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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& y) E8 v3 P1 M3 m% _: o" xGONADOTROPIN9 a0 Z" Z4 t' y( |
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 G) }5 i: [3 X5 ^From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
8 `9 m% W4 h( |: mABSTRACT
3 q8 i. U3 m- Z" N6 YFive patients were treated with gonadotropin and topical testosterone for micropenis associated& \% y# j | D1 Q, U; u6 U
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* z0 l4 w/ L: \4 n4 \1 Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ ^) P2 n! V/ t. o9 j
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# b" K7 K i4 S/ ?' C
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ r9 S* _. C, L. I! yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average3 ?$ N2 _1 e/ k2 T2 y5 O# w
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: b* A F7 C3 }" i, A! m
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
9 E# \9 q1 J. D+ j& M7 c* t# q" tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# ?5 l% y: r0 T! \" q Jgrowth. The response appears to be greater in younger children, which is consistent with previ-! f# `1 ?; ?& S/ D& f2 E
ously published studies of age-related 5 reductase activity. E% N2 N( k+ ^. J, i+ J
Children with microphallus regardless of its etiology will
4 ?2 `7 A' h5 ]$ [ V- B9 w( Crequire augmentation or consideration for alteration of exter-
0 ^. Y/ L4 h/ Bnal genitalia. In many instances urethroplasty for hypo-% q. |, |& E, X/ X# o+ Y
spadias is easier with previous stimulation of phallic growth.7 h1 p, c& J- y% }! F! i9 i, [5 c/ D4 Z
The use of testosterone administered parenterally or topically! |1 W3 V, z0 V! }1 `& L
has produced effective phallic growth. 1- 3 The mechanism of' Y1 z- C! s6 T: _& g3 |
response has been considered as local or systemic. With this
2 X, Z/ z- {2 m" I9 O" B: b- Zin mind we studied 5 children with microphallus for response* N) d( }# f" k. z a4 l
to gonadotropin and to topical testosterone independently.7 C: s# Z/ v: B5 l* x2 p2 a
MATERIALS AND METHODS
& q& z1 d+ q0 `Five 46 XY male subjects between 3 and 17 years old were* G& r# j4 _( q" p
evaluated for serum testosterone levels and hypothalamic
2 S; i8 l2 r# _6 g% L1 Rfunction. Of these 5 boys 2 were considered to have Kallmann's
7 G" W9 j7 H$ f9 O3 R5 b: I/ E3 ]1 Ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* d0 _7 a9 y0 I* p/ F* | G3 E# j
lamic deficiency. After evaluation of response to luteinizing" ]6 g* N6 j2 M: ?2 {7 d! C
hormone-releasing hormone these patients were treated with4 u. l5 l0 E' ~/ i, W0 Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
1 z2 j# E: e* O: V$ z$ S1 [; p. Safter completion of gonadotropin therapy 10 per cent topical
3 i0 r4 D9 E. A1 Vtestosterone was applied to the phallus twice daily for 3 weeks., B0 H6 o+ l5 O8 P; g" q2 M
Serum testosterone, luteinizing hormone and follicle-stimulat- H& X4 Y- a5 h$ r: B
ing hormone were monitored before, during and after comple-
# f1 _- R6 G) l% c! j8 _tion of each phase of therapy. Penile stretch length was0 d/ ^# P- S* B# Z. h
obtained by measuring from the symphysis pubis to the tip of
/ P! p* W7 Z! [+ J# Tthe glans. Penile circumferential (girth) measurements were& |# f5 H1 u, \2 }$ @2 K& a
obtained using an orthopedic digital measuring device (see$ f' y: E# ?7 p; L( R9 u- I
figure).
$ ~ Y. e& }/ p2 R, F8 M% n; g; [RESULTS% F/ l1 |! x- c0 ^% b$ p* X- D
Serum testosterone increased moderately to levels between
( L* b) J. J/ X8 T$ H( U0 g+ ?50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ U9 S+ J, C" o
terone levels with topical testosterone remained near pre-! l6 z1 k5 q0 z# I! K- Z9 m
treatment levels (35 ng./dl.) or were elevated to similar levels
5 M8 k9 n* J2 `: ?developed after gonadotropin therapy (96 ng./dl.). Higher
* Z) c1 F) ^, q. i2 E3 y# U3 @serum levels were noted in older patients (12 and 17 years old),4 a- z7 K" d* l' \
while lower levels persisted in younger patients (4, 8, and 10# m3 b9 T# `4 }1 |; ]
years old) (see table). Despite absence of profound alterations
/ [9 s* l, A( h4 V5 \ k h( fof serum testosterone the topical therapy provided a greater
; t/ f/ O( V) \4 k& F9 C! A7 p0 }Accepted for publication July 1, 1977. ·
1 j' O8 y0 k' \! i) xRead at annual meeting of American Urological Association,, P9 J7 K3 b$ s( m: V; S, J
Chicago, Illinois, April 24-28, 1977." |1 ~* |/ I3 V7 v" f$ T. a, Z3 R
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 L" {. V+ f0 h b L, c- z2799 W. Grand Blvd., Detroit, Michigan 48202.
