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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- K& A1 x9 Y+ R% F+ B5 U5 o+ w, N
GONADOTROPIN
' ]( y$ x1 Z; h. n+ v5 o3 zRICHARD C. KLUGO* AND JOSEPH C. CERNY$ m8 Y6 P2 [7 P- p2 f- i
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: ~; ~' r, x7 N2 b2 RABSTRACT4 H/ N. \8 x Z
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
; M" W0 L f% B* ?with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( m1 P& ~4 P! `% F4 Dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
6 \& z( G) x3 Y$ |! kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# ] F, {3 p2 e6 a! efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. k$ }2 k J/ |. e' V
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
# s+ }9 l7 B( I; qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
r5 H- L% t, @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This* C. j+ d& _" @3 O
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
9 a* D( J& l$ `4 M dgrowth. The response appears to be greater in younger children, which is consistent with previ-
/ E6 b$ ~" i. A- }. D& y6 Dously published studies of age-related 5 reductase activity.
6 T! v: r# C. a0 Y9 XChildren with microphallus regardless of its etiology will7 N) w# j5 T0 J. Y3 M' k
require augmentation or consideration for alteration of exter-/ {# v' q1 {3 n- V5 L% [
nal genitalia. In many instances urethroplasty for hypo-
) a+ r, ~) X# j/ m4 S* Q+ ~2 j! M( k# H! Nspadias is easier with previous stimulation of phallic growth.
, V F' v3 l4 a( x( x) FThe use of testosterone administered parenterally or topically2 f/ l; i; K; \
has produced effective phallic growth. 1- 3 The mechanism of: ?/ s+ s3 H; W( ~
response has been considered as local or systemic. With this; Y9 q( i! @6 L, y8 E5 l+ N
in mind we studied 5 children with microphallus for response
3 S) J% Z/ j# B, x( L( zto gonadotropin and to topical testosterone independently.5 k1 B' t! e4 r! z
MATERIALS AND METHODS
$ I0 Y, b# K6 L3 [' P' u( \Five 46 XY male subjects between 3 and 17 years old were
4 W) b" `) Z2 C' e2 N m- W* a7 Wevaluated for serum testosterone levels and hypothalamic
" \0 M- }1 |) t \function. Of these 5 boys 2 were considered to have Kallmann's) R; m+ X7 ~. d0 z# W, e. ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, y0 h; u- P* Q2 k/ h/ g
lamic deficiency. After evaluation of response to luteinizing
* j8 X/ ?* x) c( w% ?hormone-releasing hormone these patients were treated with7 l/ B- _$ \- p: ?
1,000 units of gonadotropin weekly for 3 weeks. Six weeks% `4 @3 Z4 p- `) I" Q, ^
after completion of gonadotropin therapy 10 per cent topical: l3 D1 H% h: z6 S2 W
testosterone was applied to the phallus twice daily for 3 weeks.
. e) z/ A- Y. z3 mSerum testosterone, luteinizing hormone and follicle-stimulat-/ ^" } t, m( t3 l
ing hormone were monitored before, during and after comple-
: g) M8 ] D4 gtion of each phase of therapy. Penile stretch length was
8 Q+ c4 _& S/ V( B3 Sobtained by measuring from the symphysis pubis to the tip of
( l: r( ?! Y- |) {% V: u! vthe glans. Penile circumferential (girth) measurements were
. l; }6 L C6 }) H; ^obtained using an orthopedic digital measuring device (see
4 y! r6 D# n1 L. d/ [figure).
