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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% J! ]9 h4 w/ V
GONADOTROPIN* n6 n+ U& g8 g0 z' ]3 r I) Q
RICHARD C. KLUGO* AND JOSEPH C. CERNY7 v. x) z0 l( j% i9 }4 | c$ U( T7 R
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan! R) ?) t( C+ {8 I7 d5 ]! a
ABSTRACT9 C' x( a- V9 X) [- s* y! J! M
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' Y5 N$ `0 H* c( X& a: l/ R
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 J7 @* e: F# ?. C2 w% qtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ X( G% A- a, B9 b, V. T; M
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. i! s, e( I4 h- [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
E7 A, b. }- n8 l. F; Iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 y/ i6 N6 _7 s; Y, }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 U& G0 J5 i' H$ q. hoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, u" [( i' y3 t8 D6 B- ^- [
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* s# n! M& S: A+ L* {; agrowth. The response appears to be greater in younger children, which is consistent with previ-0 F% s: n8 j/ X# k
ously published studies of age-related 5 reductase activity.- Q+ w F; I+ x$ k
Children with microphallus regardless of its etiology will% }* E& f& _# j* l$ S/ m- o/ m
require augmentation or consideration for alteration of exter-
" o+ n$ q5 t+ ~6 i. e% V9 M5 c( Fnal genitalia. In many instances urethroplasty for hypo-
# I2 g& e: T6 ?# i7 l: `spadias is easier with previous stimulation of phallic growth.( ?5 k Z R; a6 O$ h
The use of testosterone administered parenterally or topically
* W6 T& [$ }3 @& {has produced effective phallic growth. 1- 3 The mechanism of7 W' Z" C H5 i, c
response has been considered as local or systemic. With this
, u( s7 |6 p/ }" g' min mind we studied 5 children with microphallus for response
+ s% m9 s. J& Y9 x) U6 i( wto gonadotropin and to topical testosterone independently.
6 r6 r; L. e! n" X! N0 {: n4 DMATERIALS AND METHODS
6 @4 Z* q. E v4 H S: n) WFive 46 XY male subjects between 3 and 17 years old were
" J5 S9 t" h2 K8 C% r mevaluated for serum testosterone levels and hypothalamic
" U' A4 C! T" {! U$ ?# Efunction. Of these 5 boys 2 were considered to have Kallmann's
8 A }* v0 O; n; @6 f* Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' H/ _( D1 ]: a) g, A9 ~0 Nlamic deficiency. After evaluation of response to luteinizing
3 U+ \5 }; _0 |9 S9 Q" X! T3 e7 U0 |hormone-releasing hormone these patients were treated with
% Z5 C9 v. h4 {. ~. R1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 N0 v0 e1 T( O; O
after completion of gonadotropin therapy 10 per cent topical3 \6 }( @* \# x6 h/ t0 J
testosterone was applied to the phallus twice daily for 3 weeks.6 J) i5 N! {4 v5 G
Serum testosterone, luteinizing hormone and follicle-stimulat-
9 [4 ~' q/ S8 A9 R2 W( ging hormone were monitored before, during and after comple-' p$ t! f: q2 O6 S8 j
tion of each phase of therapy. Penile stretch length was
9 W6 s M/ z0 g# Xobtained by measuring from the symphysis pubis to the tip of
# r }( |) h+ L1 ~6 ]$ X" G6 }the glans. Penile circumferential (girth) measurements were
" [" o0 u I# D; V5 W8 Lobtained using an orthopedic digital measuring device (see8 E! C7 k5 z, |& q" H' T8 `, h- n( e
figure).; D7 K8 U" s% j$ V; j
RESULTS, T% H& V$ r# J
Serum testosterone increased moderately to levels between
$ W; n2 o* j7 f) J50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 Q8 O) ?* M) t2 ?) g
terone levels with topical testosterone remained near pre-$ r- w5 T; N8 n1 i2 C/ D
treatment levels (35 ng./dl.) or were elevated to similar levels! U9 h7 f# \$ K! V
developed after gonadotropin therapy (96 ng./dl.). Higher
5 \, g8 ?# m7 @& N$ iserum levels were noted in older patients (12 and 17 years old),
5 f; [ E. h8 ^! G2 Q) S5 Rwhile lower levels persisted in younger patients (4, 8, and 106 t) X2 n `5 Q* ~: } ?3 _
years old) (see table). Despite absence of profound alterations
1 L; B" X$ a! t7 \ B$ dof serum testosterone the topical therapy provided a greater2 o) P$ g4 A) L9 s4 W
Accepted for publication July 1, 1977. ·7 p+ `8 ~: u& m3 D8 G) n
Read at annual meeting of American Urological Association,
! J# x; T$ {6 S- BChicago, Illinois, April 24-28, 1977.
