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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND4 P9 l0 C3 R; B
GONADOTROPIN6 d# D% n! _; v+ c/ v3 D
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. `- c: `/ Z8 K; v: R- dFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 J) I, Z }2 B; O$ b: p3 nABSTRACT
$ W' f0 j- J, K, u6 D* G4 E% G8 D- p2 ]Five patients were treated with gonadotropin and topical testosterone for micropenis associated& K- ~& F9 h+ X7 A/ d! p
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# b$ r7 ]/ @1 x2 ?. Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 y7 Q$ [4 u( V0 h- v, ^cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 q( Y" e3 c+ b0 Jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent2 V6 `! n$ N' y7 g- q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 S3 `8 F/ c3 n( T! y. Jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response( C1 v% q( Z; @' q7 ?1 T
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 B& g* k; L& x. |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile) [3 a) k& j1 m% ]) C; }5 ^
growth. The response appears to be greater in younger children, which is consistent with previ-
, \1 Y% J# |# o: `" s, c: |' U( `ously published studies of age-related 5 reductase activity.
/ Q8 n/ _7 ]) Y; i- A, x" v7 d; PChildren with microphallus regardless of its etiology will% N- g1 n- C7 o) j. h& w) f m
require augmentation or consideration for alteration of exter-
% H5 [' o' x2 P, I% Lnal genitalia. In many instances urethroplasty for hypo-
$ j( I1 z2 i$ h) E( v% Vspadias is easier with previous stimulation of phallic growth.
7 [6 @: {/ U8 ?$ Y5 ZThe use of testosterone administered parenterally or topically
& j* e% z' H6 r- P, Rhas produced effective phallic growth. 1- 3 The mechanism of
. a8 y" Q, W: W* ]. Jresponse has been considered as local or systemic. With this
( E' _5 t" u9 s8 Z/ N3 ?$ [+ hin mind we studied 5 children with microphallus for response2 y Y4 A( c; w- ~1 @
to gonadotropin and to topical testosterone independently.2 P9 ~5 q* q# C( j
MATERIALS AND METHODS( G# }/ s. m0 P: ^6 n3 t% `2 {/ @' q
Five 46 XY male subjects between 3 and 17 years old were6 }1 ~: h; L0 t& _
evaluated for serum testosterone levels and hypothalamic! Y2 F( ^# ^; T9 h4 Y) b0 ?
function. Of these 5 boys 2 were considered to have Kallmann's
" p( F) h0 b3 F% s+ osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- d9 J6 G" f: \$ y. e
lamic deficiency. After evaluation of response to luteinizing
$ D3 v4 D2 a5 B; n% t5 Q# e+ thormone-releasing hormone these patients were treated with
& Q0 Y9 G" C. m6 T1,000 units of gonadotropin weekly for 3 weeks. Six weeks
- m9 K! ~. C& v* c. lafter completion of gonadotropin therapy 10 per cent topical( i0 E+ R3 D/ J, x9 E
testosterone was applied to the phallus twice daily for 3 weeks.
1 d" v9 ~% {4 ~Serum testosterone, luteinizing hormone and follicle-stimulat-
f0 P( P7 G9 I( Uing hormone were monitored before, during and after comple-
4 c2 K/ B1 M h0 C. qtion of each phase of therapy. Penile stretch length was' h9 M, {- }& b2 C8 D; k/ s, e
obtained by measuring from the symphysis pubis to the tip of
. o1 y+ a- ?/ Lthe glans. Penile circumferential (girth) measurements were
# \4 ?! `8 X. q4 iobtained using an orthopedic digital measuring device (see
) a _* n' K- J5 Cfigure)./ J9 F# g/ n4 ^. @5 \5 d. _
RESULTS
& O2 ~5 y& I/ Z) g+ USerum testosterone increased moderately to levels between
- w) W- p ?) O* g" D2 V50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-3 u& F+ p, d) K* k+ {. k- E4 H
terone levels with topical testosterone remained near pre-( G2 Q# ^) K/ m
treatment levels (35 ng./dl.) or were elevated to similar levels5 _) d5 S$ q, h' r, q* z
developed after gonadotropin therapy (96 ng./dl.). Higher
* Q5 F: U6 m/ ?serum levels were noted in older patients (12 and 17 years old),' G9 Y7 @# m# C. r! z" s5 h
while lower levels persisted in younger patients (4, 8, and 10
& Q; Y- Q7 g2 z9 E1 oyears old) (see table). Despite absence of profound alterations
" o! E' Y$ R a) e6 d! ~6 p iof serum testosterone the topical therapy provided a greater
5 v1 j$ w) j& p4 y+ K; C, m t% EAccepted for publication July 1, 1977. ·
# d$ n- B; _) r" H8 O; t" i" cRead at annual meeting of American Urological Association,; P8 ^. ]0 ?$ `2 b6 N
Chicago, Illinois, April 24-28, 1977.
