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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND$ | {) z2 P' o2 Z& |! |0 m
GONADOTROPIN3 N$ R! Z; }& i5 q- F
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. K* r. Z/ _- B" r+ w' E' S3 NFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# K Y- [9 U3 B; yABSTRACT' s- m; n; _! I- l
Five patients were treated with gonadotropin and topical testosterone for micropenis associated, {7 ]; i9 o9 J% R6 d
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
( B4 ^. T; P5 f3 v5 Y- Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% w, O5 W2 Q. J
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 s0 } K. [; S6 a& \
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) h; z7 d1 j' H1 _% oincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 ~! r; ]# B q+ lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 w/ A# m% E# _. L% n% U; K D
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 a) P9 j/ t6 ]: I: g
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 e" F1 S: m+ A
growth. The response appears to be greater in younger children, which is consistent with previ-
" s4 d) i" R4 |0 Z( q, O1 Hously published studies of age-related 5 reductase activity.( H8 }" L' V$ y p. o% W- ~( _
Children with microphallus regardless of its etiology will# ]! a4 Y! Q, y- N ?9 W
require augmentation or consideration for alteration of exter-
1 ]4 t+ L" q5 u8 }- h/ Unal genitalia. In many instances urethroplasty for hypo-) N) w4 ? h- y5 \; `% V3 P
spadias is easier with previous stimulation of phallic growth.( q. C+ E; e: Q/ d
The use of testosterone administered parenterally or topically& P/ Y& ]* ?5 n. a
has produced effective phallic growth. 1- 3 The mechanism of
i) U; F* ]( i" _/ oresponse has been considered as local or systemic. With this' ]" R& H& T: W {4 B( ]% E1 T
in mind we studied 5 children with microphallus for response) y1 _' x( V: E
to gonadotropin and to topical testosterone independently.
+ @ p/ D1 B z, T) fMATERIALS AND METHODS
p z: f) S; z$ g; f, UFive 46 XY male subjects between 3 and 17 years old were6 ^3 Q, d9 T0 t5 i7 s1 D$ X
evaluated for serum testosterone levels and hypothalamic# j6 T1 g4 {8 e! q
function. Of these 5 boys 2 were considered to have Kallmann's
/ w& l9 s4 J5 O% Lsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 @3 d6 Y' h! q9 J
lamic deficiency. After evaluation of response to luteinizing% z& P. E6 r: }- d; Z5 S) u
hormone-releasing hormone these patients were treated with: I3 e" x' _8 {; A9 A3 X' D2 e, @ C5 Z0 p
1,000 units of gonadotropin weekly for 3 weeks. Six weeks& n8 H3 {4 Q& E: w
after completion of gonadotropin therapy 10 per cent topical( `, o" ]& I9 d
testosterone was applied to the phallus twice daily for 3 weeks." h) ^1 S8 u$ o) P$ n- h/ r
Serum testosterone, luteinizing hormone and follicle-stimulat-
( A9 a! g" J l3 ^ing hormone were monitored before, during and after comple-: E6 P! i2 a) I' q% E
tion of each phase of therapy. Penile stretch length was
( L( w8 ~: h5 c: ]* fobtained by measuring from the symphysis pubis to the tip of; I7 }0 m$ k+ _! V6 u; R) s
the glans. Penile circumferential (girth) measurements were% q6 u- X5 r/ D3 Z' z
obtained using an orthopedic digital measuring device (see* p" }+ k" x( U* T
figure).
; v/ c* D+ a7 f# i2 @9 [; bRESULTS+ Y& w) f* ^ ~$ D# Y1 ?
