parenteral tes-
& b# N5 q3 s' o2 x/ Ttosterone may be used to advantage. Before skeletal matura-/ g, `( H5 g n; l8 E9 H! X5 @
tion care must be taken to avoid maintaining levels of serum+ `+ X$ Y5 y; ?: }
testosterone more than 100 ng./dl. Low-dose gonadotropin
1 X# l* Y, J" n& W# s) ^depends upon intrinsic testicular activity and may require
; u( G! o* u7 U) Y! I2 a/ \6 S$ ~prolonged administration for any response.( W7 z6 { y; r" w- S) w% U0 n3 \( y
Alternately, topical testosterone does not depend upon tes-5 ]( t9 }% B; I. L; o/ o
ticular function and may provide a more constant level of% B1 F& o: [6 h% Q: J7 s
REFERENCES3 Y" S! j7 A2 f& w& W
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, x; b2 A7 L' v% WR.: The local application of testosterone cream to the prepub-
! k8 r6 K& r: h. u+ Oertal phallus. J. Urol., 105: 905, 1971.3 |! S: u$ O, G* c# u
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( J9 G% `! I& o* m( w/ g! h5 `
treatment for micropenis during early childhood. J. Pediat.,. g+ n7 [4 I) p8 L6 v9 P
83: 247, 1973.
- F7 x4 A8 y a7 b1 o' v7 H3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-( v3 r& N/ V4 ]7 A5 k% ]
one therapy for penile growth. Urology, 6: 708, 1975.; j. C0 S% a G! N+ W$ G7 {8 ~8 ]
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone, k$ D+ i9 D S$ u- v- L# d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# e% ^; R# @1 }- m0 ~skin slices of man. J. Clin. Invest., 48: 371, 1969. Q; @! d! M( f) \7 N
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 w; |7 Z1 G3 o8 B+ |( i0 [8 }
by topical application of androgens. J.A.M.A., 191: 521, 1965.6 S0 D4 x/ g5 d! F
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 p x0 @5 ?6 ~/ o! S
androgenic effect of interstitial cell tumor of the testis. J.
$ n8 O8 a( p% x: h4 @" u: @Urol., 104: 774, 1970.
+ d' q7 o# ?6 }; n* R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 i5 E. u/ b- ~# `9 dtion in the male genitalia from birth to maturity. J. Urol., 48: |
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