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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND( e9 A r2 d- ?& q3 ~+ B
GONADOTROPIN& U8 M6 x8 F3 t5 ^9 ^
RICHARD C. KLUGO* AND JOSEPH C. CERNY
: Z' E2 v3 d1 \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan V$ s, |3 w' i/ G e2 a( R# B1 n
ABSTRACT
& A5 \% {$ }7 a8 ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated
: ^, W! I+ w$ d+ b6 o# C \with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-6 q9 C7 T4 S( i. D8 w
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, A% X' _) _" ]cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& x' |) _4 v6 E2 Q( F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent' U: A6 o$ o/ F0 n0 j$ L. Y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: G* {0 B& a6 j9 z* Yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: n" r/ j) P- ]8 zoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This/ K: W* W2 X$ n4 I! o
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" c2 ^7 r/ T. u1 |; r( s$ I
growth. The response appears to be greater in younger children, which is consistent with previ-7 ^8 z# `- y3 u. h; F* K8 ^
ously published studies of age-related 5 reductase activity.6 j1 v) h) b8 `& [9 c
Children with microphallus regardless of its etiology will
. B9 u7 X: H' Mrequire augmentation or consideration for alteration of exter-
# Y: [5 e8 H4 |% J) p/ Onal genitalia. In many instances urethroplasty for hypo-
$ A0 l9 t; ?" Y( Sspadias is easier with previous stimulation of phallic growth.: Q* X6 j3 {5 `+ I! \
The use of testosterone administered parenterally or topically
# f" E0 B' g" V- @3 [$ q v; ihas produced effective phallic growth. 1- 3 The mechanism of, C+ m6 o/ t) U! i
response has been considered as local or systemic. With this, C* s- d; q5 M7 m, E- V
in mind we studied 5 children with microphallus for response8 a1 A$ Z, R$ [4 h3 ]# _
to gonadotropin and to topical testosterone independently.
$ L) N- S' R% m3 D7 R' mMATERIALS AND METHODS
# F' \! ~: f' ]' {Five 46 XY male subjects between 3 and 17 years old were
6 ^0 [# }- R# D! l$ n }evaluated for serum testosterone levels and hypothalamic+ X# i4 L# o2 E$ } n. o
function. Of these 5 boys 2 were considered to have Kallmann's
. W* K! s( q, b& M8 h! Jsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 b7 H5 I( t- x; |4 r y
lamic deficiency. After evaluation of response to luteinizing. x6 D" [; o6 W# z/ M
hormone-releasing hormone these patients were treated with, S7 E# `% h( b P$ \
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ Z7 P( ]2 i4 ^
after completion of gonadotropin therapy 10 per cent topical8 c$ W8 R8 w* n; s, n
testosterone was applied to the phallus twice daily for 3 weeks.' x8 |0 M8 S7 ?1 ~2 U" Z, K
Serum testosterone, luteinizing hormone and follicle-stimulat-
9 t0 i/ R: v5 E+ ^ing hormone were monitored before, during and after comple-
t, l8 J. O- K% ttion of each phase of therapy. Penile stretch length was8 ^! c" o( v5 B$ m. ^& H1 Y
obtained by measuring from the symphysis pubis to the tip of# |& w O/ P S5 a
the glans. Penile circumferential (girth) measurements were# G3 P) P! O; U9 |6 c
obtained using an orthopedic digital measuring device (see$ W* |: [+ q2 u
figure).
- p) Y$ F S1 M+ ?RESULTS' \3 ]" G0 j+ I* K+ h* f6 r
Serum testosterone increased moderately to levels between- m" y7 L3 @1 l/ m7 n
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
, u' c, M. O2 bterone levels with topical testosterone remained near pre-4 O1 |" Q2 k1 d+ k3 Y* _& k
treatment levels (35 ng./dl.) or were elevated to similar levels6 b6 m+ X. r7 z( p' Z
developed after gonadotropin therapy (96 ng./dl.). Higher
' I8 R; b3 I+ c& eserum levels were noted in older patients (12 and 17 years old),3 g2 p6 {* y( R; S- N# ~
while lower levels persisted in younger patients (4, 8, and 10: S& k3 ?4 W2 k, W% ~
years old) (see table). Despite absence of profound alterations" U/ Z; x0 J: N x+ }: x
of serum testosterone the topical therapy provided a greater
" Z) [! e1 _1 m; D, cAccepted for publication July 1, 1977. ·7 T& M4 Q& @3 m
Read at annual meeting of American Urological Association,
; c: H' T7 C5 a0 uChicago, Illinois, April 24-28, 1977.
