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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% p. S0 A) x1 r& N1 T
GONADOTROPIN
& {8 T" o! `3 ?% N% fRICHARD C. KLUGO* AND JOSEPH C. CERNY$ x( c8 n; S1 f1 V
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 }" @1 T% J) N( ^3 L# CABSTRACT
9 K4 o* X! a: y& K3 c2 w( MFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 ^ R" b F/ L( A ]. S3 S
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-1 Y( [: S8 f4 Z2 U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" C: ^, i/ T! K @! n' x1 e
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# q6 i# A6 A0 S8 ?- o ^
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent9 Q$ l7 A+ m* x9 R+ n0 M0 b
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 n) y6 c6 ^8 A: Q) Jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& T* w0 C, K8 e+ Yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 z6 V1 R$ ]$ |study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: i9 L% k+ H) v( x, Xgrowth. The response appears to be greater in younger children, which is consistent with previ-
. P# \$ \! d& ?( `/ I% {ously published studies of age-related 5 reductase activity.; l# H _6 A7 y( {
Children with microphallus regardless of its etiology will' E5 k( V, W; \3 }$ r
require augmentation or consideration for alteration of exter-9 Q7 Q) i; D- J- \2 m5 ?
nal genitalia. In many instances urethroplasty for hypo-. j$ h7 E) s9 j8 a% f
spadias is easier with previous stimulation of phallic growth.
; J$ y! u8 K( Q* y+ p( [4 uThe use of testosterone administered parenterally or topically- a: Q$ d. r+ d5 s6 i% r
has produced effective phallic growth. 1- 3 The mechanism of1 H. R" e- D3 b/ q$ i
response has been considered as local or systemic. With this
& L4 W- b* n. d: z" M% Iin mind we studied 5 children with microphallus for response
* ~5 p# V2 d$ e7 z- hto gonadotropin and to topical testosterone independently.0 X0 n$ w, P9 J) j$ E8 d4 G
MATERIALS AND METHODS$ P9 W/ D6 y7 ^7 j/ w
Five 46 XY male subjects between 3 and 17 years old were0 L& w1 o; M% S) t/ k. y
evaluated for serum testosterone levels and hypothalamic* V- u6 s% h M' V' w
function. Of these 5 boys 2 were considered to have Kallmann's. a J1 V9 @, [& {: N* [! O
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 a0 }) I% C0 t! l$ Y/ n, Y* r
lamic deficiency. After evaluation of response to luteinizing$ \" K3 W8 X/ @- w# s
hormone-releasing hormone these patients were treated with
. c% f2 L+ L& y7 a+ k& f K1,000 units of gonadotropin weekly for 3 weeks. Six weeks
( r' K# t7 r8 V3 Z' x* rafter completion of gonadotropin therapy 10 per cent topical" Z& Q7 K+ K% ^9 a% F1 @2 e! R; @
testosterone was applied to the phallus twice daily for 3 weeks.* X; l/ v$ c; {! N0 H7 | `5 t$ A" q
Serum testosterone, luteinizing hormone and follicle-stimulat-/ ~. P0 w* k" w1 w |
ing hormone were monitored before, during and after comple-5 d) b% q; J5 A; t
tion of each phase of therapy. Penile stretch length was% C& r/ c: x- Z2 h
obtained by measuring from the symphysis pubis to the tip of
9 `# Y) G9 x& s/ \6 h# Z1 C3 X" R. c! qthe glans. Penile circumferential (girth) measurements were
7 U+ K! Q8 N7 w' ~obtained using an orthopedic digital measuring device (see0 s0 N8 u1 _0 O- ? U1 J4 s
figure). L* w0 M3 x1 U3 U9 Q
RESULTS$ u' M; m" O) R. p e' Z. E
Serum testosterone increased moderately to levels between" g3 C1 m2 G3 N6 b5 X
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
3 n/ @. [) A- @2 m- o$ Yterone levels with topical testosterone remained near pre-
4 _8 ~9 ?% O7 }" `+ Z5 jtreatment levels (35 ng./dl.) or were elevated to similar levels
' f, k- U( C' ^; T" ~5 jdeveloped after gonadotropin therapy (96 ng./dl.). Higher* x. V3 o# U8 t% E' y5 ^& z
serum levels were noted in older patients (12 and 17 years old),- |* g3 r( v& j: D# j+ |% f
while lower levels persisted in younger patients (4, 8, and 10
# M8 \2 p6 |/ z1 Y: A8 f5 o" `years old) (see table). Despite absence of profound alterations
; R& ]( _2 ]- ~! h" E: P: nof serum testosterone the topical therapy provided a greater
+ x3 ^3 Z. E2 C* o1 {" WAccepted for publication July 1, 1977. ·1 q5 d' `! T( U O5 Z
Read at annual meeting of American Urological Association,; ^/ C9 \+ p+ S9 J
Chicago, Illinois, April 24-28, 1977.! q8 z7 O/ @% g5 ^4 N" |
* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ z) R+ q" X& T6 e; y8 N2799 W. Grand Blvd., Detroit, Michigan 48202.
