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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' J) t1 V& V5 P% o" c
GONADOTROPIN* b. L3 @% y8 E5 Z9 i- [7 u) q1 @
RICHARD C. KLUGO* AND JOSEPH C. CERNY9 ]& D2 c) p* A8 p) V) Q
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan" B- P1 F3 Y1 n
ABSTRACT
3 S" D% N/ n. y% UFive patients were treated with gonadotropin and topical testosterone for micropenis associated- `2 W' V" o! x4 j$ W/ d% n. [2 F
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( B o/ g% N, _( |tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ m) V6 U5 N4 |$ V! `' ?+ e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent' C9 n! @& h5 G. U9 J; M9 I
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ s6 L1 y; X; B) F1 Lincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ {" L$ D. a. D5 h8 X9 ]) h9 rincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
c9 u( P: X/ noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( X: [/ D* P' w) x) y* j; Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 f+ N" r0 e% c+ Vgrowth. The response appears to be greater in younger children, which is consistent with previ-& S( O5 T( S$ z/ b
ously published studies of age-related 5 reductase activity.$ T+ |* q! H& ~: x0 H
Children with microphallus regardless of its etiology will
0 l# d5 Q% @& R- d4 D" C$ Grequire augmentation or consideration for alteration of exter-, e; [$ n& S* R, A X
nal genitalia. In many instances urethroplasty for hypo-
4 [ \% t$ L" u8 Mspadias is easier with previous stimulation of phallic growth.
% V7 f" J& _3 y( j1 H% EThe use of testosterone administered parenterally or topically/ |0 Y9 e) |9 W; d9 R# R
has produced effective phallic growth. 1- 3 The mechanism of) H* R r7 t9 ~! e
response has been considered as local or systemic. With this
+ N) Y. W( g2 w# fin mind we studied 5 children with microphallus for response
. u; `* K- M5 k6 }7 xto gonadotropin and to topical testosterone independently. B' y7 E0 Q d4 g
MATERIALS AND METHODS7 x x x( l# p) T& U$ ~
Five 46 XY male subjects between 3 and 17 years old were
3 E9 F! ?* i. C+ ^! M% b$ H7 n- gevaluated for serum testosterone levels and hypothalamic
3 N! n' O) ~& W/ R! K3 Sfunction. Of these 5 boys 2 were considered to have Kallmann's- {, _! ]& q3 l
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-2 h; Y6 W1 i% C0 U, g6 |" O
lamic deficiency. After evaluation of response to luteinizing
- d: z7 V' @" p9 t6 `hormone-releasing hormone these patients were treated with
" e4 g- g: E: J+ d2 z( F: I V* }* b1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! \2 F1 S! t0 V' W: }9 zafter completion of gonadotropin therapy 10 per cent topical7 S6 E* ?' c' R3 H0 W+ u/ f# I4 t G
testosterone was applied to the phallus twice daily for 3 weeks.
. ^6 d! ~# s% s. D b! N0 USerum testosterone, luteinizing hormone and follicle-stimulat-
2 e, ?$ [1 M. R1 S" D2 `3 G4 ^$ C' H) {ing hormone were monitored before, during and after comple-
! f* |2 C' q7 z+ |. Ption of each phase of therapy. Penile stretch length was
/ q, K/ V& B2 g' pobtained by measuring from the symphysis pubis to the tip of* u9 o/ [. w" {) x) _* |' {
the glans. Penile circumferential (girth) measurements were
7 Z. q8 R8 u( H6 e4 fobtained using an orthopedic digital measuring device (see6 X4 r# r$ I( w' z& @
figure).
