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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 I! T1 `" b1 | @5 n* |* g1 j
GONADOTROPIN
* I3 {) t3 T' x! I" f f/ H; tRICHARD C. KLUGO* AND JOSEPH C. CERNY5 J3 ^- e: [& J
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 s( M! y, }5 t( f7 v7 a% [ s& JABSTRACT
4 t" K( I) G; B1 vFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 L" r* Q! P2 F0 \4 G2 c$ e
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-" k9 _5 d- a8 t: N! u& v8 k
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone8 }1 _( b5 n( ?; Y8 d
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 o$ Z" ]: r, q$ u7 [! r' z% U
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
O- n9 E% Z, b2 A$ G4 _increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 V) e7 R d; x' n+ w( R- Mincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# r$ R- Y; Z" A. Loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 E4 p3 p4 y' j; E
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 j) n( B" B6 w7 ngrowth. The response appears to be greater in younger children, which is consistent with previ-, u M7 J; o, Q7 B$ p u
ously published studies of age-related 5 reductase activity.
9 e5 d( C( L9 j3 F9 d. Z4 wChildren with microphallus regardless of its etiology will
' y+ `5 M. q' L6 \7 K2 Hrequire augmentation or consideration for alteration of exter-
6 l. y5 @6 ]) z2 v! snal genitalia. In many instances urethroplasty for hypo-
/ R$ U" i9 o% q$ C2 b8 Jspadias is easier with previous stimulation of phallic growth.0 s, B7 W+ t/ h$ D+ e$ a( D* ?
The use of testosterone administered parenterally or topically' W5 a) Z- g% a/ M7 R( a' Y0 Q8 ?
has produced effective phallic growth. 1- 3 The mechanism of0 |6 T& X/ @2 R- i$ T
response has been considered as local or systemic. With this$ f) F7 t% i/ F& ~2 R
in mind we studied 5 children with microphallus for response
& F! ]. q8 G6 wto gonadotropin and to topical testosterone independently.5 `, F$ v9 b0 o. w3 I, j
MATERIALS AND METHODS
1 _" L" @3 b: q8 g; i* K7 qFive 46 XY male subjects between 3 and 17 years old were/ _' j( I2 H- w
evaluated for serum testosterone levels and hypothalamic
4 l1 W; \- s, h8 g3 Afunction. Of these 5 boys 2 were considered to have Kallmann's+ U. [' e l$ \
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 h4 }+ i* Y- E1 M( n
lamic deficiency. After evaluation of response to luteinizing1 H0 ~0 i) X. \2 E
hormone-releasing hormone these patients were treated with$ \# h5 y2 J4 C; y
1,000 units of gonadotropin weekly for 3 weeks. Six weeks( N- \7 @& @! C/ i
after completion of gonadotropin therapy 10 per cent topical ^2 [! w( Z% L$ @ |; q
testosterone was applied to the phallus twice daily for 3 weeks.
4 F7 W: i: W4 O9 `/ [) N" ySerum testosterone, luteinizing hormone and follicle-stimulat- X) \6 R* O1 @* \+ V
ing hormone were monitored before, during and after comple-
! C H$ d1 X5 C6 }6 T/ G3 Ution of each phase of therapy. Penile stretch length was
* c4 j/ u- V0 l# L3 J5 Dobtained by measuring from the symphysis pubis to the tip of
) e4 T( C" f" n" G% x2 bthe glans. Penile circumferential (girth) measurements were( S q( W, C& R2 a7 M6 f# O T
obtained using an orthopedic digital measuring device (see+ B2 c: D2 q; @0 g2 I
figure).
) S- S5 p8 A: \6 |, p4 m* eRESULTS8 U; ]: j. x1 M) w0 K
Serum testosterone increased moderately to levels between
/ }( A3 B% W2 y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ [% u* l9 p% G
terone levels with topical testosterone remained near pre-) A. n3 l3 u3 f6 ?) ~5 z6 G
treatment levels (35 ng./dl.) or were elevated to similar levels
1 p# R+ O& _# L/ r$ Fdeveloped after gonadotropin therapy (96 ng./dl.). Higher
0 ^% f( y( G( G; \& Fserum levels were noted in older patients (12 and 17 years old),1 ?; i) [* q( X
while lower levels persisted in younger patients (4, 8, and 10
& P% z8 l3 n6 m% Tyears old) (see table). Despite absence of profound alterations
! z6 T. r3 d- O7 {+ H ^/ x. Oof serum testosterone the topical therapy provided a greater
. W7 K+ |8 v. m# i- {Accepted for publication July 1, 1977. ·% L( G9 b$ C" C" S
Read at annual meeting of American Urological Association,, e3 d' d- r5 z! T8 A
Chicago, Illinois, April 24-28, 1977.