5 K* H: q9 X0 W, G, r: G- {9 {1 Yimprovement in phallic growth compared to gonadotropin.
# K1 b2 ^% w/ E4 t/ g: S/ PAverage phallic growth with gonadotropin was 14.3 per cent
3 n* {9 X# {0 c F2 Kincrease in length and 5.0 per cent increase of girth. Topical
1 m2 I- g' q0 Y3 L# ^testosterone produced a 60.0 per cent increase of phallic length3 q# R% V! @8 D Z7 _% M( l
and 52.9 per cent increase of girth (circumference). The
5 e# P- m8 p, W1 [( eresponse to topical testosterone was greatest in children be-
0 x, u; C$ ^% Y$ }tween 4 and 8 years old, with a gradual decrease to age 17" k+ t. e( J; ^! E1 @
years (see table).
5 u- K, o. a) o8 o nDISCUSSION+ x4 o* X- |. U; J. ` z
Topical testosterone has been used effectively by other( p) [4 O8 a3 L
clinicians but its mode of action remains controversial. Im-
$ I+ Y9 k/ X X9 j' \$ M- n3 |mergut and associates reported an excellent growth response4 n5 Z3 P' w. `9 u1 D8 X
to topical testosterone with low levels of serum testosterone,
- ~' g# s# m+ z. T/ i, ^0 k7 l5 @suggesting a local effect.1 Others have obtained growth re-' R! w9 g2 r& V2 O+ A
sponse with high. levels of serum testosterone after topical0 v: q* h9 ?& I' j3 K% b
administration, suggesting a systemic response. 3 The use of
/ n# u+ ^- w# w2 cgonadotropin to obtain levels of serum testosterone compara-
) ~& s& y5 b" g! r2 Ible to levels obtained with topical testosterone would seem to3 `/ P1 l' G1 H( C
provide a means to compare the relative effectiveness of+ ]/ O( |* E& h3 x9 `* [7 m
topical testosterone to systemic testosterone effect. It cer-
5 g: X' I4 U6 a+ c/ Q7 ~$ b! etainly has been established that gonadotropin as well as par-4 e7 l5 e1 o+ Y- x/ c' q" t. n* b
enteral testosterone administration will produce genital
8 f! k: V8 N7 p; @) Hgrowth. Our report shows that the growth of the phallus was$ w3 p w, I1 y6 B' G
significantly greater with topical applications than with go-
3 P" Q$ l6 u O9 U; L$ t& f% Knadotropin, particularly in children less than 10 years old.# d, {3 _+ Z8 p! r8 u4 | U' ?: g( {
The levels of serum testosterone remained similar or lower& H s: z3 Q) N# [& ^8 F
than with gonadotropin during therapy, suggesting that topi-
3 \" v2 \( H8 ~0 Z, I, d/ Y1 O& Zcal application produces genital growth by its local effect as
/ C3 D. ^7 H- c5 g3 Dwell as its systemic effect.
: g- R* D3 ?9 j9 QReview of our patients and their growth response related to7 f8 J6 Y% S3 o' I' n
age shows a greater growth response at an earlier age. This is- \. j6 g0 e$ e- w) n8 ?$ y; |
consistent with the findings of Wilson and Walker, who0 j( X$ _9 K! |$ B4 ]* D7 b! Z
reported an increased conversion of testosterone to dihydrotes-
- O% P4 u$ v! I& V3 `: Vtosterone in the foreskin of neonates and infants.4 This activ-
$ y8 R% a+ {0 h- Iity gradually decreases with age until puberty when it ap-
4 U) I ^1 g/ p7 `8 s$ Z+ Pproaches the same level of activity as peripheral skin. It may
% B7 z! N; u! u4 Y9 x7 p) @well be that absorption of testosterone is less when applied at2 z& o/ R: T$ ?1 v/ w5 @- t8 z. _
an earlier age as suggested by lower serum levels in children
; r; K4 a: n+ }5 o) ^less than 10 years old. This fact may be explained by the
. d) x! l [# B" v; v" _: Q8 Pgreater ability of phallic skin to convert testosterone to dihy-
, {2 w1 C+ l6 A$ o& odrotestosterone at this age. Conversely, serum levels in older
& I1 `2 g# O: M3 S L$ ipatients were higher, possibly because of decreased local
) B0 P% C* b1 L3 Q9 L: p6672 B0 V. B4 D2 p* N1 x* k
668 KLUGO AND CERNY
- M* n- Y1 C. TPt. Age. n; B4 I# P6 R& p
(yrs.)
