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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND9 h" q; z; T& x# g5 g- ^
GONADOTROPIN
3 I/ x& q& b9 y/ l# e4 n6 JRICHARD C. KLUGO* AND JOSEPH C. CERNY
- Q7 i& f" e4 K. J7 |From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
L" Q l$ |3 ~" }ABSTRACT+ ]# R/ W( [$ p) `5 `5 [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
4 O/ g& k2 w4 G. a2 S- Q4 Ewith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
" `: ]$ x" H/ Y' d9 Stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 `) u! m/ Q7 f/ ^+ [, J" v" p$ N
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( r1 Z) _' ~8 \3 ]2 I8 U$ o( qfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 |& b. G4 o5 y3 P5 R3 Z Gincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
. w& }( i- ?5 B5 Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ _* L3 H# v7 M5 i7 y- ~ f' ]occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ J, f" N& q" H( N
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- d+ j( E |* w7 y* ]growth. The response appears to be greater in younger children, which is consistent with previ-
0 n- u* v7 u: ^ously published studies of age-related 5 reductase activity.; b8 J& K9 x& {6 Z
Children with microphallus regardless of its etiology will
& v. v4 |! U- G& N/ A9 V, X9 crequire augmentation or consideration for alteration of exter-
7 `+ R& M. W* ^+ K/ j5 \nal genitalia. In many instances urethroplasty for hypo-9 f9 u0 E# W: e
spadias is easier with previous stimulation of phallic growth.
( g' }# t9 |) u5 J/ E$ x- \9 R. n1 j# bThe use of testosterone administered parenterally or topically# K7 ?' V: O+ n8 f8 ?, [
has produced effective phallic growth. 1- 3 The mechanism of
! T! I; s9 k! P( s' Z: Z3 kresponse has been considered as local or systemic. With this
5 V. \1 J$ G, Z$ xin mind we studied 5 children with microphallus for response
6 `( Y3 g+ N) N9 S+ {0 Bto gonadotropin and to topical testosterone independently.
* ^- ]- H; w' \; d# DMATERIALS AND METHODS
; ~, `' v) e" o1 {; S" uFive 46 XY male subjects between 3 and 17 years old were7 P! ~1 f* N. m# `, A# |
evaluated for serum testosterone levels and hypothalamic% s- O1 d9 P+ ?0 \& R
function. Of these 5 boys 2 were considered to have Kallmann's
- h# C0 d. p" r8 M$ O7 Xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( _$ F# V! Z' F
lamic deficiency. After evaluation of response to luteinizing
1 \9 ^! f3 ]- I' Rhormone-releasing hormone these patients were treated with8 g5 ~0 E+ N1 q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks* K5 q1 ?+ u% P0 y: p! Q; s
after completion of gonadotropin therapy 10 per cent topical @* p) A+ `- c$ u
testosterone was applied to the phallus twice daily for 3 weeks." ~. B% K2 |) O0 o
Serum testosterone, luteinizing hormone and follicle-stimulat-+ ~: G) y1 c7 y5 `
ing hormone were monitored before, during and after comple-
2 \; a/ F9 u8 @: h" `* Stion of each phase of therapy. Penile stretch length was
1 i y" a2 w- bobtained by measuring from the symphysis pubis to the tip of% d* e9 C: ^% A% \) o. E0 Q' [
the glans. Penile circumferential (girth) measurements were
; A& U' O9 k3 x4 Y" ]5 e4 k" W4 {obtained using an orthopedic digital measuring device (see
6 x/ `0 ^) p* w) Y. B* Mfigure).$ a2 l. h+ z* u/ e$ {
RESULTS5 F% X+ L, E8 C1 O# {( I; [( C! U
Serum testosterone increased moderately to levels between: M8 I. S- @* X1 b: T, j) e# y% X
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- M( y9 i9 w& @9 n; j
terone levels with topical testosterone remained near pre-
9 {( v8 v: r! S9 e0 Mtreatment levels (35 ng./dl.) or were elevated to similar levels0 t! Y$ Q9 y9 {
developed after gonadotropin therapy (96 ng./dl.). Higher
% e r- n. V6 G7 y- l1 p; e" f" n. }serum levels were noted in older patients (12 and 17 years old),' f4 o& s) C1 N# [. x1 G
while lower levels persisted in younger patients (4, 8, and 10* ?, Q' T. X2 C8 J5 }
years old) (see table). Despite absence of profound alterations: Z/ [0 T# V1 p( _# b Y, E# E
of serum testosterone the topical therapy provided a greater
( a& b" x. Y" a, H0 ?, IAccepted for publication July 1, 1977. ·- g0 u1 I1 B0 w) W
Read at annual meeting of American Urological Association,5 O3 Q) g# z! b" Q+ b, I' `" K2 z
Chicago, Illinois, April 24-28, 1977.