" I$ R q7 y3 m& L* Requests for reprints: Division of Urology, Henry Ford Hospital,
}4 s7 M' C) [2 I: W- N2799 W. Grand Blvd., Detroit, Michigan 48202.
1 @6 T9 o6 q+ p0 _* ?1 Simprovement in phallic growth compared to gonadotropin., a j% u1 d7 ~7 z5 |
Average phallic growth with gonadotropin was 14.3 per cent
2 H, z8 y$ I [increase in length and 5.0 per cent increase of girth. Topical
# W- e+ N& g/ E+ a stestosterone produced a 60.0 per cent increase of phallic length
/ D) x. Q8 Y& N1 Hand 52.9 per cent increase of girth (circumference). The
$ X& s3 l. O3 r* aresponse to topical testosterone was greatest in children be-
' E8 f$ E* \5 l% h2 ktween 4 and 8 years old, with a gradual decrease to age 17. [# Y4 c. [5 v a
years (see table).
: m3 W' C2 l# m* I! VDISCUSSION" `. {; Z6 L6 D5 P( P: p# Z: D
Topical testosterone has been used effectively by other% z3 N8 H* o8 H$ p% e6 L+ o
clinicians but its mode of action remains controversial. Im-
( z1 O! ]& s% j+ ^5 @0 Z: {! z# gmergut and associates reported an excellent growth response/ M9 U9 I- y- ?2 P ?' e/ S+ v
to topical testosterone with low levels of serum testosterone,
M1 d. J# q4 z" k' `suggesting a local effect.1 Others have obtained growth re-! N1 [2 Q3 \3 D( q' u* G& `
sponse with high. levels of serum testosterone after topical
; W5 O8 }$ x3 e$ n, Q- qadministration, suggesting a systemic response. 3 The use of+ {3 ^3 O1 [) X4 Y$ J! P
gonadotropin to obtain levels of serum testosterone compara-
6 k3 \7 O1 l4 _* b* L: i! n0 m% @& Oble to levels obtained with topical testosterone would seem to% J5 u. x& |; S. b! e
provide a means to compare the relative effectiveness of! j' y6 z7 F6 `7 l5 z! D
topical testosterone to systemic testosterone effect. It cer-
1 L- a) Q5 |$ Q; Q' Itainly has been established that gonadotropin as well as par-. p: A3 v% x5 l% M
enteral testosterone administration will produce genital/ N! t2 \( ~/ s6 `# [
growth. Our report shows that the growth of the phallus was7 D* Q! H" x* b) |$ @1 ?2 h
significantly greater with topical applications than with go-
; k1 J7 V6 ]: Z( \7 @nadotropin, particularly in children less than 10 years old.! @% V2 W9 Q) @; Y
The levels of serum testosterone remained similar or lower
/ F5 x* w& j3 Q8 rthan with gonadotropin during therapy, suggesting that topi-
( Y/ T/ ^8 c4 g: W: wcal application produces genital growth by its local effect as
9 k8 P$ D2 U& M3 f1 [well as its systemic effect.