1 v1 y5 g/ J9 KRESULTS) v% p2 u4 l- x6 p. P
Serum testosterone increased moderately to levels between
* w8 N- O) Z* K1 L$ I50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ Q1 v/ H- u0 D1 O: F9 P5 tterone levels with topical testosterone remained near pre-
. f9 H0 B. J) [+ Jtreatment levels (35 ng./dl.) or were elevated to similar levels% R: K5 _. I. a1 _0 y
developed after gonadotropin therapy (96 ng./dl.). Higher
4 p/ P: z, b4 [5 Q6 g, \serum levels were noted in older patients (12 and 17 years old),
h+ r% d0 r) v- X5 F9 C& a4 Dwhile lower levels persisted in younger patients (4, 8, and 10
+ d; i4 {& k0 c' pyears old) (see table). Despite absence of profound alterations
' c8 ~+ ~, X5 t# T3 w( C8 Bof serum testosterone the topical therapy provided a greater
( Q8 W, k" A; m# YAccepted for publication July 1, 1977. ·2 u/ j- ?& f! \* L% w" `
Read at annual meeting of American Urological Association,
# h. J& M* N5 x8 J/ T0 `+ jChicago, Illinois, April 24-28, 1977.1 f# |% \9 d5 H; w; C
* Requests for reprints: Division of Urology, Henry Ford Hospital,# S8 J* i5 p4 |& t+ h0 S
2799 W. Grand Blvd., Detroit, Michigan 48202.* [9 F& a$ k+ ? f' R2 f# U
improvement in phallic growth compared to gonadotropin.4 E' v9 N) \. k( ^, C5 F H
Average phallic growth with gonadotropin was 14.3 per cent1 j7 {0 e: O1 n$ `6 ]
increase in length and 5.0 per cent increase of girth. Topical. n3 @ _, I/ A
testosterone produced a 60.0 per cent increase of phallic length% s$ S9 i& }: \ N. `8 f4 q$ {
and 52.9 per cent increase of girth (circumference). The
1 q' e% F5 Z9 d. t! }( Q% Iresponse to topical testosterone was greatest in children be-
# _# U( M5 E3 n# ?5 r* m V7 k! Ctween 4 and 8 years old, with a gradual decrease to age 17; U2 g: K- o7 g& R) y+ V
years (see table).2 ?$ @* E7 x. d" w
DISCUSSION
+ t. P2 P# H4 {5 D% QTopical testosterone has been used effectively by other7 u0 e8 |* P3 ^7 O' C) H
clinicians but its mode of action remains controversial. Im-
: _7 x7 T- Z# T0 ~$ ~- v* z3 |5 a& umergut and associates reported an excellent growth response
- N' Y B1 w! F4 gto topical testosterone with low levels of serum testosterone,) B) k( s. g6 W% o
suggesting a local effect.1 Others have obtained growth re-, U' m p5 e5 t6 z5 V
sponse with high. levels of serum testosterone after topical( m0 Y/ g. V2 t4 \% A
administration, suggesting a systemic response. 3 The use of( @0 B2 g2 z& x& {9 T( F: Y
gonadotropin to obtain levels of serum testosterone compara-
" u3 {1 E& J; G: d' d9 @ble to levels obtained with topical testosterone would seem to
4 d' r& y" V6 q6 i& v( ]provide a means to compare the relative effectiveness of0 U! z( l4 I" @& H u Z% }
topical testosterone to systemic testosterone effect. It cer-3 x/ Z" o4 N; f% T
tainly has been established that gonadotropin as well as par-' O2 i% @: Z( s: r
enteral testosterone administration will produce genital% |3 H1 Z7 s$ V Y! Y
growth. Our report shows that the growth of the phallus was/ D w! t* S2 ?" `+ F) b3 ~
significantly greater with topical applications than with go-4 ^/ K/ n2 |3 Y
nadotropin, particularly in children less than 10 years old.
2 `9 p1 [- ]) V3 B- m. WThe levels of serum testosterone remained similar or lower$ x$ a9 l/ x) T
than with gonadotropin during therapy, suggesting that topi-
5 n& O2 a* k7 v) k& E E* W8 Gcal application produces genital growth by its local effect as# b% D3 v9 ^4 s& y: S9 O
well as its systemic effect.
