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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
7 {/ c) l1 S$ LGONADOTROPIN7 ^( ^5 ^0 B: W# W
RICHARD C. KLUGO* AND JOSEPH C. CERNY, S. r: M' E# t% a
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan R1 d# ?0 Y* ]+ y* Q: C+ A
ABSTRACT4 G, J# @8 Q3 r% I# d
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 k9 C' S6 V& U' B: R3 ~6 M* o/ Nwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: f6 G' D5 r, M8 F
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone8 M1 `( }2 b3 s: _
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' h5 u" V, B: n7 |for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent# o1 ^4 `, I+ c* k
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 P- R7 N$ E( c& Z6 Tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 ^# i4 }0 p S) G
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ M7 M; A# D. K: J' L& @6 ]
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) ^4 S) G2 |) o6 kgrowth. The response appears to be greater in younger children, which is consistent with previ-& \' O, Y$ \/ i
ously published studies of age-related 5 reductase activity.
( c$ f5 H, }4 r2 O) @% [Children with microphallus regardless of its etiology will
4 @: I% O3 ^1 q6 Urequire augmentation or consideration for alteration of exter-
+ W, N7 B4 @, |# O0 j! Bnal genitalia. In many instances urethroplasty for hypo-* w4 U' H( b$ n8 W7 T
spadias is easier with previous stimulation of phallic growth.
. g. \8 D8 J% R( GThe use of testosterone administered parenterally or topically
9 h' \3 l# m! ^) D* Rhas produced effective phallic growth. 1- 3 The mechanism of) j7 O2 \. r- [* m. ~
response has been considered as local or systemic. With this) `& W. W) [1 p
in mind we studied 5 children with microphallus for response- P+ Y" ~& p7 P( f9 V5 c9 R/ D
to gonadotropin and to topical testosterone independently.
( M# m+ a8 {8 o4 ]$ c: U) `" FMATERIALS AND METHODS8 `% i7 x' }; `; x
Five 46 XY male subjects between 3 and 17 years old were
E/ ~& w3 c2 \3 F% H; vevaluated for serum testosterone levels and hypothalamic' v% j' E2 ]: Q( B, p) O, \
function. Of these 5 boys 2 were considered to have Kallmann's8 m) P: j- u4 J3 p
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
. {( N ^: k0 k' u, g- j) Blamic deficiency. After evaluation of response to luteinizing
# ?1 b0 L$ M# j% M" G' zhormone-releasing hormone these patients were treated with' ^ m8 i4 N2 \7 B$ ?3 Q$ | U5 x
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) w) m; g! y& ]7 w# A/ cafter completion of gonadotropin therapy 10 per cent topical
/ E: e; F I. t5 Y' gtestosterone was applied to the phallus twice daily for 3 weeks.( [! I5 H8 R R- B% i
Serum testosterone, luteinizing hormone and follicle-stimulat-6 T- A6 d7 l8 a
ing hormone were monitored before, during and after comple-+ V& `/ d# R0 Z6 T: |0 x) c
tion of each phase of therapy. Penile stretch length was
) r c2 k# ]9 I0 [. W/ oobtained by measuring from the symphysis pubis to the tip of, t; ]0 K7 u& A' K6 Y8 J
the glans. Penile circumferential (girth) measurements were
# U; z( u5 S! L+ k; Yobtained using an orthopedic digital measuring device (see
0 ]* Y( Q! R) u. |( R$ I" H! vfigure).
' g" }" g( u; a8 s2 c4 MRESULTS6 o5 ~) H) a- S9 N0 [
Serum testosterone increased moderately to levels between
8 B4 g, J0 t1 W# I! j50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-! I! D. [" C5 {" @1 Y9 B7 o
terone levels with topical testosterone remained near pre-/ s# ` b8 k s
treatment levels (35 ng./dl.) or were elevated to similar levels
0 Z; H; S% E. o" tdeveloped after gonadotropin therapy (96 ng./dl.). Higher& a, [8 \8 G/ Y' T
serum levels were noted in older patients (12 and 17 years old),3 w" |* \* P" J
while lower levels persisted in younger patients (4, 8, and 10
' B1 E' T. B/ X, e$ Uyears old) (see table). Despite absence of profound alterations
. p5 m, j; Q3 l+ M; w5 Fof serum testosterone the topical therapy provided a greater
- K% L8 s9 h+ D) P/ Y- nAccepted for publication July 1, 1977. ·
. A+ {! r( _2 |$ wRead at annual meeting of American Urological Association,9 I. k$ s+ g+ O( n4 d