* I+ p) S( C9 P/ G, {7 uimprovement in phallic growth compared to gonadotropin.* j' t4 e% X1 B; u. U, w
Average phallic growth with gonadotropin was 14.3 per cent
6 f3 q' s5 F+ e4 X7 _increase in length and 5.0 per cent increase of girth. Topical. e/ T' p5 Q' ^* x
testosterone produced a 60.0 per cent increase of phallic length, O7 {+ z7 b6 U m
and 52.9 per cent increase of girth (circumference). The9 N. I' q1 Z/ L4 X Z1 y: e- Y1 g" w
response to topical testosterone was greatest in children be-& n% d1 G; c. ?3 k9 w2 {
tween 4 and 8 years old, with a gradual decrease to age 17
2 z& n G8 s2 D+ `; `+ X6 R) }years (see table).
# r8 o; q$ G; y0 D) H1 iDISCUSSION: X9 y( G T9 c6 W0 p4 O) N
Topical testosterone has been used effectively by other: X. @' z1 b5 {; o, J4 I/ g( D4 l. y+ |
clinicians but its mode of action remains controversial. Im-6 y! S7 v* F: A7 y& x; N$ R
mergut and associates reported an excellent growth response6 P+ B8 l. H: q0 q
to topical testosterone with low levels of serum testosterone,
- k9 a5 x* I9 H8 c+ }& Q( [suggesting a local effect.1 Others have obtained growth re-: w, B( G, ^9 m! e g
sponse with high. levels of serum testosterone after topical; Y8 [! S# J4 Y, c4 j, F
administration, suggesting a systemic response. 3 The use of
( \# s( o8 O6 B# Qgonadotropin to obtain levels of serum testosterone compara-
+ n# {+ k- W; F( @: q7 I$ qble to levels obtained with topical testosterone would seem to. R# }3 O q2 B, g
provide a means to compare the relative effectiveness of
+ ?# n9 x! S; l/ u! \topical testosterone to systemic testosterone effect. It cer-
2 }/ F* ~3 M' o& x5 Y J \tainly has been established that gonadotropin as well as par-
$ `6 g# W- b; centeral testosterone administration will produce genital
2 l6 _1 x) U. v5 t5 D& ?9 Q1 K; s* L' ]growth. Our report shows that the growth of the phallus was
" H& h! d0 \. W2 Q$ ]significantly greater with topical applications than with go-$ j: p. r9 Q* [) x0 s
nadotropin, particularly in children less than 10 years old.( O/ r, @% B% W& p9 o+ e
The levels of serum testosterone remained similar or lower4 `* |5 V' ]7 p+ ~2 Y! S% c9 f( w
than with gonadotropin during therapy, suggesting that topi-
/ b! E% i% U, `cal application produces genital growth by its local effect as: B4 H/ d% y$ l7 H! T! E* N
well as its systemic effect.4 @4 [! Q" p, J3 _% B
Review of our patients and their growth response related to
. s! p% d3 G8 u' ~8 t3 Uage shows a greater growth response at an earlier age. This is
. Z. Y+ N+ P! U) j4 y1 mconsistent with the findings of Wilson and Walker, who
: ?& M. v0 X( w% I+ n4 C5 wreported an increased conversion of testosterone to dihydrotes-
$ z4 }( X" n# q& ltosterone in the foreskin of neonates and infants.4 This activ-" R6 y- Z+ W0 Y0 F2 X8 R0 j
ity gradually decreases with age until puberty when it ap-
4 U4 s/ Y! B+ _5 jproaches the same level of activity as peripheral skin. It may
; @9 `& o9 L; l, [well be that absorption of testosterone is less when applied at O7 O0 s' X; y3 _
an earlier age as suggested by lower serum levels in children: B8 G* q6 l7 x1 s5 O$ @
less than 10 years old. This fact may be explained by the
$ {0 X$ R* S6 F' i5 G$ ~greater ability of phallic skin to convert testosterone to dihy-
% D) M, l% Z2 {2 F" Ldrotestosterone at this age. Conversely, serum levels in older% |. z% k- _; y4 d2 i/ m
patients were higher, possibly because of decreased local
6 y' N! T$ B/ k' q: f9 o$ x667! `2 v' O5 v0 N
668 KLUGO AND CERNY
: J5 j0 m# O$ W' A4 KPt. Age
% r- G% c) d4 U7 k(yrs.)