1 {! G( Q6 p( P8 |$ p1 S* Requests for reprints: Division of Urology, Henry Ford Hospital,
{+ o' }0 y7 a( G) T, e* M2799 W. Grand Blvd., Detroit, Michigan 48202.& Q/ D4 n8 b$ K# F, H' ?
improvement in phallic growth compared to gonadotropin.
/ i! c! f j) g% D4 t' IAverage phallic growth with gonadotropin was 14.3 per cent
5 w) V' _4 f: f/ f2 I3 `increase in length and 5.0 per cent increase of girth. Topical
8 C/ p* S) W8 q9 jtestosterone produced a 60.0 per cent increase of phallic length
( @; p0 T5 m0 H6 k* i6 y! pand 52.9 per cent increase of girth (circumference). The
: R7 [$ J0 Z8 b8 G" y- }" S3 Vresponse to topical testosterone was greatest in children be-5 K. U* t; Z7 {
tween 4 and 8 years old, with a gradual decrease to age 17: B7 N/ L0 V: A ?
years (see table).
. P3 J& ~, A8 j7 FDISCUSSION+ z, `' a( q) H- z; |0 L/ }+ y
Topical testosterone has been used effectively by other+ Y$ s5 |0 c S( d
clinicians but its mode of action remains controversial. Im-
4 S: W" q3 D" i4 i- w5 hmergut and associates reported an excellent growth response
1 B& {+ i1 Q( i2 x! x$ }* f( i: f( gto topical testosterone with low levels of serum testosterone,
; Q% p' P) T7 L4 i* ]5 Usuggesting a local effect.1 Others have obtained growth re-5 j5 T1 n& P$ R6 P
sponse with high. levels of serum testosterone after topical
% X; ]" M2 K7 F, K" s) ]; Madministration, suggesting a systemic response. 3 The use of. m0 {* T# b# v% J! f g; b
gonadotropin to obtain levels of serum testosterone compara-) n# Y) U' ]" x
ble to levels obtained with topical testosterone would seem to
. G+ q7 F, j' z4 v4 P# Aprovide a means to compare the relative effectiveness of
% s" G# Z% q7 H5 u, Ftopical testosterone to systemic testosterone effect. It cer-
8 m6 f) Z9 e5 |tainly has been established that gonadotropin as well as par-/ k' E5 c9 _8 |( A
enteral testosterone administration will produce genital6 }* ?* j3 p& I6 |! |) O1 @. J
growth. Our report shows that the growth of the phallus was# a; S e: Y7 q3 n: S
significantly greater with topical applications than with go-2 u4 e( T& }: P7 q4 p
nadotropin, particularly in children less than 10 years old.
3 c: a1 H# y2 \4 nThe levels of serum testosterone remained similar or lower
( n0 F& I! `( k9 E. Bthan with gonadotropin during therapy, suggesting that topi-2 u& c+ M/ v# D3 z4 @9 Y
cal application produces genital growth by its local effect as
- i" E5 v1 g; Q9 s+ _) Pwell as its systemic effect.8 O$ _7 ]; S3 O8 M, u0 K9 Z3 F
Review of our patients and their growth response related to
0 H( z8 K# O4 H9 V8 Sage shows a greater growth response at an earlier age. This is) h* Z! g) ]4 J9 }% C
consistent with the findings of Wilson and Walker, who3 C: l8 j! p5 a9 s7 o* d; ?