. D, \ L; e' m4 I2 y8 s! G& u* Requests for reprints: Division of Urology, Henry Ford Hospital,6 e9 O1 j9 J. L% |
2799 W. Grand Blvd., Detroit, Michigan 48202.# g7 d' Q- x" f! M2 [
improvement in phallic growth compared to gonadotropin., m/ J" \& {. s. I
Average phallic growth with gonadotropin was 14.3 per cent& L1 R8 ?! B7 T7 P3 i2 U
increase in length and 5.0 per cent increase of girth. Topical
4 I. P( W Z) o, [5 B8 X: \testosterone produced a 60.0 per cent increase of phallic length
5 v+ B. r+ z7 O8 i- F* c4 W% w) h$ i: Xand 52.9 per cent increase of girth (circumference). The( w' {( |% t& i
response to topical testosterone was greatest in children be-
- Y8 Z: }2 r" i+ K8 {tween 4 and 8 years old, with a gradual decrease to age 173 w! N/ W; R- x$ ] ~+ S
years (see table).
7 W) |4 Y- V/ ~( }8 D; ]DISCUSSION; K9 T9 i7 f. T. I4 U
Topical testosterone has been used effectively by other
' }4 q' `9 [, ~: }/ P# dclinicians but its mode of action remains controversial. Im-# [" v7 \- i# X; h- e: G: }2 \
mergut and associates reported an excellent growth response
" P+ |3 l. ~# E5 Lto topical testosterone with low levels of serum testosterone,: F/ D8 K. O1 ]. p4 K) ]0 [+ _
suggesting a local effect.1 Others have obtained growth re-
2 H# t5 O* j* C( G. x% nsponse with high. levels of serum testosterone after topical
# D: T$ p% x0 r/ Kadministration, suggesting a systemic response. 3 The use of
+ p! o: R6 @. X& s2 J$ ~, Q R# Pgonadotropin to obtain levels of serum testosterone compara-
/ B: L& t0 h1 } Eble to levels obtained with topical testosterone would seem to# \1 m5 F: G9 s* l2 l0 x
provide a means to compare the relative effectiveness of
4 J4 @/ ^2 T0 _5 N) [5 htopical testosterone to systemic testosterone effect. It cer-1 X1 C1 N) X3 E
tainly has been established that gonadotropin as well as par-
3 \3 L2 Q5 n' }3 }enteral testosterone administration will produce genital: d$ d7 @2 l) z- G
growth. Our report shows that the growth of the phallus was# n5 O' ]5 C/ u6 M. Q, ?
significantly greater with topical applications than with go-: \3 j/ \3 g+ H
nadotropin, particularly in children less than 10 years old.
9 o6 P% V& X2 t" ~5 a+ ?The levels of serum testosterone remained similar or lower
7 t3 [9 N+ r( Y9 |% [& C7 Zthan with gonadotropin during therapy, suggesting that topi-
9 O. I; \9 h8 w3 K" v1 S7 f, a1 E2 fcal application produces genital growth by its local effect as9 k7 G, g6 F @+ P
well as its systemic effect.
, |8 K5 ]( ~5 _# cReview of our patients and their growth response related to
6 H3 e) _, o: o6 P% u) T/ \. |9 Fage shows a greater growth response at an earlier age. This is- P7 ~. k _# t% t; V
consistent with the findings of Wilson and Walker, who
& M- T1 I* O" ?7 A3 ^5 S7 g; qreported an increased conversion of testosterone to dihydrotes-: z% K3 m( Z( D" Q l
tosterone in the foreskin of neonates and infants.4 This activ-
; P- H$ t1 U: c) m/ V hity gradually decreases with age until puberty when it ap-
1 D1 t/ u( F- @/ Tproaches the same level of activity as peripheral skin. It may t/ a' o! ^) u5 S0 [1 k( K
well be that absorption of testosterone is less when applied at4 h" v& M8 S/ R
an earlier age as suggested by lower serum levels in children
9 A& |0 L7 K, p' Cless than 10 years old. This fact may be explained by the
% o' Y0 x J' m7 @& wgreater ability of phallic skin to convert testosterone to dihy-
# T) o4 W7 c3 t8 edrotestosterone at this age. Conversely, serum levels in older
0 @1 A5 {7 O; u* a' zpatients were higher, possibly because of decreased local& F6 X6 Q r9 z7 B2 M7 y
6671 c+ R: F2 k% ]! R# A6 K9 Y* d; H
668 KLUGO AND CERNY
; V7 B# r' T/ d6 d ^0 ]( q+ a4 fPt. Age
6 b0 g) p& p; ?! s1 h& K(yrs.)4 w0 m& J! W6 b+ L8 F7 }& _
Serum Testosterone Phallus (cm.) Change Length
/ \$ M$ H: P- v/ v; C h4 ~(ng./dl.) Girth x Length (%)
2 v; |; H( k7 L4% ^. L5 H3 G8 }" @% Y ~4 \' d' r
8
- Z' y) {# |; _- D1 e0 h10
$ |( Z4 [# b8 o& W, X% p12, Q% @3 [; J2 w
17+ a1 G, {$ @* \; M7 U- `3 L& d
Gonadotropin0 K/ f8 E: W" k5 a( @& ]
71.6 2.0 X 3 16.65 A- E) ~1 u ?
