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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 |0 a8 D) f8 K; s% D1 h
GONADOTROPIN
1 S2 F% c( |9 ?% FRICHARD C. KLUGO* AND JOSEPH C. CERNY
# z# g0 T- [# R+ [From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 O W4 j$ _/ I! TABSTRACT
" n0 D* r) M8 }4 n) v5 qFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 v( {* Q3 x) b2 u m5 m
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 b) r# w' o( c6 H% ^) U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ H! p( T( R6 [" l
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. b. U, [: O( V6 a& F1 D3 ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. A8 p& ], a' E% M2 r
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average9 W+ Y9 U/ ^( {$ W/ L
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
M$ o+ v/ I7 [occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This9 F! d& m3 [. _5 m
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
7 y6 I9 z% h+ N1 f* p% K; qgrowth. The response appears to be greater in younger children, which is consistent with previ-+ ~) k& z4 m8 `, G- b
ously published studies of age-related 5 reductase activity.8 F/ j2 L8 l* e \# j$ X5 ?! B, B2 @
Children with microphallus regardless of its etiology will: p9 Q$ R' E4 Q5 u8 \* H
require augmentation or consideration for alteration of exter-. t& C5 d1 N$ b+ I5 I0 k: l
nal genitalia. In many instances urethroplasty for hypo-2 p! i" v+ F2 _2 T# m
spadias is easier with previous stimulation of phallic growth.
- n; ^) F6 F4 M1 V2 y+ BThe use of testosterone administered parenterally or topically- H! F7 V2 l, W: \6 y: f( N
has produced effective phallic growth. 1- 3 The mechanism of/ |' K0 d$ }' Y+ Z$ \+ L
response has been considered as local or systemic. With this2 ~' E8 l, u; L P; L/ ?% j& D
in mind we studied 5 children with microphallus for response
+ a' a) W8 w# g4 Yto gonadotropin and to topical testosterone independently.
p1 ?9 B1 W! G y8 hMATERIALS AND METHODS5 W% W7 R% ~% y, R
Five 46 XY male subjects between 3 and 17 years old were
# k1 V. P; l P6 o3 u1 jevaluated for serum testosterone levels and hypothalamic" H' j. g# o2 a" S9 ]2 S9 `/ ?
function. Of these 5 boys 2 were considered to have Kallmann's0 w, E7 T/ x! [' ?
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! @+ g$ O) }8 e8 z; P) Clamic deficiency. After evaluation of response to luteinizing
: {5 @/ u3 G9 }" Z8 I2 g ~/ R% y: Chormone-releasing hormone these patients were treated with
' L! \4 S; |1 ~/ `* I1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 s$ x, X) _8 u
after completion of gonadotropin therapy 10 per cent topical) G! a+ ~) X0 L8 e
testosterone was applied to the phallus twice daily for 3 weeks.
1 b8 P, K5 J/ v! w- y1 y" O" PSerum testosterone, luteinizing hormone and follicle-stimulat-
1 q0 R0 y7 f9 Q5 C4 U" @$ e$ \ing hormone were monitored before, during and after comple-, A8 H# w) A9 t2 a; y2 ?9 {
tion of each phase of therapy. Penile stretch length was$ K8 ^% b3 j6 \- r
obtained by measuring from the symphysis pubis to the tip of! U4 |$ k6 R6 H7 I
the glans. Penile circumferential (girth) measurements were' [9 a& D6 ?$ D, g. }/ R( C
obtained using an orthopedic digital measuring device (see
% x& Y- H: F1 {* ]3 ]figure).& ]; P/ \- u9 I; X7 l+ a9 I
RESULTS
) b' z0 A% t" y |* D; k3 I6 T8 QSerum testosterone increased moderately to levels between
9 w( }9 @# I. F* o50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-: g$ [ W2 A$ y4 ^ K+ u3 w
terone levels with topical testosterone remained near pre-
1 D- T* |% z0 X% P# J; t: [treatment levels (35 ng./dl.) or were elevated to similar levels
% d8 _& C" W( x# l) F' _ bdeveloped after gonadotropin therapy (96 ng./dl.). Higher) ^5 P2 \7 A, s" D$ v7 y
serum levels were noted in older patients (12 and 17 years old),
4 {7 Z% h% z0 zwhile lower levels persisted in younger patients (4, 8, and 104 K/ j) g" P0 y9 N; ` H
years old) (see table). Despite absence of profound alterations9 I2 c) s! ?2 u: ~) @& F4 J
of serum testosterone the topical therapy provided a greater2 Z% ]* g, F9 [. Y; z
Accepted for publication July 1, 1977. ·
: _* t( W/ p' `$ JRead at annual meeting of American Urological Association,) Q: i; d' G+ p, c2 Y
Chicago, Illinois, April 24-28, 1977.( L5 o) @. b4 y+ [. v
* Requests for reprints: Division of Urology, Henry Ford Hospital,% `! g ~/ N0 `' M( K, Y- c- B" f
2799 W. Grand Blvd., Detroit, Michigan 48202.6 m+ m; J+ Z8 ?1 P% r' x. u( p
improvement in phallic growth compared to gonadotropin.. c6 p0 S# S; M7 ?