c9 b& q: k+ \; |7 s; IReview of our patients and their growth response related to; T! D8 C. ~& _# n6 V K) E2 [% K
age shows a greater growth response at an earlier age. This is
2 G Q$ o& R' R& }; A9 s& Gconsistent with the findings of Wilson and Walker, who
# k f" q, B% I: Q6 d4 F; wreported an increased conversion of testosterone to dihydrotes-
! Z+ b' v0 ~* Itosterone in the foreskin of neonates and infants.4 This activ-0 y; d3 U8 i6 j S5 }; a, s
ity gradually decreases with age until puberty when it ap-/ A8 x; i* r' |# d
proaches the same level of activity as peripheral skin. It may4 E' E( `$ ?! h* k, E1 [
well be that absorption of testosterone is less when applied at9 ^" P7 `% d1 k# Y5 h
an earlier age as suggested by lower serum levels in children
8 r; J* j4 T" ]0 P" t2 Xless than 10 years old. This fact may be explained by the
; F8 V$ o; k5 D ~1 Jgreater ability of phallic skin to convert testosterone to dihy-. \0 e, D; o7 Z1 R
drotestosterone at this age. Conversely, serum levels in older
# i2 N) g: H' i# h' N) I9 k0 `$ G, Qpatients were higher, possibly because of decreased local
& C0 r1 _. ~0 | p) i667
" W% t! @! T' z8 y0 S+ F% U$ V0 k668 KLUGO AND CERNY
" H4 G# b' [( \6 _" wPt. Age
3 a+ {% |- V, V8 n(yrs.). j( W; Y( Q9 @
Serum Testosterone Phallus (cm.) Change Length
! D$ s, J0 I% |! h% u9 e% L5 v(ng./dl.) Girth x Length (%)% w& o3 v# \& a% i8 F# V/ M0 m
4& _/ K3 ]7 j! h5 ?. I' b) L8 T
8; |3 R1 W- W5 \* ~1 L: i
10) {" o: y3 o( ~* j, \
12
$ c+ c) T5 j/ p \8 i17
& f" L3 m. L vGonadotropin
( v/ B* w& F: I71.6 2.0 X 3 16.6
' p1 k+ r( W5 e$ ^+ j+ _50.4 4.0 X 5.0 20.0
: L+ s$ X: U/ K z8 s, |* `# s22.0 4.5 X 4.0 25.0
5 \2 u; ?( }6 g. T84.6 4.0 X 4.5 11.1/ {6 e# J( g5 K; n! X5 {
85.9 4.5 X 5.5 9.05 }' B A L1 F
Av. 14.3! X1 @, s* R- l
4
" x% A) {1 X" A* S& a) D8 n8
! \' }3 o/ }, j- q" D3 j10' t/ t* G4 |; l8 I* f& @; L' s
12
7 v- j f# z2 S4 M2 d17
$ y. u0 x, k) R# L' n" l9 eTopical testosterone
0 m& |# L0 J) ], u34.6 4.5 X 6.5 85
% Z7 t" X- V8 x' C' Q38.8 6.0 X 8.5 70. X+ L2 k9 {( G% J8 d
40.0 6.0 X 6.5 62.5
( b, A$ {) s( A93.6 6.0 X 7.0 55.5
: d+ |) B3 I. j/ V9 v6 D2 R95.0 6.5 X 7.0 27.2
* K* ?9 z. w& a5 ~; ` X4 ?/ k$ KAv. 60.0. x& U. f+ ~3 S' u
available testosterone. Again, emphasis should be placed on5 {+ o/ {+ N5 e0 }! L. j+ n
early therapy when lower levels of testosterone appear to
2 q' w; [) _" g# c) Fprovide the best responses. The earlier therapy is instituted
, n2 q, B! H$ v& b0 Gthe more likely there will be an excellent response with low
5 s: ~( S" D: J1 Sserum levels. Response occurs throughout adolescence as
$ d( a2 Y1 I: w; y; \noted in nomograms of phallic growth. 7 The actual response
' k I% R0 V z9 Jto a given serum level of testosterone is much greater at birth2 W6 G% M" H1 t4 W
and gradually decreases as boys reach puberty. This is most
. ]/ n9 M0 i8 U9 ?% Qlikely related to the conversion of testosterone to dihydrotes-
+ w- h/ F+ S. X/ D4 c% Y6 S! atosterone and correlates well with the studies of testosterone
% K+ x, ]4 Y: z' x# z7 hconversion in foreskin at various ages.
' T% K! t2 w* o. l4 Y+ GThe question arises regarding early treatment as to whether
. F' u+ T. K5 ~) |! G4 Yone might sacrifice ultimate potential growth as with acceler-
5 M. A8 T' X9 `ated bone growth. The situation appears quite the reverse
! K( v" m0 T# H1 K. swith phallic response. If the early growth period is not used ]1 ]7 U+ [) E
when 5a reductase activity is greatest then potential growth; z! U2 Q) |0 q6 h
may be lost. We have not observed any regression of growth
4 x' {1 c; o- y' q5 |attained with topical or gonadotropin therapy. It may well/ N3 ]- Y3 y( K" H$ a `& ~
be that some patients will show little or no response to any5 |3 n' d# X7 x9 m
form of therapy. This would suggest a defect in the ability to7 `: `/ U& s C2 o
convert testosterone to dihydrotestosterone and indicate that
3 U7 q6 q% ~ \, ^ \phallic and peripheral skin, and subcutaneous tissue should
1 b' Z' B6 B; S/ Lbe compared for 5a reductase activity.
