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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND; K9 c5 w3 ^6 G
GONADOTROPIN0 }. Y- g# C7 Q `7 o; P
RICHARD C. KLUGO* AND JOSEPH C. CERNY6 _/ f7 E( Z$ Q& B( N3 J
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
( Z5 ` g- [, @# @ |# cABSTRACT: x: ?, @5 o" F/ Z; e+ @& q
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
* A7 X6 `. M; v7 Y' e) rwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% _( g. m4 Q6 \9 H: Dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- g) X1 M( @, jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, G, y$ n* q8 T' H. c
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 x& j. `5 a5 P
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 c6 A) X6 p/ o; Q- z0 b- [increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# B) _; z% e+ H7 u0 L5 L. ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 E6 U! G# y5 w; S; o7 Mstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile- c7 s& \. M' @( J
growth. The response appears to be greater in younger children, which is consistent with previ-
4 V& l, w* y5 @ously published studies of age-related 5 reductase activity.
9 ?1 _* N0 A3 [6 X# c! X. ]) SChildren with microphallus regardless of its etiology will0 v+ d% y n% S% s( B
require augmentation or consideration for alteration of exter-% K( P$ J+ {1 w& y2 O7 O; ?
nal genitalia. In many instances urethroplasty for hypo-
. }" h2 u' H* `spadias is easier with previous stimulation of phallic growth.. D* @/ b1 J$ \* N; F1 L
The use of testosterone administered parenterally or topically
1 {+ j1 r+ ^' F% R, u# yhas produced effective phallic growth. 1- 3 The mechanism of! v+ Z2 y: T1 s
response has been considered as local or systemic. With this
9 ?. Y2 t# L* a! g+ g. din mind we studied 5 children with microphallus for response
. v& X5 R. P& c ]3 |4 Cto gonadotropin and to topical testosterone independently.
- R2 P5 C& R9 A* F$ D. yMATERIALS AND METHODS
* J* s& V1 V- \: Q8 @) l: Z7 dFive 46 XY male subjects between 3 and 17 years old were
, C& C" _ c, t9 Gevaluated for serum testosterone levels and hypothalamic
% T6 M! P7 n/ T+ Q6 k, P0 {function. Of these 5 boys 2 were considered to have Kallmann's ]4 f. p* T6 |
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-& W8 [3 j: ~+ O4 h) I5 x& X
lamic deficiency. After evaluation of response to luteinizing
, J% T7 C9 c c+ bhormone-releasing hormone these patients were treated with a5 r" y& K5 y6 F
1,000 units of gonadotropin weekly for 3 weeks. Six weeks* ^9 r( {4 Q4 B! X
after completion of gonadotropin therapy 10 per cent topical3 T- p1 a6 b' d: s$ f+ Z. r7 g
testosterone was applied to the phallus twice daily for 3 weeks.( U* ^" Z7 a& s/ n6 K1 O) E" u
Serum testosterone, luteinizing hormone and follicle-stimulat-
- _/ I) q( z! F) `5 h1 c$ @/ Ring hormone were monitored before, during and after comple-+ X3 G1 G/ h+ X( T( K
tion of each phase of therapy. Penile stretch length was
! G. B$ l+ G) l6 b2 R2 lobtained by measuring from the symphysis pubis to the tip of
! r( c* m1 q+ vthe glans. Penile circumferential (girth) measurements were
8 n4 G8 @8 b, D- s l& Vobtained using an orthopedic digital measuring device (see' e% m, ~# {0 T0 I
figure).4 A% l9 d& h; f$ S' A$ K
RESULTS
9 k' b/ ]. ~6 lSerum testosterone increased moderately to levels between* a" |- J8 q% a5 u. ?, p