Average phallic growth with gonadotropin was 14.3 per cent. d$ Y5 h4 E9 y$ \1 W
increase in length and 5.0 per cent increase of girth. Topical
" u& n% V: J ?# f; B, gtestosterone produced a 60.0 per cent increase of phallic length9 z6 }9 b+ c# Q+ q2 y
and 52.9 per cent increase of girth (circumference). The* {, R# K! n: n; G3 C5 K
response to topical testosterone was greatest in children be-
3 H( v+ w& g ]; _' ytween 4 and 8 years old, with a gradual decrease to age 17
. J) E) w0 s4 q7 T+ I! x3 L1 zyears (see table).
0 E# l6 e) {" y6 b% f+ cDISCUSSION
- O- T4 f. [) |: h @: eTopical testosterone has been used effectively by other
, T/ _. X& y& j5 b3 D3 ^" ^clinicians but its mode of action remains controversial. Im-: Y" Z* b: \! J( b7 g- K
mergut and associates reported an excellent growth response
; z Q2 \0 O) N: N) a) ?' z# _to topical testosterone with low levels of serum testosterone,
2 t. k! ~: e. s9 O. G! I* z Nsuggesting a local effect.1 Others have obtained growth re-$ i( e4 S' K7 X
sponse with high. levels of serum testosterone after topical" ^- b- \% l$ [* T, p
administration, suggesting a systemic response. 3 The use of
F/ Q5 J$ H: `5 Pgonadotropin to obtain levels of serum testosterone compara-# |) e+ N1 b$ T% j( f
ble to levels obtained with topical testosterone would seem to
9 e, s0 z5 w7 @5 p/ S i0 S" v9 tprovide a means to compare the relative effectiveness of+ l$ r ]" H$ b+ M0 h
topical testosterone to systemic testosterone effect. It cer-# ?. K. F. X0 F4 V
tainly has been established that gonadotropin as well as par-' |2 L5 q3 b6 A. t1 H0 {1 b
enteral testosterone administration will produce genital" r& f' @( [* _- d- M' Y- p4 m7 p
growth. Our report shows that the growth of the phallus was) v7 x( L9 Y. J4 a/ P- i/ q1 k
significantly greater with topical applications than with go-: g% X; q0 G7 R" @4 L: V/ N
nadotropin, particularly in children less than 10 years old.
7 A0 ~8 D9 A- UThe levels of serum testosterone remained similar or lower
& i% n/ y6 d3 G% Lthan with gonadotropin during therapy, suggesting that topi-
1 s5 ?; ~! J8 G4 Rcal application produces genital growth by its local effect as/ v: Y; E* x, N8 V
well as its systemic effect.