Chicago, Illinois, April 24-28, 1977.0 h+ @+ x' S8 k: p- \7 Q8 y/ W4 {& Q/ @( m
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 e" n" b$ c7 h
2799 W. Grand Blvd., Detroit, Michigan 48202.
. _. w8 e S! \! r2 {- _9 o2 O8 `improvement in phallic growth compared to gonadotropin.+ C" r1 n T1 g7 T2 d9 r
Average phallic growth with gonadotropin was 14.3 per cent
$ ?4 m9 Z1 c$ G1 p: t3 x2 bincrease in length and 5.0 per cent increase of girth. Topical
. w/ Y% t, j. i! }. ytestosterone produced a 60.0 per cent increase of phallic length
4 ]5 M; E' K i. C" I/ Oand 52.9 per cent increase of girth (circumference). The6 ~% u1 C, j% h: W
response to topical testosterone was greatest in children be-- F) H; @5 a ^6 V$ k( q
tween 4 and 8 years old, with a gradual decrease to age 17' L! j* h& a9 m
years (see table).: X! I. n, [* h3 n8 Q- `
DISCUSSION
' P! C3 I9 A6 z [Topical testosterone has been used effectively by other. B, ^ S5 m2 g2 q3 }1 P/ k% E
clinicians but its mode of action remains controversial. Im-7 w, n! @ c; N4 q1 K* d
mergut and associates reported an excellent growth response6 ~9 I4 e( K9 f6 E
to topical testosterone with low levels of serum testosterone,% R% h4 G( E j4 l! m6 K1 O
suggesting a local effect.1 Others have obtained growth re-
* O+ U" n- z0 E) y7 p$ d- S- Jsponse with high. levels of serum testosterone after topical
n- V$ E* ]! F" G$ {administration, suggesting a systemic response. 3 The use of5 g- r, N0 ~$ D. X" d: V
gonadotropin to obtain levels of serum testosterone compara-; @ e7 S3 E! ^! O; }0 @
ble to levels obtained with topical testosterone would seem to5 C0 c: t H* {% e
provide a means to compare the relative effectiveness of5 ?% v5 Z! c3 n) i! G! ~
topical testosterone to systemic testosterone effect. It cer-) f7 }( X: E( f! K# H' ?$ J: Q
tainly has been established that gonadotropin as well as par-
& Z$ J' P! `$ N2 w5 l$ @4 z: Zenteral testosterone administration will produce genital
( H7 H( a* _& f6 k3 ?* agrowth. Our report shows that the growth of the phallus was5 l' J$ R% w, c
significantly greater with topical applications than with go-
$ C' a- ^! K/ H- Bnadotropin, particularly in children less than 10 years old.6 z8 I- h- H0 w4 ?5 u: ~! G
The levels of serum testosterone remained similar or lower
9 c, P. z8 V" Hthan with gonadotropin during therapy, suggesting that topi-8 b. T, q; z: d2 a7 G8 P; U
cal application produces genital growth by its local effect as/ K1 t$ y& C4 N. h2 b
well as its systemic effect.5 |% m' E& \7 @! O: P
Review of our patients and their growth response related to$ E. o3 w0 X7 V( ~8 I) I
age shows a greater growth response at an earlier age. This is
- G2 p2 B! \- Y: w" F0 Econsistent with the findings of Wilson and Walker, who5 I# O! G. s# W( V: h) u$ ]
reported an increased conversion of testosterone to dihydrotes-' P# Y) l8 n0 A5 B
tosterone in the foreskin of neonates and infants.4 This activ-5 G2 Y8 o% @$ `
ity gradually decreases with age until puberty when it ap-5 c2 ~& I) a0 T8 ]! _
proaches the same level of activity as peripheral skin. It may
& E1 x9 [1 w3 @/ kwell be that absorption of testosterone is less when applied at
1 L8 L. C, i1 ?3 x. }an earlier age as suggested by lower serum levels in children
! l" q1 [9 |4 O4 W% Xless than 10 years old. This fact may be explained by the& v v% D. B' n K6 Y7 q- Z. @
greater ability of phallic skin to convert testosterone to dihy-, H2 [* e% x _! Y
drotestosterone at this age. Conversely, serum levels in older" L( M! Z( W3 ` v
patients were higher, possibly because of decreased local2 P. o1 m5 V6 `) F+ d, }
667( Q5 ?6 {$ t' E- |
668 KLUGO AND CERNY4 q* X: w* X- q) T3 T
Pt. Age) U& o; e% d: j& R) O8 D7 Z1 `
(yrs.)
