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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- T4 m- P- A" X% J; W S
GONADOTROPIN! r/ d7 g. |/ D/ R
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 e" ~6 \9 r! I. ~1 a6 t, ^% A( oFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan9 Q1 `' T$ ?, ]: }
ABSTRACT
8 N! V. |0 t1 OFive patients were treated with gonadotropin and topical testosterone for micropenis associated
* R) p" M" D# j. ~) Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 E$ g% n; o4 T% W* a, {
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# h# {8 c& K3 K0 R2 ycream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 E' v, w6 H5 Y4 K4 t# g$ Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 C( _ ]! |% v, m5 H
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 G! W: K# o+ Q& h( Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" {1 E3 r4 [- ~: E, roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 S: i$ o8 X5 A& Nstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 l" ?$ b" @0 b5 t$ z; egrowth. The response appears to be greater in younger children, which is consistent with previ-& Q& A* D8 t+ Z, q; y/ ?+ Q$ z
ously published studies of age-related 5 reductase activity.
Q" q8 a+ h& a9 a& `; Y% d# KChildren with microphallus regardless of its etiology will
0 d4 j. j% K2 e$ d5 E3 k( _require augmentation or consideration for alteration of exter-
, v3 I) r5 [1 A8 {5 ~. Unal genitalia. In many instances urethroplasty for hypo-
: o4 I7 G* y4 d5 Yspadias is easier with previous stimulation of phallic growth.
( a" j, j5 o5 m* y/ b# W+ \The use of testosterone administered parenterally or topically
0 k, h( N& S4 g' L7 x5 Uhas produced effective phallic growth. 1- 3 The mechanism of) C R7 d& u# ?0 v1 [. C7 T8 ]- o
response has been considered as local or systemic. With this
: V$ h+ W3 e& H; J3 j% C0 s% g2 pin mind we studied 5 children with microphallus for response2 L+ o3 p+ u8 K9 c$ C T4 r
to gonadotropin and to topical testosterone independently.
4 N& |% m1 _ QMATERIALS AND METHODS6 Q" i+ y1 b N2 W
Five 46 XY male subjects between 3 and 17 years old were! V$ I% A. f( N
evaluated for serum testosterone levels and hypothalamic8 \' |: i( l7 b1 D H4 E
function. Of these 5 boys 2 were considered to have Kallmann's2 z2 Q4 A) j' q# Y: U8 a3 S
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 \- c8 h3 R( t7 ^
lamic deficiency. After evaluation of response to luteinizing$ g4 i! E: R6 R9 N9 K, O- ^
hormone-releasing hormone these patients were treated with! r& X0 o6 I; L9 h T9 G, q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 k/ x5 x3 z0 b7 @, xafter completion of gonadotropin therapy 10 per cent topical; _2 S0 W9 E+ t: w1 z' F* p
testosterone was applied to the phallus twice daily for 3 weeks.! [6 V! x6 T, ]7 V3 D& P) t
Serum testosterone, luteinizing hormone and follicle-stimulat-# ~( G O" G( [+ h% b, L- L
ing hormone were monitored before, during and after comple-
& Z! U- v8 w0 w X6 a2 ?tion of each phase of therapy. Penile stretch length was7 c0 j0 V5 B. }" W: D/ U+ h+ `
obtained by measuring from the symphysis pubis to the tip of a5 E9 e/ [" i( l- r
the glans. Penile circumferential (girth) measurements were
! ]4 ?/ i& T# o/ bobtained using an orthopedic digital measuring device (see
# n5 v7 @0 F: l% ^5 b: j0 qfigure). b( B2 \7 X3 i; j2 S
RESULTS
3 }- A4 ]" W0 C9 TSerum testosterone increased moderately to levels between% y1 L" \1 ^/ H' e
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 J' x+ i% r4 y. |+ g* q
terone levels with topical testosterone remained near pre-. Y* I" A& S) n! f3 }! n
treatment levels (35 ng./dl.) or were elevated to similar levels
% n+ u, p: V% P. s, Tdeveloped after gonadotropin therapy (96 ng./dl.). Higher/ Y" s. T* n! b& t
serum levels were noted in older patients (12 and 17 years old),
' O) N" e3 v$ ywhile lower levels persisted in younger patients (4, 8, and 10
; M) l' G% S) q7 hyears old) (see table). Despite absence of profound alterations
* [1 X! k$ }1 _( [ e) Lof serum testosterone the topical therapy provided a greater
( e, ^: ]% ?/ w) yAccepted for publication July 1, 1977. ·; ?% W8 {. w& C: I; l$ u
Read at annual meeting of American Urological Association,
1 k! F4 ~% ~7 ?" b! W9 G1 k `9 uChicago, Illinois, April 24-28, 1977.! L+ b. a# v/ s/ m) V
* Requests for reprints: Division of Urology, Henry Ford Hospital,- l5 ^' M w. @" n
2799 W. Grand Blvd., Detroit, Michigan 48202.
' y, F5 ]6 h7 f7 r8 l! E; x( b% fimprovement in phallic growth compared to gonadotropin.