0 \; F/ c* n% l U( g# f. p; x6 ^Review of our patients and their growth response related to4 S6 X' u u8 q7 o. ~5 M
age shows a greater growth response at an earlier age. This is0 V! d: f Q# ]" ]0 r5 k; L
consistent with the findings of Wilson and Walker, who
& U# Z& K8 ]' k) e- ~9 \0 yreported an increased conversion of testosterone to dihydrotes-3 x6 r$ K# w' Y: I+ T& {
tosterone in the foreskin of neonates and infants.4 This activ-; C& b7 y ~+ Y4 Z# j
ity gradually decreases with age until puberty when it ap-5 S( I. j7 N9 F
proaches the same level of activity as peripheral skin. It may' \/ f/ C, X4 V+ C; H4 d
well be that absorption of testosterone is less when applied at
0 h% C8 f7 f, G4 {- K- |$ P% zan earlier age as suggested by lower serum levels in children3 l, ~9 {# y( J1 g
less than 10 years old. This fact may be explained by the' v/ H& o- j: J
greater ability of phallic skin to convert testosterone to dihy-
" T O! G! C; `5 q) j, |$ Ndrotestosterone at this age. Conversely, serum levels in older
" X& N2 Q* O! Q5 M7 i9 ~' q! Ppatients were higher, possibly because of decreased local: j6 |5 z. b. s2 L' D* r
667
7 B9 h: u, g" _668 KLUGO AND CERNY" ^5 g* g) ^1 `
Pt. Age
7 u" }) O% C- |& {7 O. L% Y. c(yrs.)- ~( C/ u2 f. C% Z3 x! S) t; y
Serum Testosterone Phallus (cm.) Change Length
) t& I8 R- K7 }' B7 r(ng./dl.) Girth x Length (%)
* g% |+ J7 h( ~# m6 S9 g: ?4 U" y9 ~7 {- I8 A
8
1 L% {5 f/ R+ N4 L" n4 U* z10
1 P; E) g3 l! z12
3 {* Q( T" J1 Y/ l/ e, Y7 f173 q3 L& T% N- q( s; T' e1 ]+ e$ V
Gonadotropin
! a" X# m2 I' U& y' y71.6 2.0 X 3 16.6
7 t. @# M3 G, O% \50.4 4.0 X 5.0 20.0( p) ?4 c. S3 i" c
22.0 4.5 X 4.0 25.0 N0 h( {0 z& W. l9 o% x* i
84.6 4.0 X 4.5 11.19 f; O7 r' X5 n( S% Z+ D4 E
85.9 4.5 X 5.5 9.09 j P; t b8 \4 |3 X' l8 G3 w
Av. 14.3
0 D& i' a5 g d0 ^( I, T1 G8 `. ~0 A4
3 @ F1 ^* D( G5 N+ n$ {& ^83 N& U* m9 Y5 e2 o7 C% B
10: V9 J& A7 F3 p/ @$ E y; Z8 C
12
H5 i& R1 L4 k, e/ F. s" D- K/ u17- V4 C; T& z$ m5 ~ J* G
Topical testosterone
9 ]( j) [+ [ }* o- @ }+ N34.6 4.5 X 6.5 85
8 D) v: m0 {: A0 Q6 p/ ^38.8 6.0 X 8.5 70
7 f% @8 ~/ k$ G' V3 y1 I$ W2 t w40.0 6.0 X 6.5 62.5
9 H8 Q f/ _( J) L9 j93.6 6.0 X 7.0 55.54 y* Q$ F2 w' J. b) E' J1 y3 l
95.0 6.5 X 7.0 27.2; i: [+ f$ v) b2 R8 y
Av. 60.08 \! b+ j" ?" i0 m" w$ M9 d) ?- @
available testosterone. Again, emphasis should be placed on
, k& X. x9 [2 t: V5 bearly therapy when lower levels of testosterone appear to' w* j/ e) {9 S3 J) r* @
provide the best responses. The earlier therapy is instituted
+ L# p$ D. y$ j+ ]6 Jthe more likely there will be an excellent response with low7 {7 g9 P3 u; y3 v
serum levels. Response occurs throughout adolescence as5 Z- H& p" Q* d9 v
noted in nomograms of phallic growth. 7 The actual response
$ M8 `8 U+ _% q. ?& r5 y% F- Jto a given serum level of testosterone is much greater at birth9 z1 }9 M; w% Y: c. J6 t; Q
and gradually decreases as boys reach puberty. This is most' t. g5 ?( C1 L5 g; `
likely related to the conversion of testosterone to dihydrotes-
2 b2 t2 }5 k j$ U# I. Ctosterone and correlates well with the studies of testosterone
" E. o7 h- P; o; o. Pconversion in foreskin at various ages.