1 [# C# x. j6 X& L" S: ?RESULTS. r! a. i8 y$ X
Serum testosterone increased moderately to levels between
; V$ P j3 M7 Y6 C3 p50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 K+ J& _) y8 f7 ~+ z( p. N* @
terone levels with topical testosterone remained near pre-/ ?2 p' F& O4 |0 C. ^
treatment levels (35 ng./dl.) or were elevated to similar levels
1 U N6 Y4 _* z" \2 o! w; _developed after gonadotropin therapy (96 ng./dl.). Higher
. A5 H# e \. U5 tserum levels were noted in older patients (12 and 17 years old),
6 I2 Z1 @, O3 b! x* k/ v* n$ T7 k2 Vwhile lower levels persisted in younger patients (4, 8, and 10
+ l3 v7 F% X: p* K, wyears old) (see table). Despite absence of profound alterations
* ^& e! G. m9 p. b- v: ^of serum testosterone the topical therapy provided a greater0 I- ~ [& E" H! p I" t
Accepted for publication July 1, 1977. ·2 a3 @( _+ _+ P3 n2 L
Read at annual meeting of American Urological Association,
! `- L7 i, H6 [Chicago, Illinois, April 24-28, 1977." A: h0 g9 d' x7 h+ U
* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 W+ d- ?' R6 x# m. `& ~2799 W. Grand Blvd., Detroit, Michigan 48202.5 @- G: C) ]( T
improvement in phallic growth compared to gonadotropin. E. B1 |1 ?4 p: L
Average phallic growth with gonadotropin was 14.3 per cent
) l1 }. ?8 h5 p+ p7 {& K3 Z6 C' y& [increase in length and 5.0 per cent increase of girth. Topical
1 G7 ?: [' K' z |* ]# K1 _testosterone produced a 60.0 per cent increase of phallic length
: a* n4 I! I# ]& B; @7 j5 L+ U; h" Qand 52.9 per cent increase of girth (circumference). The2 P- V, G& d& k$ \( t
response to topical testosterone was greatest in children be-* G5 B" }8 F0 E* p3 J$ ~
tween 4 and 8 years old, with a gradual decrease to age 17
! U" X( F; H% F# V7 Vyears (see table).# O, U/ p9 o6 H6 V
DISCUSSION& M2 X& M) r! J
Topical testosterone has been used effectively by other
% Q) p6 C$ [) w& h, e6 k+ oclinicians but its mode of action remains controversial. Im-
* C9 ^- e/ c, i+ e; b9 R) ]. F% t f7 Cmergut and associates reported an excellent growth response
2 g: V& ]5 t" f% z* _; \! H1 F1 zto topical testosterone with low levels of serum testosterone,9 s( _0 k N* y- k4 l {
suggesting a local effect.1 Others have obtained growth re-% T/ K; X/ S7 p- K: Z( f
sponse with high. levels of serum testosterone after topical: V( @+ B* X, t
administration, suggesting a systemic response. 3 The use of
+ ?2 e0 r6 r4 @ [gonadotropin to obtain levels of serum testosterone compara-- i# O/ G$ T. c' L
ble to levels obtained with topical testosterone would seem to, E- N1 k. n* S& e: A1 K
provide a means to compare the relative effectiveness of
8 R8 {3 ~5 e, e) H; Htopical testosterone to systemic testosterone effect. It cer-) D @; e9 X9 q- x, ~% x/ ^' S
tainly has been established that gonadotropin as well as par-, ~) ]! u3 S5 [. O3 @9 L0 t% e
enteral testosterone administration will produce genital0 ^5 N; x0 `6 S' N; O& `$ r
growth. Our report shows that the growth of the phallus was. a `, j; a9 }
significantly greater with topical applications than with go-9 _+ Z8 r$ k3 x$ _2 X% W p
nadotropin, particularly in children less than 10 years old.2 S i* i) Z; }
The levels of serum testosterone remained similar or lower
6 |0 F9 N+ U* Z& x% m9 v Dthan with gonadotropin during therapy, suggesting that topi-; }- j+ i3 s) v/ |' K( B
cal application produces genital growth by its local effect as+ e% ~& E- c6 X
well as its systemic effect.
: }. `% Q& _$ N/ q a" u) {- N3 aReview of our patients and their growth response related to
* N; D) N1 y( c3 U T; Tage shows a greater growth response at an earlier age. This is; D6 o5 E( \% W% D- O w: `, G
consistent with the findings of Wilson and Walker, who: f7 X; X0 x# j& i
reported an increased conversion of testosterone to dihydrotes-3 n! n) X. u( j! ]) G* g8 V+ L
tosterone in the foreskin of neonates and infants.4 This activ-% S0 y: q& ?: t4 s. h5 p6 B
ity gradually decreases with age until puberty when it ap-
! ]( L! N0 O" ?0 g9 Q5 D: i4 bproaches the same level of activity as peripheral skin. It may
* A4 ~0 z" \; A* Swell be that absorption of testosterone is less when applied at9 h' B# m; X- e% b e0 D5 |7 _
an earlier age as suggested by lower serum levels in children8 O+ p# o, y! p! i
less than 10 years old. This fact may be explained by the/ C" s! x( n+ s; `$ x
greater ability of phallic skin to convert testosterone to dihy-& v& m' `6 { F% p+ K4 c! b4 i# D
drotestosterone at this age. Conversely, serum levels in older, `& V0 O& [- m; {( G }# L* I
patients were higher, possibly because of decreased local
& ^; l b* h/ p% k! W! ]667
$ R3 f- b1 \( ^1 U" D# w7 n* t- w668 KLUGO AND CERNY
. t2 C. D! _) f$ D8 }2 zPt. Age5 l/ p- F( r _
(yrs.)