) ^! U8 z, |, W& Z7 I+ ?Serum Testosterone Phallus (cm.) Change Length& t3 s2 t; ~. L) J: t+ p2 _
(ng./dl.) Girth x Length (%)
: k- {$ \; c' ]* s, D$ A4* b. c1 o$ ?+ C
83 C/ l( Q- y5 R' @5 {& Y
10/ j6 J* Q7 H8 v9 E# N/ {
12' S) Z [) a* v/ E1 D: b
17; a, a% ]0 o% O) b( ~9 G8 m
Gonadotropin
; n, }* a9 \9 Y; M2 z3 ~7 s71.6 2.0 X 3 16.6
]# s- b+ p( i50.4 4.0 X 5.0 20.0: f! X% f4 X5 ~" [
22.0 4.5 X 4.0 25.0
8 }( E" @3 f0 i84.6 4.0 X 4.5 11.1
, r" g7 |1 L1 {( J3 g/ J3 U85.9 4.5 X 5.5 9.0; c, |# x/ l7 s. ^* J( [$ G. [7 r4 n
Av. 14.3
6 \2 v: E" |1 d" m% z43 V) l8 l% R8 v2 O
8
8 h* V' U$ g/ I10
5 I$ H, \# B( O. e( S0 X) n5 x123 f' }8 w* ~7 V `( D9 Q/ C
17' X9 }6 E, X" W" X
Topical testosterone; T9 A! p) {: H: V
34.6 4.5 X 6.5 85$ Y% W E7 ^5 r) e V5 w
38.8 6.0 X 8.5 70
5 R4 f" z5 f9 ^" H/ y- q40.0 6.0 X 6.5 62.5
I7 |/ y/ f0 U: I4 A* }9 D93.6 6.0 X 7.0 55.5
$ A! y6 D# N6 Q5 g3 z% T95.0 6.5 X 7.0 27.23 K9 B( v. f1 P2 `7 F% h- Z) M9 t
Av. 60.0
% ?/ z5 Z! l1 c* pavailable testosterone. Again, emphasis should be placed on/ j/ k- e; C: P+ q
early therapy when lower levels of testosterone appear to0 e3 X8 J+ C3 b( y- p9 I
provide the best responses. The earlier therapy is instituted" T$ E1 _# ]6 _7 w: y) v# `! A
the more likely there will be an excellent response with low
% r; \1 q e9 K. q7 n ~: d% m% Jserum levels. Response occurs throughout adolescence as/ X# G# ^' k ^ |
noted in nomograms of phallic growth. 7 The actual response
/ P6 u! V; B; ^" Dto a given serum level of testosterone is much greater at birth) v3 j- Z. R/ q8 D! ~$ w' o
and gradually decreases as boys reach puberty. This is most- U5 C3 F P0 u
likely related to the conversion of testosterone to dihydrotes-
/ G6 v) |' ?+ o- Vtosterone and correlates well with the studies of testosterone
0 k) U- T' u3 }) d- ~ l2 Aconversion in foreskin at various ages.' T9 g/ ~6 P% e/ R
The question arises regarding early treatment as to whether
J1 m* B. N. L+ a, f# }one might sacrifice ultimate potential growth as with acceler-2 h# U% |3 b9 s. F9 z" J' T
ated bone growth. The situation appears quite the reverse
: h3 L% k" f' Awith phallic response. If the early growth period is not used
' }/ ~" G/ v, D6 r3 g |8 K) dwhen 5a reductase activity is greatest then potential growth
J4 }; W: \3 { C [2 Hmay be lost. We have not observed any regression of growth
% {6 W4 O0 T+ j! [( { X4 {. X% fattained with topical or gonadotropin therapy. It may well
2 `$ J% C( D: J3 `) R3 u* o' r) wbe that some patients will show little or no response to any
, _0 Y/ B; R5 i" [/ W' J% rform of therapy. This would suggest a defect in the ability to
N9 p/ u2 m& {: M4 ]% N2 V5 N( oconvert testosterone to dihydrotestosterone and indicate that
& \7 }! C+ B, Y/ Mphallic and peripheral skin, and subcutaneous tissue should
' O2 p) W! e+ X! j* Kbe compared for 5a reductase activity.