: }( p m! B6 y1 m# t% I+ }* Requests for reprints: Division of Urology, Henry Ford Hospital,2 q. G1 _9 n; o* C
2799 W. Grand Blvd., Detroit, Michigan 48202.5 g, _0 v1 w6 w
improvement in phallic growth compared to gonadotropin.: I& ^& y. z8 a. B# i+ f5 `
Average phallic growth with gonadotropin was 14.3 per cent
3 o3 z7 x: w2 I( I+ b% _increase in length and 5.0 per cent increase of girth. Topical- _( C& T, R0 R6 b' D" ]
testosterone produced a 60.0 per cent increase of phallic length
; n6 u2 A4 ^3 h3 mand 52.9 per cent increase of girth (circumference). The2 I. M4 v' P$ {# N! Y
response to topical testosterone was greatest in children be-0 t: c) `7 p4 p6 z1 O! p+ f
tween 4 and 8 years old, with a gradual decrease to age 174 r" I7 E* O; A m8 Y" p, ]4 W4 r
years (see table).
2 L% @$ m0 R* s& K5 [* e5 n8 KDISCUSSION; j: a* ~' S* d/ b* [
Topical testosterone has been used effectively by other6 _% B. `4 b% V2 h" \$ `: i; |
clinicians but its mode of action remains controversial. Im-* h1 _4 ^' w Q' t
mergut and associates reported an excellent growth response
7 E$ a' i; s, v; N/ B2 Eto topical testosterone with low levels of serum testosterone,
: E& g" `% d4 | Q1 ?; e7 m- zsuggesting a local effect.1 Others have obtained growth re-3 K) ^& U) @" V* Y) B
sponse with high. levels of serum testosterone after topical" S2 Z N L$ p0 q3 y5 x/ q( v( E% z
administration, suggesting a systemic response. 3 The use of
3 r1 a6 [) ?, w; f% jgonadotropin to obtain levels of serum testosterone compara-
6 U' T1 K0 m$ d3 {ble to levels obtained with topical testosterone would seem to
/ d( V. W; @9 E# h7 a Kprovide a means to compare the relative effectiveness of
F1 t5 j4 e! xtopical testosterone to systemic testosterone effect. It cer-
3 z# j$ e6 R2 D1 B' Qtainly has been established that gonadotropin as well as par-
3 d# K H1 }2 s! ~+ [enteral testosterone administration will produce genital
; h; S) ]% f1 N/ {growth. Our report shows that the growth of the phallus was$ g& }' y& [/ ^4 w
significantly greater with topical applications than with go-# P) w( v2 f; ^ O) K, V
nadotropin, particularly in children less than 10 years old.3 L G: j) w' }1 Z. U( m* ^
The levels of serum testosterone remained similar or lower
. a+ O3 S9 f7 ]% V- C) G4 L+ Hthan with gonadotropin during therapy, suggesting that topi-+ J& [' ~+ f- q! b- @) o% w
cal application produces genital growth by its local effect as
- k# ?1 a: U) {; `: G- M$ Gwell as its systemic effect.
' @4 a$ R$ z3 v0 w4 M$ JReview of our patients and their growth response related to1 F% Q$ F) h: Z" a5 Z W3 v& ?
age shows a greater growth response at an earlier age. This is% m5 z% v3 C0 Z Y$ u
consistent with the findings of Wilson and Walker, who
5 N& p. I" i: [$ zreported an increased conversion of testosterone to dihydrotes-& v3 X& c. X7 w7 ], ]1 K
tosterone in the foreskin of neonates and infants.4 This activ-
( k K" V; p/ aity gradually decreases with age until puberty when it ap-1 ^6 t+ v& q5 |' a- Y
proaches the same level of activity as peripheral skin. It may
4 K2 Z9 r. [7 z/ t" @well be that absorption of testosterone is less when applied at( |2 `" ?3 |9 y
an earlier age as suggested by lower serum levels in children, o) w* `! o6 Q/ [2 C
less than 10 years old. This fact may be explained by the% t, c7 w' H: E3 h
greater ability of phallic skin to convert testosterone to dihy-) j, V( n8 e+ `% j ] e5 ^" \
drotestosterone at this age. Conversely, serum levels in older
- p3 J+ ] e8 X& ]patients were higher, possibly because of decreased local
. K$ Q0 L$ @9 h6 o& L667
7 d7 ?& Y- z) G# U/ k- z$ S( K. r668 KLUGO AND CERNY
4 Z+ `+ }! `9 f5 ?4 x! N) fPt. Age
$ ~! u+ x# z6 r0 [8 z(yrs.)7 E8 r; z* j. ^: [9 J8 F9 |8 i0 X
Serum Testosterone Phallus (cm.) Change Length0 g( b0 L; Z- r7 X$ M* ?