5 H. Z' t9 }, g4 A KSerum Testosterone Phallus (cm.) Change Length
% V0 Q, ]/ c: q' [! r- a u(ng./dl.) Girth x Length (%)
2 E3 K2 ^, t" R- [- L4
' r5 X& J" y( D8& o9 D7 ~1 {9 P0 H4 e) f
10
& l# z1 f4 ^. h2 u12
: U1 K( e3 }; A5 C1 q( \17
; H: B2 w# u; d4 T; ?Gonadotropin
3 ]/ O3 y+ R' E; I, w71.6 2.0 X 3 16.62 e+ C }! _# |* O! G
50.4 4.0 X 5.0 20.0! C9 A6 t" F, j7 z
22.0 4.5 X 4.0 25.0
4 l# D9 T0 J/ D84.6 4.0 X 4.5 11.11 ~7 o5 w" B C/ H( ?
85.9 4.5 X 5.5 9.06 l# r6 Z/ C9 q/ P# l% t, ]! I6 s
Av. 14.34 @6 Q- }4 ~6 m7 V
4" K- q ^! L+ O% [3 F; F+ Q
8
% I' P' V+ g! V- l; {/ }10
% g D8 h+ Y+ ]" z' J) ~12
; }; T0 \8 y# N% a17) M4 G, {# w$ c
Topical testosterone7 O! G( E& K+ {: ~- W `3 ~( R& o
34.6 4.5 X 6.5 85
# M8 B, o2 g+ [! t a3 j38.8 6.0 X 8.5 70
0 s" w& q2 B( k8 h( N0 v( a+ O' c40.0 6.0 X 6.5 62.53 x# o9 J8 i: z3 S
93.6 6.0 X 7.0 55.55 d9 P/ T; M1 n* {
95.0 6.5 X 7.0 27.2 s4 F5 N" M7 w! y' }) l- i6 H4 \
Av. 60.09 o0 B3 L' ]1 N6 K
available testosterone. Again, emphasis should be placed on$ m/ ]' T; O, i1 `, r3 P' Q$ e5 k
early therapy when lower levels of testosterone appear to! T" W' n1 }* l) U" e6 w( G5 [
provide the best responses. The earlier therapy is instituted8 ^9 \* n0 c; b- Z
the more likely there will be an excellent response with low' b3 @; q$ X- o8 d$ I/ b+ }
serum levels. Response occurs throughout adolescence as& A) W% I" T/ [) f; z* A5 W
noted in nomograms of phallic growth. 7 The actual response
! P/ N2 k) l" U, A2 M1 n- f. k- @to a given serum level of testosterone is much greater at birth/ j1 Y2 _& ^% d
and gradually decreases as boys reach puberty. This is most
: b& ]( ]9 }, h- ~3 y4 R0 @+ _( v0 qlikely related to the conversion of testosterone to dihydrotes-
4 w( Y. \9 c0 I: btosterone and correlates well with the studies of testosterone
0 D& @! g' m. B6 s7 zconversion in foreskin at various ages.
! M) d/ r& u+ K* P' P1 ^The question arises regarding early treatment as to whether
6 r! W; s3 b. G2 J6 cone might sacrifice ultimate potential growth as with acceler-( i6 ~- h8 r( S0 N" X1 y
ated bone growth. The situation appears quite the reverse
9 C2 i2 _: J0 {with phallic response. If the early growth period is not used
: Q" _( R2 ]+ J( k- q6 R6 `when 5a reductase activity is greatest then potential growth
( d8 h+ ^5 y- C w% Emay be lost. We have not observed any regression of growth
* D; I6 L; q2 J3 Eattained with topical or gonadotropin therapy. It may well
3 j5 g; W5 a( u, F- Wbe that some patients will show little or no response to any( `- b+ s+ m. X# k: P% P$ e- Y
form of therapy. This would suggest a defect in the ability to: A& A$ l% D" _/ [6 q- }, f1 q/ j
convert testosterone to dihydrotestosterone and indicate that, W% j7 p, c+ b2 R z9 S' U
phallic and peripheral skin, and subcutaneous tissue should
: s& V2 g6 Y6 F0 X8 k9 t7 D# n' j& O9 ebe compared for 5a reductase activity.$ A2 ]; E' \/ a4 ]1 ~1 Z
A, loop enlarges to measure penile girth in millimeters. B,
/ | ~. }9 r+ \; n Hexample of penile girth computed easily and accurately.