% B3 G3 R0 W5 c1 H$ v QThe question arises regarding early treatment as to whether( \1 d1 m5 e b& b/ u
one might sacrifice ultimate potential growth as with acceler-
- K+ |6 D% P% Iated bone growth. The situation appears quite the reverse
+ D' }% ~2 O0 a5 o, S6 P( u$ N4 \with phallic response. If the early growth period is not used7 W7 `0 ^6 o) U7 S4 T
when 5a reductase activity is greatest then potential growth
; i" x; E$ z& Q# I6 h8 tmay be lost. We have not observed any regression of growth
* R: G; X o: s Y3 `- }% ?4 r3 jattained with topical or gonadotropin therapy. It may well
3 p6 @3 u! G( ^3 C* t2 Hbe that some patients will show little or no response to any9 _' m |! G7 ~5 R1 @' O+ o+ K
form of therapy. This would suggest a defect in the ability to
, L% A3 L" V* B2 `9 c R9 D2 n: Pconvert testosterone to dihydrotestosterone and indicate that4 J* S: e, |, M1 \, z
phallic and peripheral skin, and subcutaneous tissue should
) Y* M( K) g: |+ |$ w( Q. Mbe compared for 5a reductase activity.: h" c* u% H, |( b k, o, u0 u
A, loop enlarges to measure penile girth in millimeters. B,
: {; |0 F' B! a* H3 ?example of penile girth computed easily and accurately.2 ^5 |7 U8 ~0 O
conversion of testosterone to dihydrotestosterone. It is in this5 g+ v( N% o. j1 ~
older group that others have noted high levels of serum: }5 k! `! P: W; G. H, z6 I! \
testosterone with topical application. It would also appear
?$ M3 q. r7 k" }9 P6 dthat phallic response during puberty is related directly to the
3 z9 o1 d r' W: x+ J1 Nserum testosterone level. There also is other evidence of local% Q$ j4 { N' v8 @! P% z
response to testosterone with hair growth and with spermato-
5 b: d/ f. ` L/ k8 d, ]- l5 Zgenesis. 5• 6
4 f: I ?) I# P- | n: S0 Z; M ]Administration of larger doses of gonadotropin or systemic9 E E, Q }) r9 A
testosterone, as well as topical applications that produce
# e) I- p3 |$ ~: Lhigher levels of serum testosterone (150 to 900 ng./dl.), will
_$ H4 W. ]% Y. v7 J, u( O, valso produce phallic growth but risks accelerated skeletal& h( b0 x* r: W+ m
maturation even after stopping treatment. It would appear: s8 a8 F' ^8 X/ q
that this may be avoided by topical applications of testosterone
# r3 i5 A- [6 N( u2 d5 Pand monitoring of serum testosterone. Even with this control
8 T/ ^5 S4 F$ d; fthe duration of our therapy did not exceed 3 weeks at any. S( X( e- p( j! t/ t
time. It is apparent that the prepuberal male subject may
8 f3 G6 ?3 s8 X3 y) zsuffer accelerated bone growth with testosterone levels near7 H8 z- p9 _5 F1 N
200 ng./dl. When skeletal maturation is complete the level of
+ f( B# ^2 H- ?) @serum testosterone can be maintained in the 700 to 1,300 ng./
8 F, j$ f% O3 ydl. range to stimulate phallic growth and secondary sexual
' ~$ N; d; L T) G7 m B1 H3 i) B6 i/ Tchanges. Therefore, after skeletal maturation parenteral tes-# }5 s$ ]8 x* D. ^5 k
tosterone may be used to advantage. Before skeletal matura-- {( X: R& X) G3 `& \
tion care must be taken to avoid maintaining levels of serum
/ @* u+ J/ S6 v1 t+ q% I! wtestosterone more than 100 ng./dl. Low-dose gonadotropin
! H% P! l% i/ _5 i7 ]5 Jdepends upon intrinsic testicular activity and may require
# v) W/ W% x% r% n+ \4 l* A6 Kprolonged administration for any response.
: H+ W6 Q" V5 Y4 h) y" BAlternately, topical testosterone does not depend upon tes-- C6 |+ ]! A" _" L6 T
ticular function and may provide a more constant level of' K9 r) s! j8 ?( Q5 t
REFERENCES
& t+ ^$ }9 e1 k/ ?; f, c1 |/ s1 j4 w1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,2 X% G4 ^- q$ o, r' @- v& B" B, T) j
R.: The local application of testosterone cream to the prepub-
3 L/ k8 ]3 Z8 B# L" t2 J! @ertal phallus. J. Urol., 105: 905, 1971.' K; Z' X2 O) e8 H
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, f6 {0 s* k& d0 ?% Ntreatment for micropenis during early childhood. J. Pediat.,
9 J6 O* K2 N+ \ F6 ~$ |; u$ |83: 247, 1973.
% {% q0 H0 Y/ s& _/ e2 U3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, }5 k4 {2 r- N. Z- k& |1 n
one therapy for penile growth. Urology, 6: 708, 1975.* q3 ]+ s* } k
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ Z' N9 ]9 V7 j6 u5 G# g! S( x. q+ vto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ E* y6 \; {* |2 N
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, d* m2 c6 M2 S7 `* x2 Z+ l; _5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# V$ q( W4 w9 w6 ^! hby topical application of androgens. J.A.M.A., 191: 521, 1965.3 x; N' `+ m+ R, Y+ F% X' m7 t
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local H* a4 ]- b7 b
androgenic effect of interstitial cell tumor of the testis. J.: x5 c7 O2 o. B! X: b$ B0 Z# T
Urol., 104: 774, 1970.
/ }5 ~" \3 W0 c9 P2 R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; e* f8 }2 p- v/ j/ F
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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