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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND4 D0 ]- m" b& B" }$ x, I/ q( U
GONADOTROPIN
# A l- p: D1 H% Z* a$ c: mRICHARD C. KLUGO* AND JOSEPH C. CERNY
7 f0 u& N/ V4 a( Q' E* T; gFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
! F" p8 `3 h, @: aABSTRACT
/ G$ B; K) { W' k+ \Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( q [9 g2 I3 r8 e0 z: Owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 p0 i/ T; w" y) M7 u
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
8 F( a& n4 z# wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- p0 ] g% e6 u$ w, hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" M8 E, n% z5 D3 j
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ v! S7 [2 W; u4 R; P' y. p
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: q/ i, Q( [. N
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 z! E/ h$ w' w6 `& @: _
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile; c: _; R2 ~0 Z
growth. The response appears to be greater in younger children, which is consistent with previ-4 B8 K$ {8 T, j0 t
ously published studies of age-related 5 reductase activity.5 M/ R2 w! }" ?0 l( [7 D# m
Children with microphallus regardless of its etiology will
& G6 c% p* g2 v( {5 W1 T" O6 K: Xrequire augmentation or consideration for alteration of exter-
3 \2 a" L) t6 bnal genitalia. In many instances urethroplasty for hypo-0 t' w, {/ m7 h8 r
spadias is easier with previous stimulation of phallic growth.2 r; e8 w6 p/ b7 D' _1 g( X
The use of testosterone administered parenterally or topically
% _4 {4 A. I" w5 Ehas produced effective phallic growth. 1- 3 The mechanism of
% A8 w* L* f! |9 u& t6 qresponse has been considered as local or systemic. With this1 h7 q3 Z2 U L5 v! l2 ^- u
in mind we studied 5 children with microphallus for response
3 G5 h7 o5 N/ l2 ]. ]to gonadotropin and to topical testosterone independently.- P( ~& A* _0 b, c, C9 A, R) a% f
MATERIALS AND METHODS% y1 z$ ]! z% }/ p6 u0 \7 y
Five 46 XY male subjects between 3 and 17 years old were
0 [! `% \! y1 q' a1 J% Oevaluated for serum testosterone levels and hypothalamic2 r: B9 Z4 u f" \4 w# e) ]3 l& X
function. Of these 5 boys 2 were considered to have Kallmann's5 T6 B0 P5 v5 X0 U: f" ^
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 ~" I Z; e. K. n. h. ulamic deficiency. After evaluation of response to luteinizing
- c- d/ V4 w1 k0 V- F; ]: b9 hhormone-releasing hormone these patients were treated with# J$ Q9 T1 }' l7 v, D. S
1,000 units of gonadotropin weekly for 3 weeks. Six weeks6 e' m# i. J' g, D& ^1 n6 J
after completion of gonadotropin therapy 10 per cent topical! t5 @! ^6 V1 R* G' z/ B5 b
testosterone was applied to the phallus twice daily for 3 weeks.
: v5 h7 @$ V: b& x7 OSerum testosterone, luteinizing hormone and follicle-stimulat-
# D, C4 a# c! v3 l$ zing hormone were monitored before, during and after comple-$ s- U2 E6 X1 i% B9 I* C7 J% H8 L
tion of each phase of therapy. Penile stretch length was2 F8 {! m- D9 g) D* e, F4 Z
obtained by measuring from the symphysis pubis to the tip of- k& t& e+ u- S( z% k
the glans. Penile circumferential (girth) measurements were
* u- y8 i ^# {0 _+ kobtained using an orthopedic digital measuring device (see
9 R' D$ a2 l+ }0 c! Cfigure)." c* ]! J- W& @" t4 d
RESULTS
3 a- I0 j" J, t3 E% ~9 b3 a. nSerum testosterone increased moderately to levels between. G P1 V3 J- {4 G* z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. i7 y; Y- n- O* N- ^terone levels with topical testosterone remained near pre-8 i7 D) N2 H/ p% C( r2 \0 P- ]3 t2 p
treatment levels (35 ng./dl.) or were elevated to similar levels C, K8 X; z- ]& u- a+ f
developed after gonadotropin therapy (96 ng./dl.). Higher8 Y/ }0 U5 B9 w9 K+ M, ?) `
serum levels were noted in older patients (12 and 17 years old),9 \# }1 T8 n1 f3 v( L
while lower levels persisted in younger patients (4, 8, and 102 G9 d' |1 O" J5 D/ Z* R
years old) (see table). Despite absence of profound alterations+ T- a9 l( [1 a* `
of serum testosterone the topical therapy provided a greater5 k9 ], v1 J2 `# ]% N
Accepted for publication July 1, 1977. ·# Y* [ P+ X/ t+ {
Read at annual meeting of American Urological Association,
/ P/ |$ D- G1 [& sChicago, Illinois, April 24-28, 1977.: t" }" i6 b/ A2 {
* Requests for reprints: Division of Urology, Henry Ford Hospital,8 }. ~5 d9 n8 D) C; V