reported an increased conversion of testosterone to dihydrotes-$ W) @( K# ?* O5 ^/ K, c
tosterone in the foreskin of neonates and infants.4 This activ- N+ i9 h0 D) J& T3 K
ity gradually decreases with age until puberty when it ap-+ v& R/ }0 s$ T0 }
proaches the same level of activity as peripheral skin. It may. f& \( ~8 z5 c; T A0 R
well be that absorption of testosterone is less when applied at
5 k5 n k# @: O* j. H0 ~9 U! pan earlier age as suggested by lower serum levels in children
f# M( Y! Q( T) U5 m2 t' F2 hless than 10 years old. This fact may be explained by the- o. W ~: I3 ] F
greater ability of phallic skin to convert testosterone to dihy-
6 V- F5 J3 m* d/ t2 v# ^drotestosterone at this age. Conversely, serum levels in older
; ]5 U" p) L. F" v& C& g: _& Ypatients were higher, possibly because of decreased local
" J# Q; J& _0 T2 S/ b' Q/ V667
, z; t- [% X8 |4 L$ Z668 KLUGO AND CERNY$ d9 c- y' ^- R% V: |4 }: X
Pt. Age
2 \, q8 }$ m# V1 [& l- \/ d' I- [(yrs.); Q0 A3 r- u, R
Serum Testosterone Phallus (cm.) Change Length
3 p; B0 D8 f& d; O* y7 z+ D(ng./dl.) Girth x Length (%)
* H# M+ z. F J4 m4 ]4
: x- h, H* T* a5 l4 U84 n* v6 Z, Y0 ^3 B! D
10, \ v( g5 p7 \
12
4 y+ `1 k5 n+ x0 P; _17+ T* q" n$ ]( M
Gonadotropin3 _* I G- K L! P
71.6 2.0 X 3 16.6% j2 _2 }( g, f$ w+ } ?
50.4 4.0 X 5.0 20.0% F2 |# w: ?; i( o! U1 Y
22.0 4.5 X 4.0 25.0
1 W% F! F% ?3 i$ _5 V84.6 4.0 X 4.5 11.1
7 o' o- _( }8 s5 i {85.9 4.5 X 5.5 9.0+ x3 r6 B: s/ q' j& v' l( S: f
Av. 14.3
: b7 P, q1 M& E! N# Q/ H3 Y4
# O0 G, e K' \! h" T( F7 |) S1 c" o85 d @4 G' O( l; J, _& x" p2 U# p
10
O/ x+ v8 ]' U3 s# ]( q12( `0 J' a* D% f
17
6 t: X( i; H& p# }Topical testosterone
- n2 T" s2 _( q$ E5 J34.6 4.5 X 6.5 853 m5 H+ j4 _2 U2 @* p
38.8 6.0 X 8.5 70
8 f' s `" v* ~, A# y! a40.0 6.0 X 6.5 62.5' z+ }! U3 _ Y) y
93.6 6.0 X 7.0 55.5
3 T J" B9 o. s95.0 6.5 X 7.0 27.2
4 C. F5 F; v6 QAv. 60.0. e/ W0 S8 A* W/ u/ \
available testosterone. Again, emphasis should be placed on9 z& i. W/ \/ [
early therapy when lower levels of testosterone appear to
. L; T: Z. ` O6 m- M6 Qprovide the best responses. The earlier therapy is instituted
. Q- K6 |0 F& W+ a. xthe more likely there will be an excellent response with low
- S7 ]* s6 P8 \7 A' q/ x, p, E- Jserum levels. Response occurs throughout adolescence as
& Y0 u% n+ c2 g- _) V/ ^) Wnoted in nomograms of phallic growth. 7 The actual response
5 O& Q5 M4 {. |9 w6 L6 xto a given serum level of testosterone is much greater at birth* s% \9 \: `+ a
and gradually decreases as boys reach puberty. This is most3 r: t( m; \, ]9 C4 c9 |* l! d
likely related to the conversion of testosterone to dihydrotes-
3 E' E8 n2 N& @# {: Vtosterone and correlates well with the studies of testosterone
& L$ w' z- G7 x6 dconversion in foreskin at various ages.
