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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 ?8 u! \/ B9 r" q5 e7 O9 m* b
GONADOTROPIN6 W# U- `: h. i
RICHARD C. KLUGO* AND JOSEPH C. CERNY
( O8 Z6 u/ O- P2 R2 `From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 b8 j9 F; L s1 a7 U& E$ T
ABSTRACT
' f! Y8 K$ c6 V+ ^' L: C2 TFive patients were treated with gonadotropin and topical testosterone for micropenis associated
1 s! G3 ~2 F: f0 |7 Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: E- x$ ?& e( w" ]
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 h3 h* U. m! o2 N' y% G9 R& Ucream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* f! w) d1 o' O Hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 k8 Y! ` p5 h Q: P
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, h+ B9 q" S' w* dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
U* M/ X3 O v# T+ G! w, w2 Soccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( H+ F! u& Z/ j: y6 V, K/ xstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; ~% Y* q m* U P, P% R4 x4 ugrowth. The response appears to be greater in younger children, which is consistent with previ-
5 i$ j8 A4 h& D& X; T( C$ A1 Oously published studies of age-related 5 reductase activity." ~5 E$ @- L( y9 v k1 E% U' s
Children with microphallus regardless of its etiology will
! I5 p: M1 z. [) e0 A1 z- frequire augmentation or consideration for alteration of exter-4 d0 w) C1 S! ?8 ~! w
nal genitalia. In many instances urethroplasty for hypo-
8 h! x. {2 U- l2 w3 S) Tspadias is easier with previous stimulation of phallic growth.' X6 Q* l! I2 V4 z
The use of testosterone administered parenterally or topically$ L* \& `# s) h) i; B: H
has produced effective phallic growth. 1- 3 The mechanism of
& r/ e1 m! V9 M! @: Y7 E2 I. y1 x% e" {response has been considered as local or systemic. With this
0 |+ j- r! Q# d3 i" A% E1 u* ]in mind we studied 5 children with microphallus for response9 x5 I2 b# A) Y7 D* u/ A
to gonadotropin and to topical testosterone independently.8 m9 L k, X5 h0 f3 \3 d, e' |
MATERIALS AND METHODS3 ?( p) [1 b' S0 t' O Z1 C
Five 46 XY male subjects between 3 and 17 years old were
/ T! H0 T6 E/ v- Revaluated for serum testosterone levels and hypothalamic
% M1 C- k* o8 Q) U4 afunction. Of these 5 boys 2 were considered to have Kallmann's% J1 {$ g, y' H4 i
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" I# G0 \; R: Plamic deficiency. After evaluation of response to luteinizing1 q9 J$ Y! n+ x. s% X! e8 ?
hormone-releasing hormone these patients were treated with' k! o" N! j# N: ]0 ?# i, W
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ e; N4 v: @7 N% N6 T; E/ k
after completion of gonadotropin therapy 10 per cent topical
: \* d1 Y& g- Itestosterone was applied to the phallus twice daily for 3 weeks.
% o/ t' }6 ^* o! Y9 c$ iSerum testosterone, luteinizing hormone and follicle-stimulat-" K) ^/ X/ ?- @) l0 H
ing hormone were monitored before, during and after comple-9 \ G6 Z: a5 B: v8 D' s
tion of each phase of therapy. Penile stretch length was5 \& a! E* D7 Q2 l; |
obtained by measuring from the symphysis pubis to the tip of
3 ~! }: f$ i- H& U9 J# Hthe glans. Penile circumferential (girth) measurements were
3 x) @, e: c7 e: lobtained using an orthopedic digital measuring device (see
W# f+ s q5 |0 Dfigure).3 ?+ a; w F+ y% C$ L
RESULTS
3 o1 @' I" w6 |! w0 CSerum testosterone increased moderately to levels between$ k" g- l" h3 }3 o/ u) E0 a
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 K4 x4 c6 m* q. I) d9 R& |terone levels with topical testosterone remained near pre-
) r4 N1 t9 [0 ~) G1 M/ B% Mtreatment levels (35 ng./dl.) or were elevated to similar levels
; g" U% X/ k X! _' Y4 bdeveloped after gonadotropin therapy (96 ng./dl.). Higher
, C$ S! B ]1 e7 R$ Vserum levels were noted in older patients (12 and 17 years old), z* K `# h# M& u% e
while lower levels persisted in younger patients (4, 8, and 10
2 M" d1 z4 Z% Eyears old) (see table). Despite absence of profound alterations
4 U, A6 I3 y) ^& } s3 @' jof serum testosterone the topical therapy provided a greater
1 p8 F( ^* ~0 S* r! J4 CAccepted for publication July 1, 1977. ·- d2 A$ n0 \) Y' j
Read at annual meeting of American Urological Association,, s& h+ j2 ]" ?