2799 W. Grand Blvd., Detroit, Michigan 48202.
9 {# [# G! D% |improvement in phallic growth compared to gonadotropin., z% g. z! z- g& X! A
Average phallic growth with gonadotropin was 14.3 per cent% f8 D. ]( k( n$ N1 Y
increase in length and 5.0 per cent increase of girth. Topical
: x1 k& g; f2 q' O& C% w( e; S wtestosterone produced a 60.0 per cent increase of phallic length$ J- b4 E4 V, R8 D! h5 t7 j8 r
and 52.9 per cent increase of girth (circumference). The
+ w6 B/ C: \8 z" i$ Fresponse to topical testosterone was greatest in children be-: v4 Y( s( b- n' n. j
tween 4 and 8 years old, with a gradual decrease to age 17
; T6 s! i) E8 w: zyears (see table).! Q4 V7 ~+ C% j" Q, {
DISCUSSION
0 H: ], k8 h( }, ~# {% x" }; mTopical testosterone has been used effectively by other' h U+ _- b A% C8 s+ N- J3 `
clinicians but its mode of action remains controversial. Im-2 O" {5 m9 K% Y5 Q+ K$ X
mergut and associates reported an excellent growth response
4 l+ J6 Y% u, z. s3 p1 D" Dto topical testosterone with low levels of serum testosterone,8 R% Q0 u u* L8 t
suggesting a local effect.1 Others have obtained growth re-) c* b% Z' z7 V7 d' K- U! H
sponse with high. levels of serum testosterone after topical
4 t6 o. K* _) o/ \administration, suggesting a systemic response. 3 The use of( w. j( H: D7 f: z, x, y
gonadotropin to obtain levels of serum testosterone compara-
' L, w5 _" ?! fble to levels obtained with topical testosterone would seem to
6 ^4 `7 j4 U. P6 Eprovide a means to compare the relative effectiveness of
2 P3 j2 L/ Q: T/ ytopical testosterone to systemic testosterone effect. It cer-
^7 ?) T: H! n/ b0 r1 Q; W8 `tainly has been established that gonadotropin as well as par-; m& Y; J4 E% u2 E) O5 S
enteral testosterone administration will produce genital
4 y% T% [- j* `) U# N9 i; {growth. Our report shows that the growth of the phallus was" `8 N+ F0 Y w/ w' ~) w
significantly greater with topical applications than with go-0 L7 E# }1 e# ^! Z) ^9 k" J
nadotropin, particularly in children less than 10 years old.; k6 y; n- n8 Z$ z0 b: C
The levels of serum testosterone remained similar or lower% |( B9 P$ R x( ^" ?5 {$ L B/ @
than with gonadotropin during therapy, suggesting that topi-$ S) `2 Z1 f$ m, h' ]
cal application produces genital growth by its local effect as7 v% g- }) ]6 |, B8 h+ C: _
well as its systemic effect.
p( }1 F! E* ^9 eReview of our patients and their growth response related to
- t4 m) z" l7 j, aage shows a greater growth response at an earlier age. This is
( r- }, X6 [, S8 a/ P) Rconsistent with the findings of Wilson and Walker, who' [3 Z* i3 n0 z7 O: h' c" d
reported an increased conversion of testosterone to dihydrotes-
2 ]6 r; e. `9 [9 H5 [, G' Atosterone in the foreskin of neonates and infants.4 This activ-' E# V- Y4 R$ \ `( i. o$ G" i# f
ity gradually decreases with age until puberty when it ap-9 E/ q1 b/ W( y/ F4 Y* i3 z
proaches the same level of activity as peripheral skin. It may1 x ]- J" v- Q; J
well be that absorption of testosterone is less when applied at
4 F6 g/ E+ {/ L" E3 y+ yan earlier age as suggested by lower serum levels in children
. w, J0 u2 e* g6 Jless than 10 years old. This fact may be explained by the- J! o" H" r+ d" |
greater ability of phallic skin to convert testosterone to dihy-* L% K% O7 e; s& J9 s8 R
drotestosterone at this age. Conversely, serum levels in older) }/ M. `" ^9 M: j: }- o+ |
patients were higher, possibly because of decreased local
1 Y `1 f2 z$ ], w0 n% J6 j( b667
" x W y* X8 m: O- ^( [668 KLUGO AND CERNY U( g& w6 U7 M* I/ L
Pt. Age% |4 U# n H: w2 o% c
(yrs.)