2 k! d% }2 a% F+ ]9 }The question arises regarding early treatment as to whether/ i8 K* S# s8 v3 V. o
one might sacrifice ultimate potential growth as with acceler-% j, e1 h: k- L
ated bone growth. The situation appears quite the reverse
& R; y9 Y" ~. f" X# Iwith phallic response. If the early growth period is not used2 ?; @& |/ t2 C9 V* R2 H" P
when 5a reductase activity is greatest then potential growth% q7 H! v9 S6 _+ c
may be lost. We have not observed any regression of growth
7 o; n. ]: H2 j& \9 n+ d B zattained with topical or gonadotropin therapy. It may well
4 m( j# b! k: n7 N' bbe that some patients will show little or no response to any
: }8 |" H/ b3 Q3 Jform of therapy. This would suggest a defect in the ability to I6 @' V: l; [5 }( }
convert testosterone to dihydrotestosterone and indicate that+ y" ?& e3 [* `0 i# I, A& v% P- H
phallic and peripheral skin, and subcutaneous tissue should# `0 v4 Y: c8 F; I o& G
be compared for 5a reductase activity.( Q$ K8 l% s: N3 g2 w) }2 S
A, loop enlarges to measure penile girth in millimeters. B,6 _& w9 ]3 N# }& y* c
example of penile girth computed easily and accurately.; r4 \" `, ]" Y5 c1 [# J
conversion of testosterone to dihydrotestosterone. It is in this
% W' m; I2 q3 Zolder group that others have noted high levels of serum
, F+ w) P5 I5 U$ f7 W* _$ `) btestosterone with topical application. It would also appear
9 g4 o* O2 i' g3 q) F' X" O: zthat phallic response during puberty is related directly to the& H2 s1 J! q' J* m. Z' R6 S
serum testosterone level. There also is other evidence of local* K N/ z% U) z8 g4 s4 f
response to testosterone with hair growth and with spermato-
/ ?! O1 d" Y' S% J. L& Rgenesis. 5• 6
; Y C- B- {. Q. zAdministration of larger doses of gonadotropin or systemic1 s# V( x8 w% ^. K! q9 }
testosterone, as well as topical applications that produce
. D* X+ r9 z& chigher levels of serum testosterone (150 to 900 ng./dl.), will
. e. ~% [& c) Q, J u. dalso produce phallic growth but risks accelerated skeletal8 n( j' Z( U" ^5 \
maturation even after stopping treatment. It would appear
% N( k( }' d) E" f, \that this may be avoided by topical applications of testosterone6 h* {% A1 s# g% `5 p; Z
and monitoring of serum testosterone. Even with this control& w7 S8 m$ }2 K. s0 W8 c5 l) h
the duration of our therapy did not exceed 3 weeks at any. C9 q4 C1 o' U5 V5 k8 N
time. It is apparent that the prepuberal male subject may/ z+ K, M9 H; b, `* s0 g) W2 ^
suffer accelerated bone growth with testosterone levels near$ V* h* q7 n5 c
200 ng./dl. When skeletal maturation is complete the level of, R% a4 F u; m" I9 S
serum testosterone can be maintained in the 700 to 1,300 ng./# {! `; Z. N7 x" S& _6 ?
dl. range to stimulate phallic growth and secondary sexual M7 p7 z2 v; f4 A w2 \
changes. Therefore, after skeletal maturation parenteral tes-# m/ p- L. r! p; g- c8 s
tosterone may be used to advantage. Before skeletal matura-
* W# p, N+ R @- U Q4 }: Wtion care must be taken to avoid maintaining levels of serum1 j- [: {$ J: R1 B8 Y3 e
testosterone more than 100 ng./dl. Low-dose gonadotropin4 X) U' L" `. W( c
depends upon intrinsic testicular activity and may require& B/ B! R. h, F7 [+ Z
prolonged administration for any response.1 o" L" _2 B' a( v& ~3 c; k! N! @
Alternately, topical testosterone does not depend upon tes-
, C) m; M2 ]5 I) {9 U8 Tticular function and may provide a more constant level of
: m# \5 a3 H7 G+ @; _) J% }REFERENCES0 n2 k+ w7 i9 [2 p N& Z3 U
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# H) D$ A) s$ r' @, W" g
R.: The local application of testosterone cream to the prepub-
/ q) t, [* N- Q- n8 ^7 \) uertal phallus. J. Urol., 105: 905, 1971.3 X6 C1 r; h5 f2 t" y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. h# W n Z! ^: W1 ^3 j) d% _3 [
treatment for micropenis during early childhood. J. Pediat.,- m3 C( c( R& p
83: 247, 1973.
5 E5 F6 ?' j T/ K) e3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ }- v* U; U$ P7 [( t
one therapy for penile growth. Urology, 6: 708, 1975.1 } T: a/ P" Z7 m
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& A) D: j7 w# h, ]+ C$ z. f3 Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by _7 D' S/ s* k* P( G% l6 J
skin slices of man. J. Clin. Invest., 48: 371, 1969.7 v* U8 k! o" Z# @- |$ Z2 d0 w
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
: \" f! y7 T5 s2 C3 [2 r# eby topical application of androgens. J.A.M.A., 191: 521, 1965.0 w; M4 E% r' O$ Y
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
7 O: w5 s, t0 w" Y7 J/ g3 ?androgenic effect of interstitial cell tumor of the testis. J.7 s/ j% L+ R; a. m: y
Urol., 104: 774, 1970.1 j2 T- l: M7 x
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; m/ D( G+ g0 f0 z4 ftion in the male genitalia from birth to maturity. J. Urol., 48: |
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