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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' X2 Y8 j7 m0 [+ g D# ]* f
GONADOTROPIN9 O( V7 X. @- Y8 j& g
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 O6 S% U1 q! [! p. y1 f3 y( FFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan. M& ?. T" f3 A2 z$ N7 l+ k
ABSTRACT, d% U; F8 V# f; Z; I) l
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 N0 J: K# \# Y7 B; q! a1 j6 j' w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
# C( Z3 i \0 F, H% M# i- wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone }( W1 A: |. h
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" v4 d- H& ]/ y+ S2 Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
* X% n+ Z" r* I9 m& ~increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average0 V' _5 q) O8 E/ N# g! E+ ~
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% p- ~/ ?( Q# E' B: i$ D8 {occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
! W* z& u$ Q' u! @( n5 m% T9 g0 r7 tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% b7 U. d6 e: S
growth. The response appears to be greater in younger children, which is consistent with previ-
$ N0 q5 [% U. a7 Y2 H# P3 q+ Oously published studies of age-related 5 reductase activity.
0 C8 ]8 z9 d4 ~6 tChildren with microphallus regardless of its etiology will2 ~- a) o7 V3 w2 ?% N
require augmentation or consideration for alteration of exter-+ o$ C) W& x9 I, C
nal genitalia. In many instances urethroplasty for hypo-
. G5 R' ]: w$ }/ P) D% s. Yspadias is easier with previous stimulation of phallic growth.
' a* M& Q% P' }$ n1 z ?3 ^The use of testosterone administered parenterally or topically( |, `4 ?- C: n$ z9 w: q! S
has produced effective phallic growth. 1- 3 The mechanism of3 C% E, P7 p7 j2 Y8 j+ U
response has been considered as local or systemic. With this0 E& c$ E0 P# d& R* V
in mind we studied 5 children with microphallus for response
: k! H& g" u3 R% i4 Mto gonadotropin and to topical testosterone independently.) ]4 H& D$ [8 x- ]
MATERIALS AND METHODS, L# @; v2 O D& e
Five 46 XY male subjects between 3 and 17 years old were
( A8 M+ ]" O1 E6 L' s2 Q: `* G# eevaluated for serum testosterone levels and hypothalamic
2 N: d5 f% o) B6 r" E, m8 d4 S( ffunction. Of these 5 boys 2 were considered to have Kallmann's" t% r" k6 G7 B/ R. |
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 F# l2 r% g' wlamic deficiency. After evaluation of response to luteinizing/ _3 {5 z: i" O' U: y
hormone-releasing hormone these patients were treated with
) l6 Z, @+ `: G1,000 units of gonadotropin weekly for 3 weeks. Six weeks; A: Q1 I& Y3 U
after completion of gonadotropin therapy 10 per cent topical
5 _7 k# p, s$ @5 r: h2 Btestosterone was applied to the phallus twice daily for 3 weeks.
# I- v f3 q& M3 DSerum testosterone, luteinizing hormone and follicle-stimulat-4 S' m8 X$ k' K! j. S
ing hormone were monitored before, during and after comple-, [; }9 {" ?4 B. T8 y) |1 }$ z
tion of each phase of therapy. Penile stretch length was
+ r" Z' e8 L) M! Y5 z. {7 mobtained by measuring from the symphysis pubis to the tip of/ f$ U1 h7 S- `) n+ O) s/ o6 a
the glans. Penile circumferential (girth) measurements were% N5 B" q' h6 {0 y
obtained using an orthopedic digital measuring device (see! I$ `9 M: |% U5 p& H+ f- r0 N* h
figure).0 ^$ I2 I2 y' t- `: J. }- M2 `) X
RESULTS
$ q8 I& n+ ~- ESerum testosterone increased moderately to levels between0 b/ Z5 `! B4 C1 o% U
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# F, R8 g/ `) \( qterone levels with topical testosterone remained near pre-) q8 g0 n+ ~! Q* b* N
treatment levels (35 ng./dl.) or were elevated to similar levels5 R* f# H. L9 S0 a: E
developed after gonadotropin therapy (96 ng./dl.). Higher
: t' H; r- Y4 F( ?8 d! t- N3 L7 Zserum levels were noted in older patients (12 and 17 years old),4 r- E% f3 w' H5 F
while lower levels persisted in younger patients (4, 8, and 10
, E% }+ R6 c- t' P* m2 s; Fyears old) (see table). Despite absence of profound alterations
h0 c x% O; h% pof serum testosterone the topical therapy provided a greater6 }/ f% e- @# Z0 d
Accepted for publication July 1, 1977. ·! Q" v4 q: M# T6 a0 u$ u
Read at annual meeting of American Urological Association,4 W1 y6 B" |- n1 p8 F O
Chicago, Illinois, April 24-28, 1977.7 k6 J2 p7 X6 F: J
* Requests for reprints: Division of Urology, Henry Ford Hospital,) j- g. I" E2 [& Y
2799 W. Grand Blvd., Detroit, Michigan 48202.! L% {. Q/ g' ~$ v& x& B
improvement in phallic growth compared to gonadotropin.