5 d( V% X/ j; m2 Y- L5 q% Y! f+ {Average phallic growth with gonadotropin was 14.3 per cent& L! f& y$ ?& d m
increase in length and 5.0 per cent increase of girth. Topical
/ @* A. P! m% `3 }4 q% K) Q4 T! Ptestosterone produced a 60.0 per cent increase of phallic length2 k- @% ^1 K/ C2 H6 z( P, V
and 52.9 per cent increase of girth (circumference). The; ?3 r" C3 ?. K+ R9 P7 \! e
response to topical testosterone was greatest in children be-
* u+ f) v+ p8 n! X+ atween 4 and 8 years old, with a gradual decrease to age 170 V* y! c/ _/ ?& w: K) w
years (see table).
: V- T9 F$ ?" w. \' ODISCUSSION
g9 T& B! j2 t; t! L8 E5 ~Topical testosterone has been used effectively by other; ~+ _6 |/ X6 j& @
clinicians but its mode of action remains controversial. Im-
- O$ t8 W: E) d2 S+ W, emergut and associates reported an excellent growth response
$ H3 m. v! u. H% [! Q/ ~3 rto topical testosterone with low levels of serum testosterone,: L! ]8 [5 T# j
suggesting a local effect.1 Others have obtained growth re-# F) M' J ]. ]& L& p' Y& T
sponse with high. levels of serum testosterone after topical
+ o5 w; U) X: X2 S9 Nadministration, suggesting a systemic response. 3 The use of- ]* I# E. |; ~6 W4 u) u5 s
gonadotropin to obtain levels of serum testosterone compara-
# D O. a' Y3 \" e0 v! Oble to levels obtained with topical testosterone would seem to$ B ]0 U6 g* W( J/ O7 t) M. H
provide a means to compare the relative effectiveness of, C& c Z( t7 h3 K4 C9 \
topical testosterone to systemic testosterone effect. It cer-8 b- S U# P7 H7 }/ z5 @, d9 @
tainly has been established that gonadotropin as well as par-- {) U: y7 s2 R ^
enteral testosterone administration will produce genital4 r, ^8 a5 V+ [8 C3 Q8 v
growth. Our report shows that the growth of the phallus was, Q( v# O( U0 C: w, H
significantly greater with topical applications than with go-
5 S- s; i: T; ]) I- v7 ~5 H( w( D; }nadotropin, particularly in children less than 10 years old.
2 S Y$ D0 {# mThe levels of serum testosterone remained similar or lower
! x) j; {* f! H% X1 kthan with gonadotropin during therapy, suggesting that topi-: b% n- r# \) [! [2 x1 z& I
cal application produces genital growth by its local effect as
, [) L! x/ h4 G9 \' w% Wwell as its systemic effect. M5 R: ?8 U( R$ k# [
Review of our patients and their growth response related to6 A; D0 o+ |2 h
age shows a greater growth response at an earlier age. This is# ?; [ i N0 v8 h! S. M4 c
consistent with the findings of Wilson and Walker, who
5 g. `2 `6 z \4 [: `/ nreported an increased conversion of testosterone to dihydrotes-
2 x/ g" Y4 D. { V) Ptosterone in the foreskin of neonates and infants.4 This activ-
' J: `4 e9 U; n! o8 w, vity gradually decreases with age until puberty when it ap-3 t: K- ~# q( j" Q* `8 t
proaches the same level of activity as peripheral skin. It may% X j) T8 G0 b4 |9 P0 f' u/ r' H
well be that absorption of testosterone is less when applied at/ x& g4 x3 c* R, A) r6 A( Z
an earlier age as suggested by lower serum levels in children+ C. r7 u& R( c" i; [' v3 f
less than 10 years old. This fact may be explained by the