Chicago, Illinois, April 24-28, 1977.4 l6 r; Z9 _" ~9 p' j" N Z6 b
* Requests for reprints: Division of Urology, Henry Ford Hospital,
& @. n1 G1 ]$ r0 x& k2799 W. Grand Blvd., Detroit, Michigan 48202.
% x& C A! a0 U: l" Gimprovement in phallic growth compared to gonadotropin.& E" l q; s) ?# O+ g' h
Average phallic growth with gonadotropin was 14.3 per cent
' K C# w4 d8 Q8 fincrease in length and 5.0 per cent increase of girth. Topical
1 O, G. C E+ Dtestosterone produced a 60.0 per cent increase of phallic length' B0 i% T+ `( p% W/ \$ a
and 52.9 per cent increase of girth (circumference). The8 M c% i0 l0 x$ s2 u# N7 T2 p5 W
response to topical testosterone was greatest in children be-. o* @5 G9 f3 T: @' C
tween 4 and 8 years old, with a gradual decrease to age 17
# T' \) s3 u: v. V1 _ Iyears (see table).
. ]' l- h. U8 d& l ZDISCUSSION0 x; R4 c- x" | o
Topical testosterone has been used effectively by other! v* t1 P- x9 Z3 a; Y9 Q* G1 Y
clinicians but its mode of action remains controversial. Im-! d- U+ H8 L% v/ A3 K/ Q! i
mergut and associates reported an excellent growth response# P. b: @% t% w) K, G9 C( W0 c
to topical testosterone with low levels of serum testosterone, z. [1 I6 L, n! }9 T( g* L9 c
suggesting a local effect.1 Others have obtained growth re-
9 C8 P. \; C8 S4 ]. C5 b. S" {sponse with high. levels of serum testosterone after topical4 K5 v2 l; ~4 y; ?1 n/ w1 S
administration, suggesting a systemic response. 3 The use of
/ K) ?3 j* n; S7 s* xgonadotropin to obtain levels of serum testosterone compara-7 w( f' T0 X$ g! J$ S% W9 T
ble to levels obtained with topical testosterone would seem to3 [) j) D+ l6 s' G
provide a means to compare the relative effectiveness of
; J) a9 L* k* g4 _% U- B' j3 S$ ktopical testosterone to systemic testosterone effect. It cer-
$ R; Z$ `5 b: ^/ H" otainly has been established that gonadotropin as well as par-
9 P0 g$ d( @% b7 |enteral testosterone administration will produce genital
9 F+ B* O1 {. e$ l3 P- Ugrowth. Our report shows that the growth of the phallus was
2 `% ^/ t7 F- k/ m: h7 tsignificantly greater with topical applications than with go-
, f0 L& ], @* M3 I ?nadotropin, particularly in children less than 10 years old./ u7 j- w7 I4 E
The levels of serum testosterone remained similar or lower; t5 o$ w6 S7 |* t
than with gonadotropin during therapy, suggesting that topi-4 K" z* W. c9 p' h, h' E+ M. ~
cal application produces genital growth by its local effect as
1 a* d/ E. `( z; h+ fwell as its systemic effect.