$ q/ E$ h4 \: U# L/ JSerum Testosterone Phallus (cm.) Change Length) a( z) @: D' C8 J1 I
(ng./dl.) Girth x Length (%)' E0 W* E% s: i v5 [2 e+ M
4
4 c. B$ r, L6 j: D ?8) S6 ^) \0 \8 O7 M
10! R; ?3 \( P- W% v
12
: B, v' g3 e) W8 P7 |+ Y' ^177 U* J" f$ g* |" [7 S
Gonadotropin
! A ~+ v( ~* s! n71.6 2.0 X 3 16.6
9 i9 Z2 y2 q2 |% Z6 A50.4 4.0 X 5.0 20.0# W9 b4 u/ G3 G! _8 e
22.0 4.5 X 4.0 25.0
4 `! d7 R! `9 `$ t3 j8 }84.6 4.0 X 4.5 11.1
: a9 }. _- {7 M8 r6 P5 l85.9 4.5 X 5.5 9.0( w. e% U; W1 t+ ?4 N
Av. 14.3
: u3 W% f$ k+ _( n4. _. ]8 j, h" t0 [5 q w! `0 u" S
8 l, B0 W/ \* |8 Q5 h, s
106 f$ c/ n2 o; `+ E% d5 }8 \
12
' O( U5 @+ y8 N2 n4 u17
" `$ b% }0 O* }: g& G" ATopical testosterone* y5 e6 g$ K# v: D2 l# ^
34.6 4.5 X 6.5 85
6 r" w& @9 @" l- r* O# W; e( D38.8 6.0 X 8.5 70
7 c' B) J- x% @2 R+ q+ |40.0 6.0 X 6.5 62.5
" V5 K; R ~7 e; R4 c0 R93.6 6.0 X 7.0 55.5$ t0 \4 d* I3 A* C% D- z; t- ^
95.0 6.5 X 7.0 27.2
' q: a5 ?0 V9 `/ J& q# o' G' g4 \Av. 60.0- |% b% J2 t" [# x P6 }$ }
available testosterone. Again, emphasis should be placed on
3 a! Q3 x' O o1 V- C$ I! }: {6 aearly therapy when lower levels of testosterone appear to* h1 _7 M5 o. _2 r8 t9 g* i
provide the best responses. The earlier therapy is instituted
( S& j t- h0 rthe more likely there will be an excellent response with low2 m, ^# z: U; h/ ^
serum levels. Response occurs throughout adolescence as; @4 G1 O9 P8 M5 {# q5 ~1 |0 u) [6 e
noted in nomograms of phallic growth. 7 The actual response
, Z9 \: Z3 Q0 F. R& X) Ato a given serum level of testosterone is much greater at birth, M( t" m: x& _, M8 k+ r4 t, w
and gradually decreases as boys reach puberty. This is most% r5 \4 |! O5 C7 o% H R2 ]
likely related to the conversion of testosterone to dihydrotes-$ |; ]; q' s5 p+ h2 E& D
tosterone and correlates well with the studies of testosterone3 r9 B9 r/ X* j2 d- ]
conversion in foreskin at various ages.; p# D, r* ~ X1 _$ z7 D
The question arises regarding early treatment as to whether
/ @8 ]" ~# c& z! p" v$ K( d4 done might sacrifice ultimate potential growth as with acceler-3 W* t ?4 b( t
ated bone growth. The situation appears quite the reverse$ Q" z* f% e* Z( n! @
with phallic response. If the early growth period is not used6 B& G4 s, w d0 }1 L* @" E4 D
when 5a reductase activity is greatest then potential growth
Q, g+ p, R" r6 u2 P+ Wmay be lost. We have not observed any regression of growth
8 B! w7 T6 g, fattained with topical or gonadotropin therapy. It may well
* |$ D8 T. b" q7 ~% Wbe that some patients will show little or no response to any6 K' V, q, p1 l0 Y6 l: x2 @! B
form of therapy. This would suggest a defect in the ability to) V; F- P0 T9 J3 R# }+ Q
convert testosterone to dihydrotestosterone and indicate that. s- y# d m0 }# [% m
phallic and peripheral skin, and subcutaneous tissue should1 T* R; {3 B* o2 Z# K. q2 U/ L+ T
be compared for 5a reductase activity.' X7 `+ f) W7 B/ o
A, loop enlarges to measure penile girth in millimeters. B,
" W/ _$ |9 \' Z0 Texample of penile girth computed easily and accurately.