; `( M8 b& w4 ^; k" bA, loop enlarges to measure penile girth in millimeters. B,/ O" Y; k. X E0 o2 z3 ?+ D- d2 B
example of penile girth computed easily and accurately.
) W* |6 |% v; u2 econversion of testosterone to dihydrotestosterone. It is in this% U$ l' @; k& E" S
older group that others have noted high levels of serum
5 T! t6 k! u+ `testosterone with topical application. It would also appear
# `$ J0 x2 \ \8 c Pthat phallic response during puberty is related directly to the
9 r8 r8 y( J4 H1 Gserum testosterone level. There also is other evidence of local# W4 @/ M3 ^( I# \. l, |8 A1 _
response to testosterone with hair growth and with spermato-6 g+ O/ K' k! e9 S6 C5 m
genesis. 5• 6
2 z9 F9 x7 |+ Y( x9 |) ^3 tAdministration of larger doses of gonadotropin or systemic! g6 Z- t; m8 O0 r
testosterone, as well as topical applications that produce
& U/ L9 ~1 }- F+ q# L9 ~# Q4 z- shigher levels of serum testosterone (150 to 900 ng./dl.), will! `) d( x% H; ~0 O& W$ Z
also produce phallic growth but risks accelerated skeletal8 k/ {. E: q; i+ t9 C& M6 `
maturation even after stopping treatment. It would appear
2 S" ^. F( h; nthat this may be avoided by topical applications of testosterone
/ O! ~" |7 v; a5 ~; Vand monitoring of serum testosterone. Even with this control0 Z: ]6 A# n7 L6 R/ B/ Z y# J
the duration of our therapy did not exceed 3 weeks at any
( y8 ~5 _ M0 mtime. It is apparent that the prepuberal male subject may
/ j# x0 e. L3 k& h& H! Ssuffer accelerated bone growth with testosterone levels near
& V& |8 [- _. O p2 v( u6 h200 ng./dl. When skeletal maturation is complete the level of
" Z+ A1 X5 z. Yserum testosterone can be maintained in the 700 to 1,300 ng./! n1 b- q _3 b' A! G
dl. range to stimulate phallic growth and secondary sexual
! \. K _+ |# ~& E3 xchanges. Therefore, after skeletal maturation parenteral tes-& w( k- i: f7 E. l
tosterone may be used to advantage. Before skeletal matura-! B: h, l( D5 W7 {
tion care must be taken to avoid maintaining levels of serum, Y, l$ [, [# C) X7 X2 E; U
testosterone more than 100 ng./dl. Low-dose gonadotropin
" `5 a$ G9 N. Fdepends upon intrinsic testicular activity and may require
9 ^1 v( T' }! z* F! G, Xprolonged administration for any response.- g8 O; B, B' L$ i1 S. Q9 Y
Alternately, topical testosterone does not depend upon tes-
6 A& G( l1 M+ @ticular function and may provide a more constant level of
9 n3 }6 Q% F" i. JREFERENCES
1 k+ E2 _' Y, k1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,, b& {0 e0 o* E4 z8 j
R.: The local application of testosterone cream to the prepub-
H0 W5 }2 J& i6 L) |: _ertal phallus. J. Urol., 105: 905, 1971.
: w# ]9 f9 [3 s1 `, a9 Z4 }% }9 H3 O2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) C, e% Z4 ], d6 Ftreatment for micropenis during early childhood. J. Pediat.,% h; V/ ^. T/ \! _. |0 s1 [
83: 247, 1973.
! s3 ?& g7 m- p3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-5 S* A1 f3 G2 t3 u6 {0 e: z
one therapy for penile growth. Urology, 6: 708, 1975.
/ b/ |* q2 V# o/ `3 ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- {" \1 {' I9 G% v* P& V: hto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% g, u# W! {+ E; G& o
skin slices of man. J. Clin. Invest., 48: 371, 1969." X F# U4 S; P0 ^: v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- J/ N; V+ d) r& d
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. W! ^' ^5 a6 w3 h6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& g9 u. _3 l! o* d3 k; q
androgenic effect of interstitial cell tumor of the testis. J. v0 j, W) Z! [
Urol., 104: 774, 1970.6 d& y6 ~, Z- A; T8 a" W" b; D
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 e p" Q! n* V3 K O5 K" mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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