7 j' b3 d! n: q. z, q7 kSerum Testosterone Phallus (cm.) Change Length' p- Y( f$ q- O4 W/ C& J
(ng./dl.) Girth x Length (%)# k' S( i' U, v& h9 A
49 r1 g$ ^* O# k" L, W4 o! n6 \
8
: g/ I) a) I' G10
/ f( d- _% e& d12! g/ l/ ^/ K7 \: ~( ]; ~: l5 {
17% Y% \/ c7 }7 |. I; b
Gonadotropin
+ h4 @' A; a: Y( G71.6 2.0 X 3 16.6
- C' V/ V* f! E5 i+ y! B$ P# y( O. P50.4 4.0 X 5.0 20.07 q! s) s# t. [: b. i3 B
22.0 4.5 X 4.0 25.07 D+ }8 M: w4 _$ i% r
84.6 4.0 X 4.5 11.1
+ S% y, c+ T% v5 }/ t h85.9 4.5 X 5.5 9.05 O5 ^& P( ^+ V
Av. 14.39 K% f) e1 Y. E( b+ H% H
4
2 G, x8 v# O4 j1 k ~8
3 k* }; t& Z# m" [+ z! T- y! b10 s7 ~- A3 q9 X
123 d8 r" @. H0 O# a1 u
17% R {' E5 }6 K; ~8 k$ h$ ~0 T
Topical testosterone
6 B5 ]$ i$ v+ ^' ~34.6 4.5 X 6.5 85
3 L+ P _( {' d" j& s1 I4 p38.8 6.0 X 8.5 701 f+ X$ q9 f, C; B+ g8 i+ ~0 |# o
40.0 6.0 X 6.5 62.5
& x5 Q4 g0 A# n* D3 T P93.6 6.0 X 7.0 55.56 _# N' N5 W0 ^! y
95.0 6.5 X 7.0 27.26 m+ w4 m3 ~* d0 m+ l* N
Av. 60.07 i3 ]7 e: d4 q: J8 F; h( F
available testosterone. Again, emphasis should be placed on
5 u$ e& X/ s' h }/ n' o5 V1 a& d8 o" ^early therapy when lower levels of testosterone appear to
$ g) |1 F" n' ?. [9 fprovide the best responses. The earlier therapy is instituted
- p3 d7 ^. z6 l4 {the more likely there will be an excellent response with low+ |) z& d8 Z% E: u) w: P6 z
serum levels. Response occurs throughout adolescence as
& X/ k* V; A' i/ B. Rnoted in nomograms of phallic growth. 7 The actual response: J, o& @+ ~* v1 ]0 a! Y
to a given serum level of testosterone is much greater at birth$ F7 f# h0 e5 \& w
and gradually decreases as boys reach puberty. This is most$ g& D& C Z2 K) ?6 [, D; p+ _
likely related to the conversion of testosterone to dihydrotes-& \: N/ ]1 ^) ^* j3 S# j7 L
tosterone and correlates well with the studies of testosterone8 w+ ^) G$ g5 E" }9 ]$ P7 @& M
conversion in foreskin at various ages./ P, m4 n; Y1 a( D
The question arises regarding early treatment as to whether9 a7 b0 \2 _0 P% W# b/ {
one might sacrifice ultimate potential growth as with acceler-# ~! z6 r5 B" s
ated bone growth. The situation appears quite the reverse
* R+ E0 v: ^9 S2 ?) F6 j( ]8 `with phallic response. If the early growth period is not used
: Y3 D% M' v' a1 s( Pwhen 5a reductase activity is greatest then potential growth
5 a/ p3 y, E6 _& y, `- J/ _! F* qmay be lost. We have not observed any regression of growth
R0 D) P8 U7 X X! M) ?, battained with topical or gonadotropin therapy. It may well( F+ w; i% N9 b5 E5 q* ^" G5 V
be that some patients will show little or no response to any
3 K% M7 A/ j2 z2 ]: L6 r7 @' R4 ~form of therapy. This would suggest a defect in the ability to" `$ ~4 v- U; V. k+ r
convert testosterone to dihydrotestosterone and indicate that8 @0 M. Y1 s! Q! d+ q
phallic and peripheral skin, and subcutaneous tissue should
! l1 p6 \1 A3 ^6 x. ^+ }3 `be compared for 5a reductase activity.