2 i2 v9 m+ y4 EReview of our patients and their growth response related to& M: p" L, Q5 m( H
age shows a greater growth response at an earlier age. This is
; n0 P! f9 h3 B: W: v& Q6 r6 o0 H9 [consistent with the findings of Wilson and Walker, who
( U& z$ p- `% Vreported an increased conversion of testosterone to dihydrotes-
7 A( o3 Y+ ~5 T0 Etosterone in the foreskin of neonates and infants.4 This activ-
5 O: ], X9 W- z# R% r; g6 zity gradually decreases with age until puberty when it ap-$ I( r, F2 J1 e' t% k( @
proaches the same level of activity as peripheral skin. It may# P2 |# \% D: @- n1 S
well be that absorption of testosterone is less when applied at: W; P: s2 q; _: N: Q# Z
an earlier age as suggested by lower serum levels in children
5 ^+ Q+ t( p' rless than 10 years old. This fact may be explained by the) P6 C+ W3 z$ [5 \
greater ability of phallic skin to convert testosterone to dihy-4 g9 n2 o' Y( C( j |; |% M8 K2 G
drotestosterone at this age. Conversely, serum levels in older/ x2 ~/ |2 t% O. x' g# S- c
patients were higher, possibly because of decreased local
2 @0 z5 k# j1 a4 S2 F667, [/ q: C! f$ }& W( `
668 KLUGO AND CERNY* T {6 z+ J X8 M* @
Pt. Age: x% D v, u5 g; L6 v. l
(yrs.)# r5 k8 b+ W* W$ j
Serum Testosterone Phallus (cm.) Change Length
1 v A. f; e+ l+ R5 }6 q) ~(ng./dl.) Girth x Length (%)6 t2 S R7 [) H2 h5 @
4
. c& {3 `) h: _# h89 m7 C: H; D# g
10! \" l9 q. @1 j. j* [$ Z
127 w3 b7 P+ r- W( Q" \* `
17
, [0 a* O _" e6 UGonadotropin$ s, `8 G: t; |! O; l+ C4 A
71.6 2.0 X 3 16.6
$ B3 R% Z* z3 r% {: x5 ^& ^2 ?50.4 4.0 X 5.0 20.0, i( Q2 j, }$ l1 }
22.0 4.5 X 4.0 25.0, o4 l; r/ S; t
84.6 4.0 X 4.5 11.18 U- ]& Z4 B8 l8 F* ]
85.9 4.5 X 5.5 9.0) f# D. P# f: H( b2 t) k
Av. 14.37 M" \2 o; _+ r; @
4 H4 M3 J7 b; Y
8
2 }& G6 E; {+ x/ U/ X+ P ]- V10
/ f7 e& ? r0 q12 \/ z) ?# S0 W; m' X
17! H+ y1 P) @3 V$ u, l' p& F* O" e
Topical testosterone0 ~/ h# _5 h' `( b4 ^+ j' S1 s0 g
34.6 4.5 X 6.5 85
3 U2 c' N4 a3 L2 v+ e38.8 6.0 X 8.5 701 r; Y. j) E# A/ e# Y* ~
40.0 6.0 X 6.5 62.5' R! W4 D' d+ R1 X* W8 J. m8 B
93.6 6.0 X 7.0 55.56 I4 X; d y- C1 R+ D
95.0 6.5 X 7.0 27.2$ [% G3 r& l& V) [% k; o) `
Av. 60.0- `2 b: b$ ^) b D" f+ e/ l3 n; K! t! Z
available testosterone. Again, emphasis should be placed on
6 q: o' I7 V" N+ ]- Jearly therapy when lower levels of testosterone appear to) W" J' p1 l( w0 x# ^1 v v
provide the best responses. The earlier therapy is instituted
a2 A1 s. j+ ^, \# a1 Pthe more likely there will be an excellent response with low0 l7 q- _4 v# ^/ H
serum levels. Response occurs throughout adolescence as( F! a. I: N. G
noted in nomograms of phallic growth. 7 The actual response$ |8 m5 `( D% h/ r
to a given serum level of testosterone is much greater at birth! G" M% _2 l: n" J1 K
and gradually decreases as boys reach puberty. This is most8 B4 w3 ~' V. w- T5 ^4 X3 O# `
likely related to the conversion of testosterone to dihydrotes-1 q9 o& h" h8 u$ k$ c4 J
tosterone and correlates well with the studies of testosterone
" m/ ~5 x/ O! h, K7 S. E2 @, mconversion in foreskin at various ages.$ s, U7 I, }4 q# j3 _# a2 }6 e
The question arises regarding early treatment as to whether
2 u5 \' ?: |3 j' z+ M3 Jone might sacrifice ultimate potential growth as with acceler-! p! _+ j" Q6 G: q. \, B
ated bone growth. The situation appears quite the reverse
( R3 D* ~* s: i! w# b1 Bwith phallic response. If the early growth period is not used9 W! o% K, P! F& C! N) A
when 5a reductase activity is greatest then potential growth
$ F/ N4 i. n% U+ v* k& t/ dmay be lost. We have not observed any regression of growth
$ e. ]; q ~; A9 G4 eattained with topical or gonadotropin therapy. It may well0 v$ F# p( Z0 {: `/ g
be that some patients will show little or no response to any
* Y5 `4 c' z4 x5 o/ M$ o' l# l0 _; w; aform of therapy. This would suggest a defect in the ability to) A/ q! `) U+ d* a: R
convert testosterone to dihydrotestosterone and indicate that: U# g/ s0 D @3 g
phallic and peripheral skin, and subcutaneous tissue should
}) \, z! I+ Abe compared for 5a reductase activity.