, I+ W* {4 a/ H0 a) o2 \4 y4 MReview of our patients and their growth response related to% ^) ?2 ? Y8 H2 H2 ~% Y P/ }
age shows a greater growth response at an earlier age. This is
/ n" \, x, n$ U& K/ q9 _consistent with the findings of Wilson and Walker, who0 O* ~9 A" J) V2 S. d9 b5 G
reported an increased conversion of testosterone to dihydrotes-
) X" u" T# C5 q: W3 ntosterone in the foreskin of neonates and infants.4 This activ-
# G' F; P* G" f' ~. `" [: Rity gradually decreases with age until puberty when it ap-4 u6 s4 u. f' n; U
proaches the same level of activity as peripheral skin. It may+ x P4 r8 R; h* ~
well be that absorption of testosterone is less when applied at) Q. E- U7 `9 @! z4 x* F
an earlier age as suggested by lower serum levels in children
: C* [ C5 ]5 I" d: p$ C1 F- O( g$ wless than 10 years old. This fact may be explained by the
1 `- F; B0 w2 Qgreater ability of phallic skin to convert testosterone to dihy-
3 L- }, S# o: fdrotestosterone at this age. Conversely, serum levels in older! W7 C2 \ z) Z- b. U
patients were higher, possibly because of decreased local6 P2 n6 w5 n. w6 |4 {
667
: U' O7 m$ a. g0 z b6 O4 @7 l668 KLUGO AND CERNY* f7 u7 b' K/ ^4 ~5 q9 ~" _* o
Pt. Age
! @& K* |! q ?4 K& ?0 |+ J(yrs.)' h! U' S9 J4 @ Z" G* N1 y( ~
Serum Testosterone Phallus (cm.) Change Length; x( l' n3 k; `( Z0 _% ]' S
(ng./dl.) Girth x Length (%)1 U p& W* D2 F9 c2 L0 A! a* z
4/ c. J/ E8 r3 ^* t6 G3 n k
8% d2 k* w$ \& G ?4 E, v7 F" t
10$ {- x0 a( Z4 W8 Y- b
12
7 ^* k, w3 A- v2 U17
, q6 ~! E; {8 W4 f0 N( A ]2 mGonadotropin
9 S: F( o) p9 o" M' f% t71.6 2.0 X 3 16.6- `5 r5 W1 U2 o6 `2 `, H" ^" a
50.4 4.0 X 5.0 20.0
8 W8 Z' _: [; n! W- Q8 p$ X22.0 4.5 X 4.0 25.0
2 X- K! S0 s) k2 u84.6 4.0 X 4.5 11.1
: m6 m/ l2 n/ w1 D2 D: _3 x85.9 4.5 X 5.5 9.0, a+ \5 Y7 ]/ H; ]4 X, ]4 ^
Av. 14.3$ l7 _4 |8 V, z! A
4
# i) k& X: j+ Z3 M1 x# W8( I4 s6 I. G" A- a b5 {8 Y; N$ [: D
10
$ R, L% o& C# G' u V12
$ c* h, R% }) T1 u8 V! Q179 j1 H2 H9 v8 H7 A+ a
Topical testosterone5 p6 x4 M; `) s: u
34.6 4.5 X 6.5 85
! p" S# @0 U I0 Q' k38.8 6.0 X 8.5 70
+ a. x! Q( G r- M! \% |; U40.0 6.0 X 6.5 62.5; M: d: S4 {6 r; u$ W
93.6 6.0 X 7.0 55.5
9 f8 V! h4 `! J95.0 6.5 X 7.0 27.2
- n3 p5 q: ?, F" RAv. 60.0) \& | P3 C9 F, E7 P$ r" ~
available testosterone. Again, emphasis should be placed on0 B6 [9 ]" T" V3 Y2 j1 O- Z
early therapy when lower levels of testosterone appear to
2 @7 b( Q& U0 G# ~" k0 L9 V- nprovide the best responses. The earlier therapy is instituted
- {0 a9 z* C# P; jthe more likely there will be an excellent response with low
) o5 @& b0 d* N+ @( x* Userum levels. Response occurs throughout adolescence as! r/ r3 A* Z# S) R+ w
noted in nomograms of phallic growth. 7 The actual response
2 i: t4 b" m9 X7 ito a given serum level of testosterone is much greater at birth
4 H9 _- C# [. U7 Fand gradually decreases as boys reach puberty. This is most$ i" [. y3 [7 J# m
likely related to the conversion of testosterone to dihydrotes-
K+ f/ w3 M/ R5 z/ v6 D7 Otosterone and correlates well with the studies of testosterone
% g8 ^; I! l i' J0 pconversion in foreskin at various ages.