1 X: z9 l# B" ^ k2 w J* Requests for reprints: Division of Urology, Henry Ford Hospital,! j% [1 M% h9 ?7 h8 @( W
2799 W. Grand Blvd., Detroit, Michigan 48202.
1 B' a U- p9 z6 h0 z Eimprovement in phallic growth compared to gonadotropin./ l6 D [ k0 W
Average phallic growth with gonadotropin was 14.3 per cent
* B0 l5 @ P6 Z$ r4 l! Cincrease in length and 5.0 per cent increase of girth. Topical
' {' ~5 K% z) Gtestosterone produced a 60.0 per cent increase of phallic length- w0 N# X/ V" a0 Z
and 52.9 per cent increase of girth (circumference). The8 U0 C% r8 P7 V; _
response to topical testosterone was greatest in children be-- e; D4 D& S8 F @; O7 N$ N, q6 n7 k
tween 4 and 8 years old, with a gradual decrease to age 17
7 B1 ?9 u5 v2 A6 ^5 m; F$ s: m; fyears (see table).
; m) M G& ], L" ^* QDISCUSSION2 A: i7 R! O* W8 J& B- M$ c4 y
Topical testosterone has been used effectively by other9 m* o& L! _, l( b% G4 r
clinicians but its mode of action remains controversial. Im-
( g( T+ a8 k/ E) U, p3 O8 ymergut and associates reported an excellent growth response+ e& K. s) d8 g* D
to topical testosterone with low levels of serum testosterone,) u( u: C1 k, |+ J( P
suggesting a local effect.1 Others have obtained growth re-
' x' L u! z' T! c% G" msponse with high. levels of serum testosterone after topical0 J7 }( W: t: ?7 F9 b: S" I% }- u) r, @* r
administration, suggesting a systemic response. 3 The use of
" t: a$ V! s4 D# x) v1 X) c+ Ogonadotropin to obtain levels of serum testosterone compara-
9 ^' | @2 { e0 j$ [, A9 [ble to levels obtained with topical testosterone would seem to3 S# H9 E8 D6 U6 a& V9 B
provide a means to compare the relative effectiveness of' O' q2 u a# h5 q
topical testosterone to systemic testosterone effect. It cer-9 ~- ^0 V, {4 g
tainly has been established that gonadotropin as well as par-
' L% m/ O& k! S, u+ B2 |' P- O& ]' Aenteral testosterone administration will produce genital0 L$ P F4 N0 q
growth. Our report shows that the growth of the phallus was
" M1 W+ V. P, f9 T7 qsignificantly greater with topical applications than with go-
- o) m5 L2 |8 u/ t& anadotropin, particularly in children less than 10 years old.5 r, Z( V8 z) C1 y. a7 ~5 K: [
The levels of serum testosterone remained similar or lower! H) t: H R# [9 ^0 w
than with gonadotropin during therapy, suggesting that topi-
`/ D5 w# u; l7 o: V! g E; d, z$ a+ ical application produces genital growth by its local effect as: j' S5 M6 U$ k4 X
well as its systemic effect.
3 G* F! Q" y$ U% C3 c! sReview of our patients and their growth response related to
( ^2 g( ?4 T& k q; i3 m8 ^age shows a greater growth response at an earlier age. This is
5 q/ B- r4 R4 o, T0 _consistent with the findings of Wilson and Walker, who
7 K" v7 r" s$ Q, f" _9 Vreported an increased conversion of testosterone to dihydrotes-7 }5 S3 c4 Z# b7 m; m
tosterone in the foreskin of neonates and infants.4 This activ-
( J7 h: @2 |3 I; D; R; Zity gradually decreases with age until puberty when it ap-7 r U" y0 t, n; ~$ [ s
proaches the same level of activity as peripheral skin. It may$ e' I* C7 A. L& N, u; C4 E
well be that absorption of testosterone is less when applied at1 o! Q$ E3 U8 M! m: L3 V% b
an earlier age as suggested by lower serum levels in children
0 }+ R1 G! l% H: B9 Cless than 10 years old. This fact may be explained by the
. H# w1 R9 G" {- }greater ability of phallic skin to convert testosterone to dihy-) j7 ]" T& P) H
drotestosterone at this age. Conversely, serum levels in older/ A. K2 E* @- k3 U* W