3 p, [: ^7 k& ~4 m8 Y1 z9 SSerum Testosterone Phallus (cm.) Change Length
" I% ~+ _3 M* d* U! M; Q" j, }. [(ng./dl.) Girth x Length (%)8 f3 }! O0 c7 p* a- U
4* k1 {7 Y% q2 U* B- o4 }. n/ [$ h
8
' Y' G8 d! T) g6 W. n! J1 n6 `10" F7 v) R# }# v1 b% @4 A5 p
12
b5 a$ W0 M7 n17+ f! }5 ?7 G2 i$ i
Gonadotropin
$ [8 s. S6 s! e& d4 o/ V# R) Q71.6 2.0 X 3 16.6! o/ T& X! U; i1 z" y
50.4 4.0 X 5.0 20.08 r: }; y( |8 P+ c- t T4 O3 w
22.0 4.5 X 4.0 25.0. f) _+ d" O& p+ u: }1 J
84.6 4.0 X 4.5 11.1
. F+ @8 l6 O8 b7 a85.9 4.5 X 5.5 9.0
6 ?+ z0 H8 R# H- FAv. 14.3
$ c4 A5 m9 N( S4
. @0 T3 ?; y& z1 R" u8
8 r! l/ I! F/ P8 w- ^* ]5 ?/ `10: Z, P! a7 {9 Q0 n
12
; F" q' j, I1 V( `( v9 a17
1 H1 y* \5 Q( R& uTopical testosterone6 r1 W1 V7 h5 S4 Y5 K
34.6 4.5 X 6.5 85/ |. x. h, r7 d, S( d7 R
38.8 6.0 X 8.5 70
% Z* H" r) Y* M8 o, M( M40.0 6.0 X 6.5 62.50 H; F7 v0 t1 D+ ^' k- A Q
93.6 6.0 X 7.0 55.5
3 |' u/ K! c- C6 H4 n& V. z4 ?95.0 6.5 X 7.0 27.26 y/ e% J2 D+ V5 S3 R0 l5 l
Av. 60.0( F* A$ x4 o; {; B8 o0 l! P
available testosterone. Again, emphasis should be placed on
1 r8 [- |0 B, ^) W: L! Zearly therapy when lower levels of testosterone appear to7 n# v5 O- _; p
provide the best responses. The earlier therapy is instituted/ N$ M# s% }8 C0 D8 U. K
the more likely there will be an excellent response with low
" N& Y' Z' e3 m* ~( l9 Eserum levels. Response occurs throughout adolescence as
; R" j1 c0 g/ l8 z1 X( B! tnoted in nomograms of phallic growth. 7 The actual response. B/ z% ]; `& m, q
to a given serum level of testosterone is much greater at birth
2 j4 L, z k8 D4 Dand gradually decreases as boys reach puberty. This is most
/ _% u) b1 n" G J* W5 alikely related to the conversion of testosterone to dihydrotes-$ @8 t. E1 }: }) I
tosterone and correlates well with the studies of testosterone- X- E* L2 c; e* O
conversion in foreskin at various ages.
+ T( n! e* G ]5 @; qThe question arises regarding early treatment as to whether/ }2 b0 N# o% D& V5 v
one might sacrifice ultimate potential growth as with acceler-
9 n+ W8 K4 v3 T4 V+ y/ cated bone growth. The situation appears quite the reverse# p" T' `$ v0 t) k6 y7 ?( C
with phallic response. If the early growth period is not used1 Q1 H: K; d1 q! h
when 5a reductase activity is greatest then potential growth
+ D- J) k& T( T# Y* f' i- wmay be lost. We have not observed any regression of growth( H4 v( |2 D& H4 ~
attained with topical or gonadotropin therapy. It may well
( v! r/ y( S0 |) ^) vbe that some patients will show little or no response to any
2 H; s% I, }; Cform of therapy. This would suggest a defect in the ability to8 H9 s. D! {6 G
convert testosterone to dihydrotestosterone and indicate that1 ^ e% J7 j! J6 K" [8 I
phallic and peripheral skin, and subcutaneous tissue should6 M2 s3 G$ d# r s9 V; i5 z
be compared for 5a reductase activity.. N+ R- I2 o4 z( B7 `
A, loop enlarges to measure penile girth in millimeters. B,
/ D1 z- q- r& \( Uexample of penile girth computed easily and accurately.