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
$ u9 g- {. z2 Q! ^- X! G" Q" sterone levels with topical testosterone remained near pre-
* @1 A- }- ?. A+ ktreatment levels (35 ng./dl.) or were elevated to similar levels
6 ^; K% k- k$ Q4 _( Fdeveloped after gonadotropin therapy (96 ng./dl.). Higher% o8 E$ O( \1 N c3 f: X1 d" H- x, X3 p/ D
serum levels were noted in older patients (12 and 17 years old),
$ W; d% F+ d h( X5 `while lower levels persisted in younger patients (4, 8, and 101 N2 b. ]4 U! a# | I5 q7 d! V& z. @6 M
years old) (see table). Despite absence of profound alterations0 M" |( b3 x2 g- V% A& Z$ @8 \" J
of serum testosterone the topical therapy provided a greater8 n7 F+ O9 f; N$ \; x
Accepted for publication July 1, 1977. ·
" _; l+ s9 Q4 oRead at annual meeting of American Urological Association,
) \7 o4 c2 m: X) kChicago, Illinois, April 24-28, 1977.1 q$ M& ~0 Z6 |6 w0 s
* Requests for reprints: Division of Urology, Henry Ford Hospital,2 V; W1 L T0 w( o
2799 W. Grand Blvd., Detroit, Michigan 48202.! x7 Q' g2 k( N, w) D
improvement in phallic growth compared to gonadotropin.$ W' {* z. E- ^! t, K
Average phallic growth with gonadotropin was 14.3 per cent. m" v1 ]7 r$ T9 q- k
increase in length and 5.0 per cent increase of girth. Topical
% |; x) I/ C, Q' Etestosterone produced a 60.0 per cent increase of phallic length) N# X6 _+ b) o d; z
and 52.9 per cent increase of girth (circumference). The
3 P3 ^6 j0 o1 h; Uresponse to topical testosterone was greatest in children be-" @ \$ N ~2 S# S
tween 4 and 8 years old, with a gradual decrease to age 17
0 V2 R! n1 T! w( ^3 B9 @" Y! _5 Kyears (see table).2 J- M6 |1 S8 s& ~
DISCUSSION
8 A$ A r' J" V9 I: B- E/ qTopical testosterone has been used effectively by other
" C$ q2 i+ ~5 q$ {9 r( f) b& J5 ?0 wclinicians but its mode of action remains controversial. Im-+ O/ a) V( ^3 l" S5 i2 o5 U5 @' [6 x
mergut and associates reported an excellent growth response
% p1 ~3 t# ^0 Ito topical testosterone with low levels of serum testosterone,
X1 C3 G1 e/ `6 H* j* j4 `& Wsuggesting a local effect.1 Others have obtained growth re-) q* J$ Z' c9 [8 R6 T# l
sponse with high. levels of serum testosterone after topical
2 d O" D' O5 n5 D# padministration, suggesting a systemic response. 3 The use of
7 k4 Q' ?/ I! n6 n: p+ {, i+ j& Egonadotropin to obtain levels of serum testosterone compara-
5 b5 e1 O* f3 I" Z- ` ?* E( @ble to levels obtained with topical testosterone would seem to- S0 q6 J% q7 B' b2 m
provide a means to compare the relative effectiveness of# n7 Q+ A" B, l2 P6 t# H
topical testosterone to systemic testosterone effect. It cer-7 N* v; k7 }. r) J$ Z" y
tainly has been established that gonadotropin as well as par-
1 _9 F4 r- v# Z/ L. J+ centeral testosterone administration will produce genital
( x4 A% L1 q' F$ D, W0 {9 n* D7 ~# ggrowth. Our report shows that the growth of the phallus was# \% e4 N7 C8 [/ F5 J3 X4 t I7 s
significantly greater with topical applications than with go-7 H- B5 E1 G2 E$ }5 @9 g7 ]8 X2 H
nadotropin, particularly in children less than 10 years old.
8 v( z3 x! V% [( _+ b* { B8 u" f4 xThe levels of serum testosterone remained similar or lower
8 i' q1 V/ _! Z0 Q8 Pthan with gonadotropin during therapy, suggesting that topi-$ j- R7 \' g4 M
cal application produces genital growth by its local effect as
. d! ^6 ]& d8 a5 T8 K$ A# L% m8 awell as its systemic effect.