patients were higher, possibly because of decreased local; F' o+ V* v7 q: v8 i
667: f- T' x0 z& v1 F( z
668 KLUGO AND CERNY
# ?) }, v3 w! H% [Pt. Age
8 J1 h) m* O) o8 |. M(yrs.)
; H" [ y+ u$ c# n2 Z; V, MSerum Testosterone Phallus (cm.) Change Length
3 O8 f. G u' W% m' c8 @- }(ng./dl.) Girth x Length (%)' E" k, c' [3 |7 h+ b
4) I' a: V0 p& `
8
# X* F3 v3 M: Y& R- s8 ?7 g10" I2 ]- |9 x6 g6 }- h
12
9 b/ m# t3 n5 q% S1 h& Q2 c& w17. \9 g6 k0 w+ {5 [9 _: n4 Q
Gonadotropin
/ i& T3 Q' J& T71.6 2.0 X 3 16.6! j0 q9 W: }6 M7 j$ b' {
50.4 4.0 X 5.0 20.03 i0 {, R1 v8 u8 E) e; T' {
22.0 4.5 X 4.0 25.0
9 C! ?3 m# {; O; b4 y' w84.6 4.0 X 4.5 11.13 ?8 K! K% ^3 t9 F: m" n; V- |! C
85.9 4.5 X 5.5 9.0
8 _$ S" I' e5 ^9 E% A, C UAv. 14.3
! ?) M7 o1 L+ i4. N0 @, e) W/ [* E
8
) K+ ^. ?6 L8 B8 \, h10& t; C$ W+ S# C* Y' @
12
' J% o1 F0 T( p7 k. _7 V17
9 R8 l6 F. ^( p" z1 \Topical testosterone
* O- \& H6 P$ H' }- }6 a9 I4 F34.6 4.5 X 6.5 855 @7 Q1 {( Y* q" v5 C0 Y( L) q
38.8 6.0 X 8.5 70
0 b1 X% i% _) ~/ V40.0 6.0 X 6.5 62.5# X" p7 g1 i$ K6 g3 t
93.6 6.0 X 7.0 55.5" j+ n# Z' {3 D i, z1 H; G
95.0 6.5 X 7.0 27.2, e1 P( h# o, g8 K9 d
Av. 60.0* w' P9 e( Q* c+ Y; O
available testosterone. Again, emphasis should be placed on
V: k4 F9 U! Tearly therapy when lower levels of testosterone appear to l, _4 \: r& l; Y9 d
provide the best responses. The earlier therapy is instituted: n5 r/ P3 ~$ h1 N
the more likely there will be an excellent response with low4 _6 l) K8 v% W
serum levels. Response occurs throughout adolescence as
% E9 s" Z# r0 ~* `5 fnoted in nomograms of phallic growth. 7 The actual response* [% ^* i! w4 H6 j4 {
to a given serum level of testosterone is much greater at birth
' D8 e7 N) t$ Wand gradually decreases as boys reach puberty. This is most% q' K$ E0 u5 @5 O( j) t
likely related to the conversion of testosterone to dihydrotes-4 _5 l) {; x. X& E+ N+ V$ q3 X. A% c
tosterone and correlates well with the studies of testosterone# V2 t6 U! N- q* i3 F2 F) Z* n
conversion in foreskin at various ages.
1 v0 r- D2 \# i1 L3 IThe question arises regarding early treatment as to whether
! u% i+ V' L/ w8 w y! Tone might sacrifice ultimate potential growth as with acceler-+ m% I. W: H0 u' K6 e& o
ated bone growth. The situation appears quite the reverse
3 w$ M% w* v4 awith phallic response. If the early growth period is not used
1 y) r+ x" O6 Vwhen 5a reductase activity is greatest then potential growth
! ^; M6 s" t% ]4 [( A: [may be lost. We have not observed any regression of growth1 _9 [0 C4 `) s+ R6 C3 ^% L* R
attained with topical or gonadotropin therapy. It may well
- c6 J5 h& b! Q2 [be that some patients will show little or no response to any+ q5 y C6 n. Y- j8 ~' ?0 U, g# v
form of therapy. This would suggest a defect in the ability to
# R+ Y1 U: H" A% T$ Mconvert testosterone to dihydrotestosterone and indicate that
, `5 q- E! t+ x7 Hphallic and peripheral skin, and subcutaneous tissue should
- k. b( }$ u2 J3 k) L! Ube compared for 5a reductase activity.