! G9 a9 P6 e3 J& K/ C& dAverage phallic growth with gonadotropin was 14.3 per cent5 f1 [* G: M3 Q i; l5 n1 J- h1 c
increase in length and 5.0 per cent increase of girth. Topical0 z$ v4 R) u1 H9 K" |) b @8 r- y
testosterone produced a 60.0 per cent increase of phallic length2 a% F" j, t9 v4 S5 S) @: c( s
and 52.9 per cent increase of girth (circumference). The& b, M, _1 s3 C
response to topical testosterone was greatest in children be-
6 e: L, o, g! ]+ X/ S7 mtween 4 and 8 years old, with a gradual decrease to age 17
4 g$ h7 t5 X" J1 t5 N! M1 fyears (see table).
9 V' ?' y |- ^8 ?2 b) KDISCUSSION" y1 i+ n! d5 p H* d" u. A1 ^& D
Topical testosterone has been used effectively by other
0 a' B9 L% ]( f8 R1 J5 b2 \% Tclinicians but its mode of action remains controversial. Im-
: V: |$ \, Z- P; ]3 h) Fmergut and associates reported an excellent growth response
; ?8 \! ]1 k# |- {4 }; \to topical testosterone with low levels of serum testosterone,; p- U) I/ K4 W
suggesting a local effect.1 Others have obtained growth re-4 \# p% X' T; g: z- m& p. |
sponse with high. levels of serum testosterone after topical
3 t; `: ^" H! k$ D$ Nadministration, suggesting a systemic response. 3 The use of
5 d5 s" `; p$ `6 W; n; I5 F ~gonadotropin to obtain levels of serum testosterone compara-7 [) V: q r. ^9 A( d2 }
ble to levels obtained with topical testosterone would seem to9 E7 F) v+ H2 d3 }5 C; V
provide a means to compare the relative effectiveness of0 b0 T* N, K0 k! J3 r7 c1 p
topical testosterone to systemic testosterone effect. It cer-5 u& e, p4 u7 R5 U# j/ N% O0 c# O
tainly has been established that gonadotropin as well as par-* x r2 q5 d" m, t: t" S' G
enteral testosterone administration will produce genital" t( q1 [ Y' Y6 N% J) M# n& Q7 w
growth. Our report shows that the growth of the phallus was
: A2 |& i% ?+ ?; esignificantly greater with topical applications than with go-) A$ @4 A% B# D- S! U5 x. V
nadotropin, particularly in children less than 10 years old.7 U$ K/ q6 s2 d0 F" t4 @0 Y! i
The levels of serum testosterone remained similar or lower
/ q0 g+ t$ K; v& _" w) Othan with gonadotropin during therapy, suggesting that topi-; g1 H9 J2 u/ D( g/ Q
cal application produces genital growth by its local effect as
' B2 L& D/ E/ h: H0 N* hwell as its systemic effect.