. C; i: E5 I3 r5 c2 [% iconversion of testosterone to dihydrotestosterone. It is in this: f# P$ i, _/ Q
older group that others have noted high levels of serum9 P' g: Q+ K7 [6 w: L7 V: Z( Z
testosterone with topical application. It would also appear7 T7 T8 @" _5 n) \0 ?
that phallic response during puberty is related directly to the0 c; e4 C8 l7 ]4 t& b k
serum testosterone level. There also is other evidence of local" o! z7 T% [6 M* U
response to testosterone with hair growth and with spermato-
3 K* [5 a6 o) n) Rgenesis. 5• 6
9 E! r8 V2 D! ?1 B* M) }Administration of larger doses of gonadotropin or systemic
& N+ W( t7 R0 {/ P+ T( Vtestosterone, as well as topical applications that produce
- F( Q; Q8 W; }+ S }7 f1 Ghigher levels of serum testosterone (150 to 900 ng./dl.), will: n# M' j% g8 q' q, t# `1 D
also produce phallic growth but risks accelerated skeletal
9 }* ?: @# i- `3 R2 B# _; U" gmaturation even after stopping treatment. It would appear/ N6 [5 M+ o; K9 m! q' s
that this may be avoided by topical applications of testosterone
' ]- j4 }+ L8 \- {# I/ Kand monitoring of serum testosterone. Even with this control
* _2 d4 v1 J. Y: A5 G8 t9 pthe duration of our therapy did not exceed 3 weeks at any
& R: _1 x) m9 t" c! jtime. It is apparent that the prepuberal male subject may; O- J4 }! g# ^
suffer accelerated bone growth with testosterone levels near
# \, W- P ^+ B4 n( n6 W, }200 ng./dl. When skeletal maturation is complete the level of; n$ `+ c% Y( R. O; ~* X/ u
serum testosterone can be maintained in the 700 to 1,300 ng./! {5 g. L! K, e" `$ `% F( f3 V
dl. range to stimulate phallic growth and secondary sexual0 I' t0 i% j/ S% y3 s, J7 Z, ^6 J# F
changes. Therefore, after skeletal maturation parenteral tes-
' K8 g8 A1 n1 Q3 [6 `. \tosterone may be used to advantage. Before skeletal matura-
. s4 b9 ]; \, N/ ]8 F' n' J4 Mtion care must be taken to avoid maintaining levels of serum
; B) X) z/ r8 I0 utestosterone more than 100 ng./dl. Low-dose gonadotropin
8 j+ I1 V$ i Z' N3 F) U3 G0 g2 }depends upon intrinsic testicular activity and may require" _4 D/ g2 W" o4 w/ M$ E% a
prolonged administration for any response.4 ]7 ~# {9 _" m
Alternately, topical testosterone does not depend upon tes-( V( e" s, I2 b. o7 T8 ^
ticular function and may provide a more constant level of
7 m7 x7 `- p3 MREFERENCES( |* X3 @3 z2 v. p3 S/ ?" h
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 S1 {0 ^/ c; t7 f/ YR.: The local application of testosterone cream to the prepub-4 G4 L- H# `$ }
ertal phallus. J. Urol., 105: 905, 1971.
0 Y: p2 o! C6 D/ B* E# q9 X2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
/ h) o: v7 Y: Gtreatment for micropenis during early childhood. J. Pediat.,, r3 W! H$ d g. L' z2 K, D' E
83: 247, 1973.
2 D0 L# @- W: r* m; C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& ~2 o1 {2 K2 U, k+ i2 h w$ E& e
one therapy for penile growth. Urology, 6: 708, 1975.
3 p- ]8 M) g O3 ?1 L/ E. x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone3 Z% ?# G' A! w8 q* l9 r% X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 c/ N! Z5 `9 }$ Jskin slices of man. J. Clin. Invest., 48: 371, 1969.; w5 x E i7 B
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 Y# s, M: q1 ?by topical application of androgens. J.A.M.A., 191: 521, 1965.4 H+ a. p! J* {
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local( d% S! O; h! p. U1 [
androgenic effect of interstitial cell tumor of the testis. J.
3 [) T$ ~/ c1 a* QUrol., 104: 774, 1970.
! f* B. k; r5 O& ^) }( p( K0 O1 l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 V+ s+ t! A& ?7 | y3 q) u! etion in the male genitalia from birth to maturity. J. Urol., 48: |
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