9 D4 e% E# _$ c/ rThe question arises regarding early treatment as to whether
# B; |* e5 o8 s g9 ~; Lone might sacrifice ultimate potential growth as with acceler-5 Q, i$ k) m5 [+ V: }
ated bone growth. The situation appears quite the reverse. L) h2 ^7 `) u& h
with phallic response. If the early growth period is not used3 i2 {3 y0 c' D1 Q$ Y9 G
when 5a reductase activity is greatest then potential growth
* E2 T/ O/ k9 U" T& C. c7 zmay be lost. We have not observed any regression of growth
. }0 o9 z" C. A) Q1 }+ k' Kattained with topical or gonadotropin therapy. It may well
7 n! ^5 D, d0 J0 j( Mbe that some patients will show little or no response to any3 B# f4 }1 m. k; r
form of therapy. This would suggest a defect in the ability to
1 u: }) Q5 ^. @1 K2 x+ Oconvert testosterone to dihydrotestosterone and indicate that
# z+ p; F7 p% t' k% Fphallic and peripheral skin, and subcutaneous tissue should
' B# Z% |8 j* g$ i0 Mbe compared for 5a reductase activity.: _$ v, O3 J9 c0 C0 h
A, loop enlarges to measure penile girth in millimeters. B, k7 Z! X) j7 \
example of penile girth computed easily and accurately.# F t2 N% f: [
conversion of testosterone to dihydrotestosterone. It is in this ?" b+ R0 E- n* x: H0 Y; z
older group that others have noted high levels of serum
" J5 _" E; q5 ~, Etestosterone with topical application. It would also appear
+ { T0 S, k; I1 @that phallic response during puberty is related directly to the
& p$ ?6 W: ]8 u; p nserum testosterone level. There also is other evidence of local
$ n O* |; v5 A/ L% M# O3 ^ g- jresponse to testosterone with hair growth and with spermato-4 ]3 X# J2 d+ p4 J I
genesis. 5• 6
+ h4 R" [. l' @( R* bAdministration of larger doses of gonadotropin or systemic7 h; {" j, M3 p3 l
testosterone, as well as topical applications that produce
: D$ U$ J, q% D" L$ k2 |. I7 T+ ^higher levels of serum testosterone (150 to 900 ng./dl.), will( T W6 N- l0 B% G& v
also produce phallic growth but risks accelerated skeletal
7 H" ~4 ^' W; smaturation even after stopping treatment. It would appear4 h% s2 j" |$ J) l2 y" Z
that this may be avoided by topical applications of testosterone3 q, ~; N, r( b9 a
and monitoring of serum testosterone. Even with this control
O- @5 b$ Q/ l0 nthe duration of our therapy did not exceed 3 weeks at any# W. r W2 \$ e* j
time. It is apparent that the prepuberal male subject may7 q( k7 t/ V* }1 P" U
suffer accelerated bone growth with testosterone levels near' Q+ E2 j/ L/ k5 Y7 @2 D
200 ng./dl. When skeletal maturation is complete the level of
' \3 Z( ?7 |' y# H- tserum testosterone can be maintained in the 700 to 1,300 ng./
/ a6 X+ W; a) ^dl. range to stimulate phallic growth and secondary sexual$ s3 g Z) n z# C# \; x- u2 Z6 m
changes. Therefore, after skeletal maturation parenteral tes-" m) j; O3 @$ U# p( r& g+ Q
tosterone may be used to advantage. Before skeletal matura-7 X- Q6 z5 `! n: F
tion care must be taken to avoid maintaining levels of serum
# u1 g. C. \) w0 H% D- @testosterone more than 100 ng./dl. Low-dose gonadotropin
' Q1 r9 E/ m4 p9 T$ e0 f8 Y3 ddepends upon intrinsic testicular activity and may require0 ?3 d! j' M+ l/ v5 C0 x
prolonged administration for any response.
4 v7 J+ x7 g8 F* D$ nAlternately, topical testosterone does not depend upon tes-7 H4 U) l% t2 L
ticular function and may provide a more constant level of Q9 }) W9 H( @/ T$ X. Z
REFERENCES4 r- t4 o8 `4 G. V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
. k+ a2 c' ?! l: P2 ^R.: The local application of testosterone cream to the prepub-
% A- }) v2 w+ j7 O' P8 p* hertal phallus. J. Urol., 105: 905, 1971.
6 _+ a0 p3 S) _/ I/ s2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
. U* o6 ?, l( y& Xtreatment for micropenis during early childhood. J. Pediat.,
{/ D7 \" W8 A2 G" b( t' S83: 247, 1973.
; R+ A% H* a( V- M+ K2 }- t1 ^3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. `. ]2 l3 W* ]8 u! U
one therapy for penile growth. Urology, 6: 708, 1975.
) \7 b, a0 [7 b+ p8 P: V4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone L; k* ?$ ]. @- _: A w% B
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( U5 l2 q5 }. ?- Y5 r t
skin slices of man. J. Clin. Invest., 48: 371, 1969.& s8 h# n' f3 q) j# g* D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth3 o+ \- \* u' [6 [( U
by topical application of androgens. J.A.M.A., 191: 521, 1965.
" C' {1 V2 t- |' \8 [: ?6 h( j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ F- u) F0 y! Aandrogenic effect of interstitial cell tumor of the testis. J.) e0 W/ \! s# L; Z4 ^
Urol., 104: 774, 1970.
/ b0 r4 P2 f, d7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ f2 D$ M, M% t% ^9 {: G. S& Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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