% o1 n7 u% M% cReview of our patients and their growth response related to; c( G. @# n# Z$ |
age shows a greater growth response at an earlier age. This is
( g! ?! x8 T1 \ wconsistent with the findings of Wilson and Walker, who
4 I) n3 x r3 Y8 ~/ mreported an increased conversion of testosterone to dihydrotes-% @) F+ U" H0 h3 }
tosterone in the foreskin of neonates and infants.4 This activ-
$ C8 ]7 [8 B; Pity gradually decreases with age until puberty when it ap-
- e' `) F& }+ m- s( Hproaches the same level of activity as peripheral skin. It may
) s9 K. Q3 O4 `% T/ k, S: Dwell be that absorption of testosterone is less when applied at" S. A: W, m# l0 v
an earlier age as suggested by lower serum levels in children
4 v2 A5 l2 l7 P6 f# iless than 10 years old. This fact may be explained by the" v: ], ^4 L$ G1 }; {9 E
greater ability of phallic skin to convert testosterone to dihy-$ Y( F$ J% J( |2 A; e' X( T6 J
drotestosterone at this age. Conversely, serum levels in older
) c* G2 D1 _8 ~3 a tpatients were higher, possibly because of decreased local
2 Y. j. Q: d! j* W w! q2 h6679 c3 f7 N* y+ Q* O
668 KLUGO AND CERNY
, Q8 w+ j' h$ V5 ]2 @Pt. Age5 b } Q: I3 i8 J4 E; S
(yrs.)+ m6 t9 W/ s. j7 X& p
Serum Testosterone Phallus (cm.) Change Length% r2 _! Q1 l9 B- A
(ng./dl.) Girth x Length (%)& g& R' c; J4 J; ~5 u
4( q+ ], W; Y. H R. s' d( a
8
9 D# u% p$ T s0 o104 N' W+ [" A, T0 q) ?; C9 E
12: I( }, W& R9 G' o
17
: T" o3 i5 Z0 D0 ~9 b' SGonadotropin6 C$ ?' q6 y0 x: H- v
71.6 2.0 X 3 16.6
( b4 Q! a3 N' z9 J. u6 t! F% U50.4 4.0 X 5.0 20.0
* @/ t# u! r4 k$ | h22.0 4.5 X 4.0 25.0( p/ ? s6 d; a$ n; H2 v5 ^
84.6 4.0 X 4.5 11.1& A! J- S C% Q/ T X8 L
85.9 4.5 X 5.5 9.0
$ [$ D; z1 I6 mAv. 14.3: Q9 r$ c* c$ P1 t& o/ y; G
4
) z5 b: w9 j r1 g3 i% q2 [6 V86 M! u; ]4 H. t
10' ?! v' K$ ~* R2 M) f7 x. X; O
12" L0 w" {, `0 C* F1 s" a6 n
17, D/ G5 T+ H' M" z. b0 n
Topical testosterone/ |& A, Y L7 e( O
34.6 4.5 X 6.5 85
, n% b9 O! @, S38.8 6.0 X 8.5 70$ e8 L' v4 O5 ]# B. n7 v% v
40.0 6.0 X 6.5 62.52 J, `/ f# n$ t% H2 Q
93.6 6.0 X 7.0 55.5
! f) I- \( G+ J+ F7 K95.0 6.5 X 7.0 27.2% y/ h0 j8 r* C. W3 g9 d& r' {) A
Av. 60.0 F6 B9 M4 C5 v+ z' c
available testosterone. Again, emphasis should be placed on
7 N+ Q6 U! _: h- G1 x5 i4 hearly therapy when lower levels of testosterone appear to
. n; [% b/ K8 }! kprovide the best responses. The earlier therapy is instituted
( }$ v3 s- l+ Pthe more likely there will be an excellent response with low
4 v' T* |- j+ V( H" S" Q$ mserum levels. Response occurs throughout adolescence as+ G) h, f2 }- a* J( {% h& U
noted in nomograms of phallic growth. 7 The actual response/ v( R. c& B7 \2 z: T5 \; }
to a given serum level of testosterone is much greater at birth
" t! N0 k( R0 c' k% S& Q0 Wand gradually decreases as boys reach puberty. This is most* T8 i5 Q' W# M$ }
likely related to the conversion of testosterone to dihydrotes-
$ O4 V4 _% x4 Z0 w4 Qtosterone and correlates well with the studies of testosterone
9 G' y; }' X" a7 }9 J6 O+ B: `conversion in foreskin at various ages.( A: g' ?% c, i4 D8 M
The question arises regarding early treatment as to whether
; q4 E% O' _0 wone might sacrifice ultimate potential growth as with acceler-
9 i! G# M p5 n; ^5 {9 J# Y3 i7 vated bone growth. The situation appears quite the reverse
, X! Z' h8 t2 q) ^with phallic response. If the early growth period is not used9 V! ]4 R2 B5 r9 g! d
when 5a reductase activity is greatest then potential growth' K4 v$ e% i' r- Y6 ]
may be lost. We have not observed any regression of growth( G' x( Z: P. ?