50.4 4.0 X 5.0 20.0
9 {# q3 H. g2 H* p# }! Y6 n4 ?; G22.0 4.5 X 4.0 25.05 V, j# D$ \2 |9 W2 ^3 f/ c: @
84.6 4.0 X 4.5 11.1- M9 X5 E: u; W1 G
85.9 4.5 X 5.5 9.04 J9 a4 Y* T0 ^* y' E" n: X: l
Av. 14.3- Q! r5 n2 i8 C. x$ C2 q$ R
4
2 B! i- J% w! V$ g5 X$ B4 G8
5 {5 M6 B4 M; M/ J10 r! E# z2 T2 S8 N/ _5 _4 O- H
12% K% m: {: t0 O- T7 [7 `/ L. Q( c
176 \0 D/ k2 x8 C3 J& W! g; ?( w
Topical testosterone7 P: p2 r0 f. Y$ c) Q. E/ ?
34.6 4.5 X 6.5 85/ Q+ _( H4 S) Z/ L0 C N
38.8 6.0 X 8.5 70( K) U! i F1 n
40.0 6.0 X 6.5 62.5
5 ]& n" a" j3 b* k93.6 6.0 X 7.0 55.58 { B! d: f' U3 P
95.0 6.5 X 7.0 27.29 m4 l- D5 T) v# C6 U- V
Av. 60.0
5 `$ x( B! q3 C9 [) b8 aavailable testosterone. Again, emphasis should be placed on: J, D w' t+ b* g: @
early therapy when lower levels of testosterone appear to! ]% W; C$ I" O* b* R
provide the best responses. The earlier therapy is instituted9 g# J; x; r: X( B }- C
the more likely there will be an excellent response with low
$ b3 u, @% ^9 [! F4 z. m/ Userum levels. Response occurs throughout adolescence as: |& d- v$ B# f4 t( f
noted in nomograms of phallic growth. 7 The actual response
& o6 B( h( J& e- C- w' w5 Wto a given serum level of testosterone is much greater at birth
0 p4 w x' s0 [+ }: J* H* Q2 n$ w# \and gradually decreases as boys reach puberty. This is most
+ ~3 Y( U' l) A$ C' \! \likely related to the conversion of testosterone to dihydrotes-
: X" t# k% M! a" X) q; ktosterone and correlates well with the studies of testosterone
' |) }$ c- J5 _3 T) _: R& wconversion in foreskin at various ages.7 Y( |2 U$ z' W1 h5 m2 m
The question arises regarding early treatment as to whether
. R" h! z0 J6 l, T% {' aone might sacrifice ultimate potential growth as with acceler-
- Y8 w3 U' P l& O. V8 Q6 }ated bone growth. The situation appears quite the reverse
/ A" Y% D6 A0 i, E' p bwith phallic response. If the early growth period is not used0 a+ [& l, l# q! ^. D O% w
when 5a reductase activity is greatest then potential growth
1 h0 D' }( s# Mmay be lost. We have not observed any regression of growth: ^+ g& h. L; C5 E; f
attained with topical or gonadotropin therapy. It may well w, x+ ^6 Q" y3 {% K
be that some patients will show little or no response to any5 t) j: u! N; f- _+ w( c/ b
form of therapy. This would suggest a defect in the ability to
, O& a# Y! C0 m) tconvert testosterone to dihydrotestosterone and indicate that- p+ y/ O9 o& J, R* s+ q q3 z4 ~
phallic and peripheral skin, and subcutaneous tissue should) L# J$ G2 H$ g! c/ m2 @$ g9 |
be compared for 5a reductase activity.& f+ \9 k* K, Y8 t
A, loop enlarges to measure penile girth in millimeters. B,/ d# Z" a8 i' b7 K+ X
example of penile girth computed easily and accurately.1 i. K* M( ^/ V8 w2 R0 \0 d% K
conversion of testosterone to dihydrotestosterone. It is in this. `4 @8 c, V- u
older group that others have noted high levels of serum
/ v! X& R0 ~, J8 n- S- d3 gtestosterone with topical application. It would also appear
& D3 R2 |. b6 n" d+ [that phallic response during puberty is related directly to the
. f5 O) h/ I2 O3 Bserum testosterone level. There also is other evidence of local
) W. j2 ?: o( G9 L7 _5 L7 s- ~, dresponse to testosterone with hair growth and with spermato-