5 C+ w) G. }- ^8 x+ e' S4 M5 S( `conversion of testosterone to dihydrotestosterone. It is in this
. `8 n8 W D: }older group that others have noted high levels of serum3 q) W% v2 q7 g; s. u7 @
testosterone with topical application. It would also appear
: x: X. J7 C7 a! h7 B6 F5 ]: tthat phallic response during puberty is related directly to the* X4 v5 t# q# ~0 H3 |! N4 d2 T
serum testosterone level. There also is other evidence of local1 U( Y, t& X/ `! O6 f3 C
response to testosterone with hair growth and with spermato-$ S: L: h8 E5 [! v
genesis. 5• 69 m" b, g6 w9 j/ ?: X
Administration of larger doses of gonadotropin or systemic* }* j; i2 T+ m4 \
testosterone, as well as topical applications that produce. i- S8 R4 S }
higher levels of serum testosterone (150 to 900 ng./dl.), will
3 G' ]2 D2 W5 w$ valso produce phallic growth but risks accelerated skeletal
% u# _% J/ q4 j' N6 D. ]; smaturation even after stopping treatment. It would appear
( S& t& X- c# [2 w7 o% V+ lthat this may be avoided by topical applications of testosterone
, F8 J, i7 h; d- l( n# J' aand monitoring of serum testosterone. Even with this control
6 c0 l, n, U/ u# Q. Nthe duration of our therapy did not exceed 3 weeks at any) N- x( ~" f, D2 S7 t/ ?' j
time. It is apparent that the prepuberal male subject may* _# b. D X# h0 k# g! ^- L- Q4 M1 e
suffer accelerated bone growth with testosterone levels near1 M$ ~" H) P9 t! u/ t1 J/ v
200 ng./dl. When skeletal maturation is complete the level of8 B4 \% ]% U0 P
serum testosterone can be maintained in the 700 to 1,300 ng./
! O: M4 o* l/ y6 h1 V Y5 rdl. range to stimulate phallic growth and secondary sexual; K9 [) m: ~0 s! M
changes. Therefore, after skeletal maturation parenteral tes-
" i' o' g: q, P l; c. Utosterone may be used to advantage. Before skeletal matura-
* T i8 ]; b3 a! gtion care must be taken to avoid maintaining levels of serum
5 N3 s; }* ?+ c* ntestosterone more than 100 ng./dl. Low-dose gonadotropin! p9 q; g4 B& W7 a# Q3 P
depends upon intrinsic testicular activity and may require
1 M5 W2 c4 _8 s3 |2 R3 S I& Gprolonged administration for any response.
: ~0 j* l* V5 dAlternately, topical testosterone does not depend upon tes-
# d: I0 g9 t; w$ Xticular function and may provide a more constant level of
8 m$ u* m- M+ ]6 N7 OREFERENCES
7 B" Y0 [ ?) R2 H; o: D, E( z$ y1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 H; g; V* D: d* ~R.: The local application of testosterone cream to the prepub-/ K1 h7 M$ f+ v* N8 `
ertal phallus. J. Urol., 105: 905, 1971.+ K6 d' F' {5 n [8 z9 P8 ]4 a' s
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
( G) j" v8 O b5 _9 ^# ~8 b% C. Dtreatment for micropenis during early childhood. J. Pediat.,( u+ n) j! d0 k( P8 f
83: 247, 1973.
( W/ X. Y# d1 r. K0 H# G3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( Q5 N. J) a. I: R% `one therapy for penile growth. Urology, 6: 708, 1975.3 H7 T+ f, w5 O7 ?5 m/ r
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 |3 N& o6 z7 o0 i. v6 M+ H! G+ h8 X
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 j5 h1 o: c6 _+ E6 Z
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 O4 X+ H5 Y8 v/ [. u1 O- A
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
% s2 E8 R8 M. ^8 M, ~# Y; R+ lby topical application of androgens. J.A.M.A., 191: 521, 1965.8 q' v3 o; y6 O( ?0 O9 A" ]6 L, M
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
5 U" h+ u7 A* Y/ X9 E+ bandrogenic effect of interstitial cell tumor of the testis. J.
# t6 e4 m! n9 `% i4 j' |Urol., 104: 774, 1970./ p% n: o' W7 v. _. g; P9 r- Q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* F) j. _+ d; A7 l% \* k8 ? t% g
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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