7 q' O, c& [" E$ K: d2 V" ?A, loop enlarges to measure penile girth in millimeters. B,/ }; `+ J* x4 |4 K! `
example of penile girth computed easily and accurately.
; e1 ]7 N0 f" i0 }9 C0 Vconversion of testosterone to dihydrotestosterone. It is in this
, w6 u$ m$ b$ C$ ]% B- K" U" e& a, e& |older group that others have noted high levels of serum5 ~8 }/ e3 L5 [" ?. V9 F; }
testosterone with topical application. It would also appear
# ]1 z' V& ]; uthat phallic response during puberty is related directly to the
9 s d6 p7 A5 c4 \6 {" V! f7 Zserum testosterone level. There also is other evidence of local
0 b1 ^( }7 [- f4 R8 f. dresponse to testosterone with hair growth and with spermato-
$ r, u7 @" y) P) @genesis. 5• 6
, t" I" n' |+ }- T. w! vAdministration of larger doses of gonadotropin or systemic
( r$ x$ R/ [- xtestosterone, as well as topical applications that produce6 K- \: N8 Z- T; P
higher levels of serum testosterone (150 to 900 ng./dl.), will' i+ ]- ~, J; S+ [ `$ u6 `
also produce phallic growth but risks accelerated skeletal
2 ~% L+ |: g7 Pmaturation even after stopping treatment. It would appear* S- }& v+ [9 |7 P2 X H6 J1 Y
that this may be avoided by topical applications of testosterone
4 v9 S% ^$ S! P5 Eand monitoring of serum testosterone. Even with this control* w) O, | q! C7 f& h& a4 y) Z
the duration of our therapy did not exceed 3 weeks at any* z/ m( Z& Y* U' \4 O, k5 ^
time. It is apparent that the prepuberal male subject may
! H" I1 S& m/ ssuffer accelerated bone growth with testosterone levels near0 H! H6 N, w7 P2 W3 ]; \ A& s
200 ng./dl. When skeletal maturation is complete the level of
; Q9 a; C+ C3 ^6 P: y9 v3 eserum testosterone can be maintained in the 700 to 1,300 ng./- @3 Q# ?# \' b+ Y
dl. range to stimulate phallic growth and secondary sexual0 ~: x4 E, I$ a, E" f! C# [
changes. Therefore, after skeletal maturation parenteral tes-
2 D% h, m1 Z0 F- @1 Ctosterone may be used to advantage. Before skeletal matura-
. N' l& r5 @( L D( ?tion care must be taken to avoid maintaining levels of serum+ ]5 m. t( M8 S1 h) h0 V
testosterone more than 100 ng./dl. Low-dose gonadotropin
7 s5 l- ?4 K; R1 Kdepends upon intrinsic testicular activity and may require5 s$ M/ W0 _ O8 y" H. m" K
prolonged administration for any response.
) @3 ?0 S) X6 @* S gAlternately, topical testosterone does not depend upon tes-
1 F+ i* N7 N1 z# R* |( t( g E" @ticular function and may provide a more constant level of
" N; j' [, A$ ?; a, Z9 b8 fREFERENCES8 t7 M% z9 L t' b" i: {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ G0 {) b- G6 g; r' C
R.: The local application of testosterone cream to the prepub-+ n! n- N4 m, T
ertal phallus. J. Urol., 105: 905, 1971." y8 M( ^; W" x. A0 l8 f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
- a* w {, k: Jtreatment for micropenis during early childhood. J. Pediat.,
& ~) `# d6 s' H$ y* \, y$ G83: 247, 1973.
( }! a3 g3 M' L7 ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-: V" r* G9 T2 n8 F! ^2 J
one therapy for penile growth. Urology, 6: 708, 1975.( w& I* @) Y' a) g0 w
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 v r- h8 L5 g( gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: A, k3 U: B5 L6 Mskin slices of man. J. Clin. Invest., 48: 371, 1969.
" K1 T& A6 A* f3 A) |0 [5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
, u$ }' n! R. D0 Gby topical application of androgens. J.A.M.A., 191: 521, 1965.: [0 R( W: _1 _/ h M
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; G* \5 t1 ^: T, }
androgenic effect of interstitial cell tumor of the testis. J.5 h: e1 d0 `8 m7 h/ d5 u$ o% E3 w
Urol., 104: 774, 1970.
& {- G" Q$ `( x- P3 C, l- P4 ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-& S# h0 ]+ o9 v3 y Q7 p
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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