7 Z0 n5 ~2 x7 }3 ^+ m' F9 c% pgenesis. 5• 6
4 \* H2 }6 `+ {9 \ @Administration of larger doses of gonadotropin or systemic/ G L( _& C# S* G
testosterone, as well as topical applications that produce$ ]% M0 m; h# Y8 o
higher levels of serum testosterone (150 to 900 ng./dl.), will
- g" p! G! T" ^6 o, d" f$ S! Ralso produce phallic growth but risks accelerated skeletal) U' |+ m1 w8 [8 F8 k z# n
maturation even after stopping treatment. It would appear
% `8 y5 N3 s; e5 }that this may be avoided by topical applications of testosterone
; J8 B3 v5 _" P7 f& Y% Z2 land monitoring of serum testosterone. Even with this control
' x1 j# f8 V9 R; q* t( ?the duration of our therapy did not exceed 3 weeks at any
# W8 ?% K _) [/ xtime. It is apparent that the prepuberal male subject may( A7 u- M* y4 j3 a. i5 w! I1 X
suffer accelerated bone growth with testosterone levels near$ l0 k$ J* Y0 H: x S( I" Z3 p, a9 g
200 ng./dl. When skeletal maturation is complete the level of
3 n7 u( s, ^% z, B% g% s+ A0 Bserum testosterone can be maintained in the 700 to 1,300 ng./
& K& t5 u& b+ l) kdl. range to stimulate phallic growth and secondary sexual( i' N; C0 Q; M) D# i5 P
changes. Therefore, after skeletal maturation parenteral tes-: Z: \, O4 @( a
tosterone may be used to advantage. Before skeletal matura-
. m8 h: i0 N% y# ction care must be taken to avoid maintaining levels of serum
s9 {% [5 v+ _0 {1 T& ztestosterone more than 100 ng./dl. Low-dose gonadotropin
" w! _9 N2 Q; g7 Y. qdepends upon intrinsic testicular activity and may require
' ?( T; ?% k6 {" c4 O r' ]1 J/ ]prolonged administration for any response.
6 V! b- M6 |' p% m' n2 sAlternately, topical testosterone does not depend upon tes- a* Y' B T- @! W6 b
ticular function and may provide a more constant level of: w* I5 K" Y4 Q5 o- y4 k
REFERENCES. f9 h8 W9 v9 \6 E6 B" }- k
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
" o# J, O: V" P' i% d6 x3 v& R/ TR.: The local application of testosterone cream to the prepub-
+ \# i9 }+ _) Iertal phallus. J. Urol., 105: 905, 1971., N9 I- N: A! O7 L2 @/ v
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# T* { T; H& H
treatment for micropenis during early childhood. J. Pediat.,- i- S* I( d' g7 t4 R* f
83: 247, 1973.0 e* G8 {# c( ^. N& I# M
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* D; i& B! N; q8 k8 P: gone therapy for penile growth. Urology, 6: 708, 1975.
# @- T4 z: L& |2 j" W( n! J% J4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 u' b& m! S- t, K! P" _ J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* S# S# M& z) ?skin slices of man. J. Clin. Invest., 48: 371, 1969.5 s# s+ d4 ^/ f
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) S' `$ V- n: S# C8 O
by topical application of androgens. J.A.M.A., 191: 521, 1965.
9 k+ }; P2 s/ K+ f" }% @* {' k6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local8 _8 [% s% y( h j9 y9 ?
androgenic effect of interstitial cell tumor of the testis. J.
: [$ \* F: ~ f# ` y% U$ ~2 T( b+ ?Urol., 104: 774, 1970.
, O* {. P) @2 v. b4 s2 k. }7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 k& G8 g; E) h4 f; ltion in the male genitalia from birth to maturity. J. Urol., 48: |
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