(ng./dl.) Girth x Length (%)
. a' V2 Q/ M) i1 [* x4
- }. @5 _" l$ \- [8+ ?5 m0 [( B) C! S# \
10% j- ^$ o: q2 N! E; o+ |
12
+ [* C2 m/ ~- X/ A17
4 c# C8 L& K- ?2 m- `3 e; S( HGonadotropin. \/ R% d, G& i9 T, }
71.6 2.0 X 3 16.6
4 P# i0 b6 G' I$ J50.4 4.0 X 5.0 20.0: `$ {" o7 B9 U. j9 }. u
22.0 4.5 X 4.0 25.0
( Y: Q: T5 @* `$ q+ }; v84.6 4.0 X 4.5 11.1
. m# ]. H2 Q* |1 n5 ?+ a85.9 4.5 X 5.5 9.08 X" A! ~8 Q+ G N6 @) u) K! U
Av. 14.3
. D# N' U, S- C8 H" s* u4 ]. D48 T# `- G( i _& a- @ W5 ?
8- M. h% ~ D2 r3 P
100 I5 U* B# M7 j) R4 P6 j
12; _4 ~/ |; E$ L6 v" y
17
* `/ I: v" \- W$ mTopical testosterone
3 k) y/ Q$ M, {" M1 j) U34.6 4.5 X 6.5 85
, n0 G( c# q4 |" J1 H+ E) ~" c38.8 6.0 X 8.5 70; K! h& R# k, o# ]6 g
40.0 6.0 X 6.5 62.5. F- q. f4 p5 P: X* o
93.6 6.0 X 7.0 55.5
* I& e+ E) K% g95.0 6.5 X 7.0 27.2
/ o, U* J$ c8 s8 wAv. 60.0
. q6 }1 m0 A" j. f+ M; z3 |: D, Qavailable testosterone. Again, emphasis should be placed on5 o, t* w6 D- S
early therapy when lower levels of testosterone appear to% w% C- E( \' ^
provide the best responses. The earlier therapy is instituted8 z- z, G/ R* O) d4 s
the more likely there will be an excellent response with low
) c* E5 `( F9 I. q# nserum levels. Response occurs throughout adolescence as$ o) r% L# ~- }! f. x( J
noted in nomograms of phallic growth. 7 The actual response5 l. S! D: d' W, Y0 X: x- t9 Q% j0 T) Y
to a given serum level of testosterone is much greater at birth
5 {& J- S, z; n; C& N, \# |3 d7 @and gradually decreases as boys reach puberty. This is most, N% }: g1 Q- Q
likely related to the conversion of testosterone to dihydrotes-# Y" o5 n6 b7 \6 \1 O' @
tosterone and correlates well with the studies of testosterone8 x" b$ R7 q8 g. P7 o
conversion in foreskin at various ages.
, N; X* c: n3 ]+ RThe question arises regarding early treatment as to whether7 H* v$ l$ x' e& ?" z1 E
one might sacrifice ultimate potential growth as with acceler-
9 L5 Z6 h; s* rated bone growth. The situation appears quite the reverse
3 k. f% u0 J# @* a- T0 l/ n# ywith phallic response. If the early growth period is not used
1 [0 ]" N' c- W4 L# e: hwhen 5a reductase activity is greatest then potential growth
" p; p" J. c7 J( jmay be lost. We have not observed any regression of growth# Z5 q( m& k: f$ g
attained with topical or gonadotropin therapy. It may well' U+ j$ V( o$ o* J& Q3 A
be that some patients will show little or no response to any k/ j/ A4 ?! b4 @9 `1 q9 Z
form of therapy. This would suggest a defect in the ability to) L' ~& K9 Z% ^/ N1 R9 h x
convert testosterone to dihydrotestosterone and indicate that8 h1 ~) W7 }6 ]" @) T D/ ^! o
phallic and peripheral skin, and subcutaneous tissue should. {2 |0 n) @& u R# {/ G( A* c
be compared for 5a reductase activity.