; p# m- L* u3 Y" l3 H% h2 {greater ability of phallic skin to convert testosterone to dihy-9 D0 l1 ~- b1 A" X; q7 B
drotestosterone at this age. Conversely, serum levels in older
I" N. m" Q; V l# p$ Kpatients were higher, possibly because of decreased local
R9 r1 W& P+ Q, \0 H7 t667; M/ A! K! R; z3 F5 p2 A
668 KLUGO AND CERNY; n6 p# x& U; i/ Y
Pt. Age
. o# `% o- u b/ r. ~7 g3 v& ~(yrs.)/ t8 l* C4 @9 c( U
Serum Testosterone Phallus (cm.) Change Length; l6 Q4 J' {. j
(ng./dl.) Girth x Length (%)
( W( I, U/ y/ w4
$ }# E% a0 W3 d% f8
7 b- y9 i* \9 k) s10, I9 }9 q w! z9 Q- g1 Z1 ?$ D. _
12
, [8 @8 a- a0 f& q* a3 M8 c175 Z% M3 a: |1 Q6 D
Gonadotropin( [4 o# i8 Z" b7 L' [: i W
71.6 2.0 X 3 16.6: L; i0 e7 d( V8 z
50.4 4.0 X 5.0 20.0) k; J- C$ a: _
22.0 4.5 X 4.0 25.0% C6 e7 {; C8 R/ ]# u
84.6 4.0 X 4.5 11.1
$ \2 `* C2 g( \! d: v85.9 4.5 X 5.5 9.0( _% h- f) F1 Z: T( K
Av. 14.3
8 h- ~) m1 `6 L6 f- e& M4
% e2 m z5 I: e4 R$ N8& q% F1 }; p- t
10
' ~% n1 [: Q5 {121 ~5 n& m' X S: }% c8 K
17
/ ^4 K& C# l4 Q2 ]) }8 q) @Topical testosterone4 X/ O: \7 ?. _
34.6 4.5 X 6.5 85
8 R3 g6 j" w) O" o* W38.8 6.0 X 8.5 70" r6 s! \ Y7 v- O
40.0 6.0 X 6.5 62.5
% v8 e8 u. ?/ l3 R R, P, i93.6 6.0 X 7.0 55.5
7 ]8 i a5 R% X95.0 6.5 X 7.0 27.2
. A% L; a" w4 k& X8 eAv. 60.05 ~/ Q1 \5 G/ s' P: v4 I
available testosterone. Again, emphasis should be placed on
4 H- j4 _8 k) k c* ^ Qearly therapy when lower levels of testosterone appear to
4 P7 ?! C7 P6 {! Cprovide the best responses. The earlier therapy is instituted
) w5 i% A/ k; c7 _, r/ Q' dthe more likely there will be an excellent response with low
; O! U9 [' E/ x0 x2 P. i6 Kserum levels. Response occurs throughout adolescence as) P& r3 f& O6 z# \0 l! n3 z
noted in nomograms of phallic growth. 7 The actual response
5 V7 [. n, K* f5 m( ?to a given serum level of testosterone is much greater at birth; U4 B, J+ b& M' [$ h1 y/ U* ?8 R
and gradually decreases as boys reach puberty. This is most
7 t3 s' y6 C. wlikely related to the conversion of testosterone to dihydrotes-
- \0 q2 R, T/ H# g. v9 U; stosterone and correlates well with the studies of testosterone
" C" m* |$ `: w. @" Y) gconversion in foreskin at various ages.5 R4 z" r& p2 T( C8 K
The question arises regarding early treatment as to whether
9 B" ~. Y# }5 l, b1 Z) ?: none might sacrifice ultimate potential growth as with acceler-9 h1 _- t W8 V! F6 b
ated bone growth. The situation appears quite the reverse
1 T& Q( s$ N, ^# ^$ t0 @9 kwith phallic response. If the early growth period is not used) i- ^& P6 Z* z4 H i7 Y& u
when 5a reductase activity is greatest then potential growth
) V( }5 U2 E: a+ H* Zmay be lost. We have not observed any regression of growth$ \( I5 ]5 A# O% ^ c* X
attained with topical or gonadotropin therapy. It may well b" @: t( E6 x, ?
be that some patients will show little or no response to any
- C; v) {, @' b* rform of therapy. This would suggest a defect in the ability to
7 f9 G$ _/ |& u Q+ aconvert testosterone to dihydrotestosterone and indicate that
3 V# G7 {. Q: Y i2 d5 Uphallic and peripheral skin, and subcutaneous tissue should& x; B; s4 a- y( t
be compared for 5a reductase activity.# |- j# q k/ N0 u8 C, ?