" {1 z. j u( j3 H' GA, loop enlarges to measure penile girth in millimeters. B,! o$ s. O( q2 M/ w! _0 M' g+ s
example of penile girth computed easily and accurately.
, c, A& m# r" U! h: h) f% X( Tconversion of testosterone to dihydrotestosterone. It is in this" O: }+ N/ A u/ _) [$ X3 M& o; G
older group that others have noted high levels of serum
% ]: Y, d- z; ctestosterone with topical application. It would also appear& I" M- a) h/ g; P1 |! _
that phallic response during puberty is related directly to the
7 k+ G; l5 E0 a& @# v6 I6 `9 y4 ]serum testosterone level. There also is other evidence of local
9 x" U( x0 b+ x5 [( u' Hresponse to testosterone with hair growth and with spermato-
3 E" _) F8 I9 E9 M( L; A1 dgenesis. 5• 6
/ I% ]/ E: R- \Administration of larger doses of gonadotropin or systemic
/ E# ^. ^7 h* ?, E; B4 Jtestosterone, as well as topical applications that produce# K q$ T$ q: v' k' y( m
higher levels of serum testosterone (150 to 900 ng./dl.), will
7 _$ }; ]! d$ j+ l4 X& w6 `also produce phallic growth but risks accelerated skeletal1 ]3 k# p7 p) y( O( |8 t: D& n
maturation even after stopping treatment. It would appear; `5 ]0 j; c4 y! e
that this may be avoided by topical applications of testosterone
0 B& ~/ M! ]/ C9 ?2 i; Aand monitoring of serum testosterone. Even with this control$ V0 f0 ]! l3 p. K) h% k: K
the duration of our therapy did not exceed 3 weeks at any
" _$ n- c6 z4 B- |8 r( ?' Jtime. It is apparent that the prepuberal male subject may: Z( k2 C% R4 I5 S0 z" r2 b) j9 r
suffer accelerated bone growth with testosterone levels near3 u$ N2 L' J' l0 i
200 ng./dl. When skeletal maturation is complete the level of
9 Y' i+ z8 g9 B+ `$ G8 dserum testosterone can be maintained in the 700 to 1,300 ng./
% k+ o( l- d3 [% R) S6 ~* y( Kdl. range to stimulate phallic growth and secondary sexual1 c+ ~' l) |! e- m) E. c$ j
changes. Therefore, after skeletal maturation parenteral tes-' L* o8 J8 A0 g. L, I# ?
tosterone may be used to advantage. Before skeletal matura-
+ w9 U. k, u& E, S! rtion care must be taken to avoid maintaining levels of serum
" U0 K1 L: y7 N* \" C# Htestosterone more than 100 ng./dl. Low-dose gonadotropin
8 I5 k! i% t' G' n$ Ydepends upon intrinsic testicular activity and may require
* L0 [8 J+ Z* E0 n" |) q. Eprolonged administration for any response.
* W2 P, ?6 r6 B' KAlternately, topical testosterone does not depend upon tes-
, T( w" n# X7 M. L# M1 W7 sticular function and may provide a more constant level of1 k' T4 M5 _; P0 U$ h% T5 b' i
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& @- B3 C! e+ Y9 O& g1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; |4 x) W- ^. }, [5 D. a9 t3 d8 N% O" A
R.: The local application of testosterone cream to the prepub-" p/ `0 ~! S. |. e e
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" [/ h. }1 h0 c* N2 j7 T+ [! }2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 p- b( O3 p' g: F& a% l
treatment for micropenis during early childhood. J. Pediat.,
5 R/ r' u- r' a8 s% T! d83: 247, 1973.
* J Q' D5 [& n, Y3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% n: k( h" t5 M5 C$ {2 O8 B( u
one therapy for penile growth. Urology, 6: 708, 1975.
6 n2 a o! N \* s' u. V) T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 C& C+ O* ~+ a0 O4 I s3 m
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by8 h& I, H7 b/ N
skin slices of man. J. Clin. Invest., 48: 371, 1969.2 C! F6 _' ~! u% X+ V- b
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 b# t( Y# b w% f5 ~
by topical application of androgens. J.A.M.A., 191: 521, 1965./ w: {0 x/ C1 `* N% e8 e" e O
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
2 l1 u' B- O0 a0 [/ @androgenic effect of interstitial cell tumor of the testis. J.
3 n' \- K* i, S6 Y. n6 HUrol., 104: 774, 1970.
* \9 C$ ^$ }6 ^% D2 b7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( T' E* H# D: a }* ~
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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