attained with topical or gonadotropin therapy. It may well
3 G1 T1 j. \0 v3 V2 k5 Mbe that some patients will show little or no response to any5 h$ f; E* I2 h! G$ W4 I0 J
form of therapy. This would suggest a defect in the ability to1 N# D- h4 s% J) V3 d) v
convert testosterone to dihydrotestosterone and indicate that* V2 G7 e# t6 q: {: h
phallic and peripheral skin, and subcutaneous tissue should
$ a; m% ~5 a( g+ `8 N& ]& W xbe compared for 5a reductase activity.% {3 r- e6 E& U+ R* L+ A/ U
A, loop enlarges to measure penile girth in millimeters. B,4 j6 W7 ~7 ~/ O& q5 @
example of penile girth computed easily and accurately.' t0 E ?; W C3 y
conversion of testosterone to dihydrotestosterone. It is in this
: b2 \1 {8 t' q1 j/ c) _ Oolder group that others have noted high levels of serum
- ]) X" w' c5 o- K8 J* _ dtestosterone with topical application. It would also appear
( L1 s4 q2 J5 O6 {7 e5 z5 J) a0 x1 I* ~that phallic response during puberty is related directly to the
; ^& M! ^3 ?4 I, ]) |serum testosterone level. There also is other evidence of local _0 ]" j8 b# [
response to testosterone with hair growth and with spermato-* H; J [+ f1 @2 }, Y9 s% e, @
genesis. 5• 6( u+ ]/ a2 [& j1 z0 a- g7 l" c
Administration of larger doses of gonadotropin or systemic
* g0 Y3 L# V( @- `testosterone, as well as topical applications that produce
, B! F1 n; F, |& T# i2 |higher levels of serum testosterone (150 to 900 ng./dl.), will
# L5 B) Q2 c4 n! \also produce phallic growth but risks accelerated skeletal& d1 C! P3 B4 r6 _
maturation even after stopping treatment. It would appear
7 _, I' {1 U: V7 j, l4 Lthat this may be avoided by topical applications of testosterone8 P1 F# N; T U1 v
and monitoring of serum testosterone. Even with this control4 p2 I7 J( K+ \1 p/ i, G# o3 c
the duration of our therapy did not exceed 3 weeks at any; L# a" @$ M. q5 a5 I- i* Y
time. It is apparent that the prepuberal male subject may; c" ]: {% G6 J& M b8 I
suffer accelerated bone growth with testosterone levels near
B, W: v) c7 T200 ng./dl. When skeletal maturation is complete the level of$ L9 }* Y( W+ p
serum testosterone can be maintained in the 700 to 1,300 ng./! } g9 u4 G+ T# s! k
dl. range to stimulate phallic growth and secondary sexual
6 z- f2 u' v7 g/ f2 fchanges. Therefore, after skeletal maturation parenteral tes-3 _3 F1 N4 c5 A$ p" p, O# i' m1 M
tosterone may be used to advantage. Before skeletal matura-; f' l/ m% D+ H8 W$ O
tion care must be taken to avoid maintaining levels of serum. T$ ]8 b6 S, R/ z, Z4 S9 `& p7 D
testosterone more than 100 ng./dl. Low-dose gonadotropin" X4 i5 f: G( M+ y$ g9 U
depends upon intrinsic testicular activity and may require. Y" e/ g. I+ e
prolonged administration for any response.
; K9 Q u4 _! E6 c- p1 o4 tAlternately, topical testosterone does not depend upon tes-
" g1 Q' Q9 D! Z' d0 v2 [, h: Mticular function and may provide a more constant level of
, r$ {7 v7 E, ~0 NREFERENCES
0 h5 E8 |) Y1 O5 r- w1 a1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 L! i' q# Q" L1 m5 C* d
R.: The local application of testosterone cream to the prepub-
2 g9 O' d" U) x9 L# R" B; oertal phallus. J. Urol., 105: 905, 1971.
5 ~, q7 B! a! e6 \5 ?( T b$ O/ H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 s- y. T* A* u1 @8 Ttreatment for micropenis during early childhood. J. Pediat.,
# Y- R) E6 m$ _7 H83: 247, 1973.
% b M3 I( {+ E; C% k3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 h. E0 {7 k) V2 L: T P
one therapy for penile growth. Urology, 6: 708, 1975.
, k2 O' l" A9 R2 i) [/ H! z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
9 F# i; H4 h# u7 V e% r. g1 cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! X+ ? x9 \; [7 dskin slices of man. J. Clin. Invest., 48: 371, 1969.4 n; F$ ^2 `" W8 N, z; b7 V) Z' \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ g$ T, f( \( w
by topical application of androgens. J.A.M.A., 191: 521, 1965.
5 W H: R k( X- L1 x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ t+ w6 L, z9 j7 G
androgenic effect of interstitial cell tumor of the testis. J.4 g- x8 z# `: s& N( h# E. q( O
Urol., 104: 774, 1970.
' f- c8 W$ Y8 ]1 R2 e7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
, l, ?2 r8 |' A6 i- W- v7 Ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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