A, loop enlarges to measure penile girth in millimeters. B,$ h* l# z" B0 @0 r
example of penile girth computed easily and accurately.
) F* f1 }* B9 Q$ ~/ Q1 m' L; _. Bconversion of testosterone to dihydrotestosterone. It is in this
0 q1 ~. g' O7 O: X8 Wolder group that others have noted high levels of serum$ o! o! Q8 `$ ?: X; Z
testosterone with topical application. It would also appear# Q9 V2 [4 m, G$ F7 Z: c
that phallic response during puberty is related directly to the+ a: Q, r; z& g) ^
serum testosterone level. There also is other evidence of local
% A) J0 L9 ]' k @response to testosterone with hair growth and with spermato-
" I* l, h- h: z8 W" _9 Y/ _genesis. 5• 62 L! _0 u$ y5 v5 F3 o
Administration of larger doses of gonadotropin or systemic
) Q) [/ `' U9 r0 I3 i1 N Jtestosterone, as well as topical applications that produce+ J" y- _+ Q# Y6 R1 @( h& B
higher levels of serum testosterone (150 to 900 ng./dl.), will
+ J+ a' f! \5 t) Galso produce phallic growth but risks accelerated skeletal
6 k6 R! m9 b* h7 cmaturation even after stopping treatment. It would appear
/ W; m; z$ y7 b `, zthat this may be avoided by topical applications of testosterone
+ k1 o C% Z1 ` a+ e4 Fand monitoring of serum testosterone. Even with this control
4 D; Y0 |7 }8 q; c7 Hthe duration of our therapy did not exceed 3 weeks at any
0 n% l$ v9 P9 F- f3 h, [0 [! L: Otime. It is apparent that the prepuberal male subject may
2 x; E3 N- b+ r! p: Z7 L! R3 V/ G3 C- o1 tsuffer accelerated bone growth with testosterone levels near9 ~# J. ?7 F$ x8 R2 t
200 ng./dl. When skeletal maturation is complete the level of4 Q$ ^2 _6 \- V* S
serum testosterone can be maintained in the 700 to 1,300 ng./+ E! ^: y. N6 W' Y* k0 ]
dl. range to stimulate phallic growth and secondary sexual
8 B" z( L/ [6 D& y! c1 Nchanges. Therefore, after skeletal maturation parenteral tes-
+ u' }! j. K. utosterone may be used to advantage. Before skeletal matura-3 }; N1 C8 ~; F# Z4 L5 C- T j
tion care must be taken to avoid maintaining levels of serum
/ V6 `* [$ P9 x0 N; z( V* u# Z L* Atestosterone more than 100 ng./dl. Low-dose gonadotropin" X7 P& M* g' u# I B
depends upon intrinsic testicular activity and may require
+ @, x- h- j1 v& M" }prolonged administration for any response.
7 y% z4 o; y, }) LAlternately, topical testosterone does not depend upon tes-3 Z& Q2 k& ]5 W0 @: B d
ticular function and may provide a more constant level of
) i- n3 _7 X7 w" FREFERENCES
5 {) h7 q7 H/ d, s/ f" Q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 l% G4 s+ [4 u! \9 W8 _1 R/ D% kR.: The local application of testosterone cream to the prepub-3 E2 F+ |- f1 H4 W* m$ x9 X
ertal phallus. J. Urol., 105: 905, 1971.
% B; S; d# t, q( U7 W) F2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" J+ s; \5 K5 R3 ]! U
treatment for micropenis during early childhood. J. Pediat.,
- O4 `6 P9 g# s0 U2 K! M. N83: 247, 1973.8 Z. z, a# F3 O, O
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 t: z/ O5 }# l+ I: o* E# E8 c. t
one therapy for penile growth. Urology, 6: 708, 1975.) d+ q7 k v6 n0 ?; r3 L# d
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone. d9 O" {4 s" v# a* A7 ?
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
6 K1 B& F6 U8 ?* q+ P% Kskin slices of man. J. Clin. Invest., 48: 371, 1969.
! ^. o' L- a% W& p4 T/ g5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# Y! y3 ^- R- g+ n1 T" ?- nby topical application of androgens. J.A.M.A., 191: 521, 1965.
: M/ C& O# o& i6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% S. l( k: O; _1 _) ~4 u
androgenic effect of interstitial cell tumor of the testis. J.$ E- [( B) a7 m5 ~7 Y9 F/ F
Urol., 104: 774, 1970.
& x$ T g4 d& U3 _" L' I1 v1 }+ |( G X7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# v, k' }" o9 c3 \0 g2 O
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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