' c; M2 u, Q+ F, X! x0 Z# Q7 Hconversion of testosterone to dihydrotestosterone. It is in this- l {5 t* a1 f
older group that others have noted high levels of serum
0 _; `. D$ `( @: s' `$ Itestosterone with topical application. It would also appear; \/ g, h9 h; z1 n: P p, ?
that phallic response during puberty is related directly to the$ b3 x+ p* a3 l+ L
serum testosterone level. There also is other evidence of local
, \; Y- S8 u. ~1 Kresponse to testosterone with hair growth and with spermato-
6 l* W6 T. i3 ?) ?# Kgenesis. 5• 6# z. B9 Q" S+ t: J3 \$ z* Q( U
Administration of larger doses of gonadotropin or systemic
8 R D; w$ I w# u# Dtestosterone, as well as topical applications that produce
" }' s: z2 E0 {higher levels of serum testosterone (150 to 900 ng./dl.), will; C3 V( ?$ p" V6 d' {6 b
also produce phallic growth but risks accelerated skeletal; S* a' H( {' O2 }$ d" b+ C5 Y7 k
maturation even after stopping treatment. It would appear
* K z2 p1 L1 athat this may be avoided by topical applications of testosterone8 ]& N% y5 ]& {% [8 {# }& u
and monitoring of serum testosterone. Even with this control; n8 h: H/ M$ G5 E$ Z/ R
the duration of our therapy did not exceed 3 weeks at any% [" f2 \ [* }0 c# B4 |# s7 g
time. It is apparent that the prepuberal male subject may
4 M' `/ v1 z5 o: Y( ?' x1 Ysuffer accelerated bone growth with testosterone levels near0 F8 S: a5 E) D% g( L f: Z6 d
200 ng./dl. When skeletal maturation is complete the level of
& ]. o; a0 m4 j3 t9 T5 _8 sserum testosterone can be maintained in the 700 to 1,300 ng./
0 ^4 l/ B: @6 Z/ K% \# }; D, ldl. range to stimulate phallic growth and secondary sexual& J# E+ W$ g3 H, N8 W
changes. Therefore, after skeletal maturation parenteral tes-; l( X5 R- N5 a4 a
tosterone may be used to advantage. Before skeletal matura-$ n3 m/ ^) s0 X2 [4 t; @
tion care must be taken to avoid maintaining levels of serum
7 m$ p5 u$ [; Z1 O) R2 t+ Dtestosterone more than 100 ng./dl. Low-dose gonadotropin9 k2 |; H" W5 B. M) k6 i9 }
depends upon intrinsic testicular activity and may require, D* Q* i9 F0 L; v" R
prolonged administration for any response.' N O. m7 w& b1 a# D- L+ j6 R
Alternately, topical testosterone does not depend upon tes-$ D% A M H/ ~
ticular function and may provide a more constant level of E2 g7 P# p& j6 C8 o
REFERENCES
! `; p r1 M5 m/ D) M0 m3 V1 m1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
+ C; ^; H: X( p+ F, T kR.: The local application of testosterone cream to the prepub-
* \# |) {& ], v0 |ertal phallus. J. Urol., 105: 905, 1971.
. ?6 G& F9 {/ r* Z7 B( o* g: e2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' m! o0 S5 u1 F2 Y6 c' P
treatment for micropenis during early childhood. J. Pediat.,
( m, r; ^4 o" ]3 N8 w! I" y83: 247, 1973.
$ F/ @/ H. `1 p: o# v* I; A3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-+ Y6 `5 r8 o$ m) ?4 k1 P
one therapy for penile growth. Urology, 6: 708, 1975.
h" S# Q4 V2 Y- Y/ W0 H. ^" i# c0 |3 W4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone. t4 J0 g; f: ?
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ E; \- C* v+ E, A5 T! L& E
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 D1 I, B$ M* X0 r, n5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, ^7 I: y4 H/ e0 ^# ~by topical application of androgens. J.A.M.A., 191: 521, 1965.
: \* z" N/ k4 D+ m# @( Q4 Q6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local3 v! g6 m8 c. v( ~
androgenic effect of interstitial cell tumor of the testis. J.) m+ p. a: M2 ]: Q( p
Urol., 104: 774, 1970.6 D2 _; w# H+ g
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 G: D. n. }$ n, A6 y3 v1 wtion in the male genitalia from birth to maturity. J. Urol., 48: |
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