" i5 b/ d5 k$ ~+ a ?A, loop enlarges to measure penile girth in millimeters. B,& _# T% x; u' b& w6 W6 [! Q
example of penile girth computed easily and accurately.
, U) e0 T W& Q; [conversion of testosterone to dihydrotestosterone. It is in this' Q2 k0 L n6 i5 e6 J. G6 u
older group that others have noted high levels of serum
, n4 L! q2 e/ G1 rtestosterone with topical application. It would also appear
: D7 s6 W- f' M$ q7 ]that phallic response during puberty is related directly to the
4 q4 Z) d: J& ]+ v; i5 f: m4 @serum testosterone level. There also is other evidence of local
$ N/ H( B7 O4 bresponse to testosterone with hair growth and with spermato-
4 X( v/ L# L) L" O6 g+ tgenesis. 5• 6* ?* {0 V/ Q% T9 T- Z
Administration of larger doses of gonadotropin or systemic6 _# m' G8 u# |, p
testosterone, as well as topical applications that produce$ u" R+ \ M" J2 i$ v
higher levels of serum testosterone (150 to 900 ng./dl.), will
: B) ?# e& z; i2 d; t, @& b. m8 X* |also produce phallic growth but risks accelerated skeletal: a, R' V; X4 F( _% J
maturation even after stopping treatment. It would appear
) D, _5 k* e+ H6 u8 k( I* n' t/ `0 uthat this may be avoided by topical applications of testosterone
/ _& o& D! y9 t; l# c% ~% l( ^and monitoring of serum testosterone. Even with this control
9 Z x7 h, f$ ^3 Y( c+ X. k+ Q& `the duration of our therapy did not exceed 3 weeks at any
( ~4 f# i1 l" a% Ltime. It is apparent that the prepuberal male subject may! x! H, T5 m! T
suffer accelerated bone growth with testosterone levels near' _6 a* G- |7 m; V, }
200 ng./dl. When skeletal maturation is complete the level of( |+ u9 E5 l" F6 R2 E5 [9 ]- N
serum testosterone can be maintained in the 700 to 1,300 ng./' ?$ ^+ u3 M' q. k( g
dl. range to stimulate phallic growth and secondary sexual5 i4 g, a7 Q, ]5 U+ X$ N" D
changes. Therefore, after skeletal maturation parenteral tes-
h# o. J4 T) A, T& r8 f6 atosterone may be used to advantage. Before skeletal matura-5 C2 {# o6 E- X1 @. F& G6 K9 H
tion care must be taken to avoid maintaining levels of serum# c# r! v8 D. O0 ^+ C3 q# L! C
testosterone more than 100 ng./dl. Low-dose gonadotropin
2 I& m' c- i/ ~: H+ bdepends upon intrinsic testicular activity and may require
, T) V8 z4 t+ q* S! q, p' c8 x. zprolonged administration for any response.
( e! l3 P `4 H- i1 sAlternately, topical testosterone does not depend upon tes-
/ p8 b2 V* c5 b7 G% x# _ticular function and may provide a more constant level of
s1 f" o$ b9 n; l* k) _REFERENCES
( o, Q/ `; {! U& P5 s1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks," h* t1 Y5 a }7 Y
R.: The local application of testosterone cream to the prepub-7 d& p9 z3 R/ ]9 c+ U7 _9 w
ertal phallus. J. Urol., 105: 905, 1971.
5 W e: e; c$ D+ V! l! |7 G2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ z, U% M7 n5 q0 p' @4 o
treatment for micropenis during early childhood. J. Pediat.,2 b$ {( Y6 C7 |4 [
83: 247, 1973.% f' t2 x$ u; v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ c( F: l0 N2 X! O. h- R' v0 U: M" [
one therapy for penile growth. Urology, 6: 708, 1975.5 L( M {; p5 B* p1 U- m3 ?' f& w
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. f9 G/ R9 _ L% m+ q. dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, i6 ~9 a0 t. D/ Z
skin slices of man. J. Clin. Invest., 48: 371, 1969.
: A! o2 k0 W$ ]1 x# ^. d4 s5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 b! ~! g3 G j5 u) h. X( [by topical application of androgens. J.A.M.A., 191: 521, 1965.
. W9 y2 W# x$ s; m6 P6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
w6 D1 u3 i3 p" N; O$ ^# iandrogenic effect of interstitial cell tumor of the testis. J.
* I- `1 E- l) M9 gUrol., 104: 774, 1970.) j( y- g3 U P. k
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
J2 b% X) g. e" r; ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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