4 _; s1 @5 i5 _' w3 D) LReview of our patients and their growth response related to
2 D1 d5 I- P2 U$ Y1 D0 \! g, kage shows a greater growth response at an earlier age. This is+ `) [0 N7 o7 _' u! {9 K) p
consistent with the findings of Wilson and Walker, who
% Z9 d2 L2 U$ f& t+ Vreported an increased conversion of testosterone to dihydrotes-
) K2 w9 ^8 p/ |+ g0 ytosterone in the foreskin of neonates and infants.4 This activ-
0 O# B& e/ x; W" vity gradually decreases with age until puberty when it ap-# y% \6 ^& ~; i9 R
proaches the same level of activity as peripheral skin. It may
) u/ o1 R9 J5 ]( r) X5 u8 ]6 Pwell be that absorption of testosterone is less when applied at0 X4 z; U- G* W* N3 }3 ^: q& \
an earlier age as suggested by lower serum levels in children# ?8 k0 k. R: F; A$ O
less than 10 years old. This fact may be explained by the
4 ?$ A3 h+ Y8 g9 H9 l& }greater ability of phallic skin to convert testosterone to dihy-
, S( U; Q5 ]9 `& Sdrotestosterone at this age. Conversely, serum levels in older
: S8 k2 C% K: s+ {: v- v/ S5 I3 tpatients were higher, possibly because of decreased local# V- K' s+ _) o8 k: s
667
% w2 i( ?. X; t8 t* O! ]6 B668 KLUGO AND CERNY
2 \5 {1 T. f* UPt. Age
( z T9 |( d m6 R(yrs.)3 K _0 o8 i( M* P) m( \" ]8 x, @0 R9 {9 S
Serum Testosterone Phallus (cm.) Change Length
7 O1 A( ?$ n' F4 }0 ^(ng./dl.) Girth x Length (%)
9 F4 u+ y/ i s' K. A( I( U4
( Z% L" n' _2 o1 I85 T, O* U( P7 p4 B7 o3 W+ N
10
+ s. ?% R# K1 t+ E6 ]" Z8 E. W7 Y, K12* N* ]- ~* ~- G; D) J% r
175 Y ?; I6 Q2 Z& _' x0 g
Gonadotropin
0 c8 o4 M- _+ n. `& y- ^71.6 2.0 X 3 16.6
! }; s1 n/ Y# q. r% `50.4 4.0 X 5.0 20.0, ?5 u/ s( R8 [( q
22.0 4.5 X 4.0 25.0- [% B2 o# X% m% m3 Y
84.6 4.0 X 4.5 11.1' o; I9 y6 {0 A3 c+ ?3 |5 U
85.9 4.5 X 5.5 9.00 k, u( M: U; m5 e1 ]6 t! s
Av. 14.3
8 d$ v% s [, p* t' H7 V; h4( W9 c6 b$ N6 F- l4 v% h/ Q( s
83 \5 o- C) x9 k- }& R% p6 k1 Z( y
10
. v T+ S0 Q6 a k; B8 u. h1 V6 f12
; V' C( g! |, W17
) u# D4 A6 x; _( Y( Y# fTopical testosterone) u1 A( `( g; i/ @- Z
34.6 4.5 X 6.5 85
3 i' [* W/ o- V- [0 i38.8 6.0 X 8.5 70
) ^" O3 j* O7 n6 t# y40.0 6.0 X 6.5 62.51 _0 j, x. Q% @6 K5 L0 p
93.6 6.0 X 7.0 55.5
% s ?& o2 \3 i4 X! s95.0 6.5 X 7.0 27.20 c/ E; @8 F3 S0 o8 z3 R1 {
Av. 60.0. B5 k0 d3 c; p* J
available testosterone. Again, emphasis should be placed on
, l4 `, n8 H9 l6 Vearly therapy when lower levels of testosterone appear to
7 O* q8 T% D* ^, Oprovide the best responses. The earlier therapy is instituted0 q* g. X7 b& x$ L
the more likely there will be an excellent response with low8 }' w: p* ?3 y2 i
serum levels. Response occurs throughout adolescence as
; x# T% D- d* w* r% E) H9 y: K8 t3 d4 |noted in nomograms of phallic growth. 7 The actual response. g' w3 d7 N+ Q
to a given serum level of testosterone is much greater at birth$ U6 c+ x) U, F. f: l0 |, ?* E
and gradually decreases as boys reach puberty. This is most
" e3 s4 D9 V1 M# r2 o5 R- [7 Plikely related to the conversion of testosterone to dihydrotes-. M! h' N; N! h
tosterone and correlates well with the studies of testosterone% j$ m2 c4 V/ \$ C8 X) x X( \% @% F. m
conversion in foreskin at various ages./ g9 z5 v" H+ s2 v
The question arises regarding early treatment as to whether
6 p8 b4 p" r6 ~one might sacrifice ultimate potential growth as with acceler-! {+ P: l7 a1 l9 s' y/ G+ ?
ated bone growth. The situation appears quite the reverse
) f% Q; a. k, F! c! _with phallic response. If the early growth period is not used
8 E) p* d! M- h& S: F, E/ ?' Twhen 5a reductase activity is greatest then potential growth0 \8 \: ?1 v3 ?( g4 e
may be lost. We have not observed any regression of growth' _- Y3 E9 p5 O; c3 B2 k, r3 ~5 q
attained with topical or gonadotropin therapy. It may well8 |; @ I& a$ ~
be that some patients will show little or no response to any
. T+ T! y9 V# X! s% Aform of therapy. This would suggest a defect in the ability to
6 d X" l7 {6 u7 j0 M3 h2 H6 Aconvert testosterone to dihydrotestosterone and indicate that
/ d% Z5 k y& M8 Y4 Jphallic and peripheral skin, and subcutaneous tissue should) [- I2 [, j7 _7 t; X$ e
be compared for 5a reductase activity.