8 q6 U+ R5 w) D4 \: ^7 Y. ?& n3 EA, loop enlarges to measure penile girth in millimeters. B,
# ]$ Z2 P, f9 @* o) z# G; `6 q" Pexample of penile girth computed easily and accurately., g/ W# {& Z+ _7 t1 m" @# k
conversion of testosterone to dihydrotestosterone. It is in this& z6 q7 |& F) I7 |8 Z
older group that others have noted high levels of serum
1 @- g+ |7 U, ttestosterone with topical application. It would also appear. d3 Z/ N$ ?6 H, p
that phallic response during puberty is related directly to the
: x7 ]; ]* ?6 L) v# B- Tserum testosterone level. There also is other evidence of local
1 {! Y d$ {. j' J1 O# e+ gresponse to testosterone with hair growth and with spermato-: B+ S1 c& ?$ J8 M% Q4 r5 p
genesis. 5• 6, |* h! ? p: f1 a6 r+ o7 j# F+ C
Administration of larger doses of gonadotropin or systemic
& A$ \7 F: o& x1 y. o2 F, ^/ G: dtestosterone, as well as topical applications that produce% H9 f) [; |" ]( D- U
higher levels of serum testosterone (150 to 900 ng./dl.), will# c0 ^4 U& h& Z; H7 a
also produce phallic growth but risks accelerated skeletal
- W2 M% N/ E+ t# |% C3 R- vmaturation even after stopping treatment. It would appear
1 C0 d# D- ? nthat this may be avoided by topical applications of testosterone
, [3 Z% Y$ D& p; r9 _- Zand monitoring of serum testosterone. Even with this control
: d) b2 ]& r! _- {' S4 z: O, v- y: {the duration of our therapy did not exceed 3 weeks at any q2 B0 m0 L% I% d! x
time. It is apparent that the prepuberal male subject may! }! k% @3 E" t0 c0 A0 d% h8 G% D, ^
suffer accelerated bone growth with testosterone levels near1 G# s/ @' L1 h1 [. q
200 ng./dl. When skeletal maturation is complete the level of, H5 J0 f: j( Z# _0 c, R' V8 |7 y- w
serum testosterone can be maintained in the 700 to 1,300 ng./3 H# d4 r8 A# Q' ]# t, C; D) u0 j
dl. range to stimulate phallic growth and secondary sexual
2 \- H% X+ A6 ?" [ V& K8 |+ dchanges. Therefore, after skeletal maturation parenteral tes-
6 q/ _4 q# \7 b4 Vtosterone may be used to advantage. Before skeletal matura-& [7 l7 F7 [8 n9 H: G C8 I2 [
tion care must be taken to avoid maintaining levels of serum
: V4 ~: `# j( s( S$ E4 u) e' Rtestosterone more than 100 ng./dl. Low-dose gonadotropin
`1 n8 A0 v& w# odepends upon intrinsic testicular activity and may require
+ K5 z# S. M$ |% rprolonged administration for any response.
8 o" {1 Z y$ q8 mAlternately, topical testosterone does not depend upon tes-+ X! p z' q/ G' M, b, H V" _
ticular function and may provide a more constant level of
5 N; |8 t3 U8 n# x& E2 _REFERENCES
: o- Q6 t+ d* g, m* a$ {1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ U, E! j" }4 R( q; m6 D6 o
R.: The local application of testosterone cream to the prepub-8 a% O5 h4 ?8 m: B
ertal phallus. J. Urol., 105: 905, 1971.
{* k+ v3 `1 i9 a9 ]1 I2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' V* c2 k5 X& r# ?9 {( H9 Y0 J3 ]/ ^+ Ktreatment for micropenis during early childhood. J. Pediat.,
0 Q& Z' t: S6 ^( `6 W( b83: 247, 1973.( X* _' y# T2 s
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-0 V, X9 a5 X/ J, S
one therapy for penile growth. Urology, 6: 708, 1975.# i- I! `9 X; n; H* @/ h+ l
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" D/ g. X3 k: O2 ^3 u `/ I
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
/ J9 X4 c, ~5 g5 Uskin slices of man. J. Clin. Invest., 48: 371, 1969.
! l! s( T: Y. C9 j; r2 ?/ ^5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth H) v( d2 M/ M- I. Q
by topical application of androgens. J.A.M.A., 191: 521, 1965.* f7 A2 {7 J) A
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. [+ E( z1 r' y% bandrogenic effect of interstitial cell tumor of the testis. J.
% |: y; l& V3 L1 wUrol., 104: 774, 1970.
% ], c. _/ A g& A7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" t4 _5 G. o1 d* Ation in the male genitalia from birth to maturity. J. Urol., 48: |
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