; ]% |1 m# {; g3 I5 r/ ]9 h4 V0 FA, loop enlarges to measure penile girth in millimeters. B,3 P5 O: u# l) J0 Y2 H+ r" k
example of penile girth computed easily and accurately.
0 C0 Z% \4 |; J+ K5 W/ v1 aconversion of testosterone to dihydrotestosterone. It is in this
4 W" D$ V4 `# G) _5 A, R4 u; g% Oolder group that others have noted high levels of serum
* T# c* Q) T$ X; Atestosterone with topical application. It would also appear9 o c6 ^5 ~9 {6 \, ?, C6 _
that phallic response during puberty is related directly to the
6 ?/ {0 W/ W4 M. h$ E N- Sserum testosterone level. There also is other evidence of local- w9 K+ [: A( E
response to testosterone with hair growth and with spermato-
|) a1 i) q& s' Pgenesis. 5• 6' n0 O# `5 {9 `
Administration of larger doses of gonadotropin or systemic8 r( |4 J/ t B5 g# D3 N( K" r! e
testosterone, as well as topical applications that produce' V% y- o9 M `. v4 Z- H
higher levels of serum testosterone (150 to 900 ng./dl.), will3 a9 l7 P+ A6 ?; S( K; l
also produce phallic growth but risks accelerated skeletal
, |. G* m% V, G$ N& Mmaturation even after stopping treatment. It would appear
( J% K! |4 R9 P/ `- A: a+ sthat this may be avoided by topical applications of testosterone# S% l1 r: y" F) c
and monitoring of serum testosterone. Even with this control* b) K' c9 o4 u) L7 ]
the duration of our therapy did not exceed 3 weeks at any
) ]# P' t% T* ~# B4 w( ^time. It is apparent that the prepuberal male subject may, J2 l; Z7 Y3 P9 u' F7 \) I
suffer accelerated bone growth with testosterone levels near% C# _ L" V2 }. r, }
200 ng./dl. When skeletal maturation is complete the level of
# V9 ~. R, G+ Q4 K% Rserum testosterone can be maintained in the 700 to 1,300 ng./ r- S" p, t$ e. w8 k: i9 y% q
dl. range to stimulate phallic growth and secondary sexual
6 `6 M* y6 I: @" mchanges. Therefore, after skeletal maturation parenteral tes-/ M/ r' m: n9 m) W+ I
tosterone may be used to advantage. Before skeletal matura-& ^; ?2 ?' E/ p3 W% p
tion care must be taken to avoid maintaining levels of serum2 y* f# n8 I! U" h: {/ P
testosterone more than 100 ng./dl. Low-dose gonadotropin" M6 T- ^, O. B5 o+ a& z4 X
depends upon intrinsic testicular activity and may require2 I2 v7 W1 p k0 \$ L2 d7 u
prolonged administration for any response.. d- W" W# _9 g' W" b/ G
Alternately, topical testosterone does not depend upon tes-
) m' G/ Q& e7 H) ~ U: N) \( tticular function and may provide a more constant level of
2 x8 ?* k' o ?% z7 g2 yREFERENCES
% R5 T& g* [" M8 w1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 u7 o# e. {0 P* V# k
R.: The local application of testosterone cream to the prepub-: @6 j5 o2 D x7 g' [: c
ertal phallus. J. Urol., 105: 905, 1971.
) Z( z, E( q9 p, R6 v. g2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. b7 }/ u) D# W- b q6 t0 n/ l
treatment for micropenis during early childhood. J. Pediat.,8 p+ m: C3 M* _# S
83: 247, 1973.
6 [1 P% {* C. d- Z; b3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-5 |" H$ F- |9 D5 B) x# c" W0 l5 r
one therapy for penile growth. Urology, 6: 708, 1975.# c6 s% D D- k) f. W9 S0 \
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone j) k& X$ k3 l0 J) F. t
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 q9 t: l+ G+ }& B* ^. T
skin slices of man. J. Clin. Invest., 48: 371, 1969.
- Z8 V# {" E. z6 f+ @9 l5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) Y: T) |0 ?( y/ _" G
by topical application of androgens. J.A.M.A., 191: 521, 1965.$ h& |% c" \" F3 z) a1 B. _
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, d, K0 |5 h- ?androgenic effect of interstitial cell tumor of the testis. J./ i5 F4 _% \" h$ L4 t
Urol., 104: 774, 1970.0 \" D1 O) \( y4 V0 D+ L
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 o2 L- P1 S6 L$ ?+ n4 Ltion in the male genitalia from birth to maturity. J. Urol., 48: |
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