6 f1 q) a+ B' z3 wA, loop enlarges to measure penile girth in millimeters. B,6 D, t; o3 y- P ~' d) i% v! Z# B% h! S
example of penile girth computed easily and accurately.& O5 ?, i+ a+ W7 R3 S/ Q
conversion of testosterone to dihydrotestosterone. It is in this9 ~1 {$ X+ ?! |6 s) H3 W
older group that others have noted high levels of serum
+ |) d, ~1 E& i0 }, ?testosterone with topical application. It would also appear# P) q- p; w2 W! o- j) L% z
that phallic response during puberty is related directly to the
+ g J- r2 h* D0 {, |serum testosterone level. There also is other evidence of local
6 w( K, B4 I8 |9 ~) Oresponse to testosterone with hair growth and with spermato-
! ^5 M5 Q- c' [8 V# Y# f% Ggenesis. 5• 6% E/ K( W/ P( Y5 r) ^
Administration of larger doses of gonadotropin or systemic+ A; ?- u* T! V4 K. r0 D
testosterone, as well as topical applications that produce
9 X$ d, Z M- Rhigher levels of serum testosterone (150 to 900 ng./dl.), will$ Z; _& S/ s0 x1 H$ h1 Z$ P
also produce phallic growth but risks accelerated skeletal1 f* r" h& l3 |, F" J& d" P
maturation even after stopping treatment. It would appear; c( f/ C# X: @
that this may be avoided by topical applications of testosterone
; O, d1 s9 C S1 z! jand monitoring of serum testosterone. Even with this control# A: F m/ Z, C+ O1 i$ B- u0 j
the duration of our therapy did not exceed 3 weeks at any
& \ q) N+ _/ V) Xtime. It is apparent that the prepuberal male subject may
" L, T2 l) H& l" f4 Zsuffer accelerated bone growth with testosterone levels near
& N+ K+ h( |! g/ d200 ng./dl. When skeletal maturation is complete the level of2 [% m# U/ z; Z, F1 t: Z* A
serum testosterone can be maintained in the 700 to 1,300 ng./
0 @4 F4 q- n# y: udl. range to stimulate phallic growth and secondary sexual
' d% |; B8 o8 l6 |; A; ^9 q& Fchanges. Therefore, after skeletal maturation parenteral tes-/ ?3 G9 S* D4 }$ k/ T7 i
tosterone may be used to advantage. Before skeletal matura-
5 X6 p+ p; Y* S: i! F+ ]tion care must be taken to avoid maintaining levels of serum
) e2 I+ _/ S1 W5 ~testosterone more than 100 ng./dl. Low-dose gonadotropin- v$ y; F) |0 L O# w6 s8 X
depends upon intrinsic testicular activity and may require
! s5 P3 j* U2 a- H9 |9 a. d" Qprolonged administration for any response.
* H7 r4 z$ [4 w# h( VAlternately, topical testosterone does not depend upon tes-
! b6 i7 z$ z2 [$ Sticular function and may provide a more constant level of
% S* _ U( a. y% ]2 [. R r: v% |REFERENCES
/ N# {1 i! n9 [( k1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ V5 ]& s+ W2 V( W' P- L
R.: The local application of testosterone cream to the prepub-
+ y, {# _, Y" u( C0 oertal phallus. J. Urol., 105: 905, 1971.* N7 s; A9 H( W% n& ~5 T
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 ]( S+ N9 l. w3 U( G! s6 Ttreatment for micropenis during early childhood. J. Pediat.,
4 ]! |; ~5 p8 {: R9 E' n6 i3 W83: 247, 1973.& R7 v' _- u$ b$ W0 B" v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 H; e2 y. ^5 X5 w7 d
one therapy for penile growth. Urology, 6: 708, 1975.
2 T2 v2 N& h1 f8 z6 Z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( \$ u" e8 t8 u- ?3 D/ p, S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by6 G, S8 ~" i, C4 O" p+ F
skin slices of man. J. Clin. Invest., 48: 371, 1969.. R( e8 |9 j1 C- O+ v m
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) L9 M' |. e) }5 t' P7 \
by topical application of androgens. J.A.M.A., 191: 521, 1965.
, h% j/ `# W, j- y6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 [' W1 H1 k+ K8 u1 x9 X1 O( }androgenic effect of interstitial cell tumor of the testis. J.4 v% R% g8 i% n7 m# _8 N
Urol., 104: 774, 1970.
2 M+ R2 ?9 b7 Q/ c7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ _' @3 H/ S5 \. _3 C9 l; S. O6 Z+ vtion in the male genitalia from birth to maturity. J. Urol., 48: |
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