Serum testosterone increased moderately to levels between
# ~* N* e$ i% Z7 R/ [# d! N F50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ \5 f2 ]$ R4 U8 R" M% R. `terone levels with topical testosterone remained near pre-- d7 R. i0 b! X7 U' }* P5 R
treatment levels (35 ng./dl.) or were elevated to similar levels
, q% f8 {+ ~' w" |developed after gonadotropin therapy (96 ng./dl.). Higher
$ }; [) {; |- E/ iserum levels were noted in older patients (12 and 17 years old),
: N% H' w- Z; _& jwhile lower levels persisted in younger patients (4, 8, and 10" p8 H. T5 O. I2 G* X
years old) (see table). Despite absence of profound alterations
: p4 x: `+ p0 Dof serum testosterone the topical therapy provided a greater
. G( m9 a8 v$ {: DAccepted for publication July 1, 1977. ·: p& C3 a: i' W7 i2 O" e
Read at annual meeting of American Urological Association,, Y! A5 w) T. `: E% x* ]
Chicago, Illinois, April 24-28, 1977.; U8 o; c0 ~/ e9 s3 T
* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ c% h/ i! A( x% ^5 |) k2799 W. Grand Blvd., Detroit, Michigan 48202.; K, l4 ]) S+ w7 `- Q
improvement in phallic growth compared to gonadotropin.' J" i: L# L6 k/ h% V+ d
Average phallic growth with gonadotropin was 14.3 per cent V$ b0 Z+ \# U+ O
increase in length and 5.0 per cent increase of girth. Topical0 U3 e% V: z% U
testosterone produced a 60.0 per cent increase of phallic length2 X& b o; z+ [. E) D5 o
and 52.9 per cent increase of girth (circumference). The* k; D/ n: J3 g- d2 T
response to topical testosterone was greatest in children be-
5 ?" r+ w1 d/ \4 c4 M* L9 e4 h* Btween 4 and 8 years old, with a gradual decrease to age 178 M7 o- ~* b8 [
years (see table).( }4 I$ F8 s) y" u4 h0 \& A) ]
DISCUSSION
1 z+ `) S& [( yTopical testosterone has been used effectively by other
" k$ b3 [# W6 Aclinicians but its mode of action remains controversial. Im-2 ~3 ?# m" p4 W. O
mergut and associates reported an excellent growth response1 \/ E% j, Q' V$ e! f V" _
to topical testosterone with low levels of serum testosterone,
, n- U; n) j9 P- gsuggesting a local effect.1 Others have obtained growth re-: H( [6 U/ V- v
sponse with high. levels of serum testosterone after topical
0 `: ]% Y' [$ I) @1 h4 I& Hadministration, suggesting a systemic response. 3 The use of
! N6 q2 t5 g9 B5 O9 ^$ F$ e) rgonadotropin to obtain levels of serum testosterone compara- h+ C i7 J4 D
ble to levels obtained with topical testosterone would seem to. E3 s( N# K2 {# a# J$ f' m
provide a means to compare the relative effectiveness of
+ v$ |( X: e# t& y! {; g& a w8 htopical testosterone to systemic testosterone effect. It cer- Y! h ]( E7 f# u: Y+ c
tainly has been established that gonadotropin as well as par-
7 X0 W- i! r: f* I% g3 z8 Kenteral testosterone administration will produce genital" `- e v8 N! f7 O, R7 P
growth. Our report shows that the growth of the phallus was; v% E, t4 g, c$ w
significantly greater with topical applications than with go-# P v. g0 }6 V( Z1 s3 L9 R
nadotropin, particularly in children less than 10 years old.
2 F" p- k1 k; d/ ]+ H: ]The levels of serum testosterone remained similar or lower2 @% \( o @7 x8 R' E$ n9 ~+ {3 s' U
than with gonadotropin during therapy, suggesting that topi-# d+ x8 R" N' X! v
cal application produces genital growth by its local effect as# F3 T3 n( D, Y ~$ b
well as its systemic effect.
; \( L$ o$ ^1 r2 Y" P1 C! a( u) W0 }Review of our patients and their growth response related to
5 f' Q# b! V n8 H, V$ X3 \; xage shows a greater growth response at an earlier age. This is
: e+ I# w2 D/ t+ P$ G5 p* Sconsistent with the findings of Wilson and Walker, who$ Z+ v6 r) F$ ~( N. }' {
reported an increased conversion of testosterone to dihydrotes-
8 H; z3 C7 J/ htosterone in the foreskin of neonates and infants.4 This activ-5 A; O, n0 X8 p* C/ v* \4 T
ity gradually decreases with age until puberty when it ap-
" ^- D. s* ]/ i kproaches the same level of activity as peripheral skin. It may) K" F6 Z. u4 T7 E9 q0 [3 p0 @7 ^
well be that absorption of testosterone is less when applied at- n' `& O1 N7 y' C0 K4 ]
an earlier age as suggested by lower serum levels in children3 N# T) m" p4 ~% H4 x% p }
less than 10 years old. This fact may be explained by the/ o! q4 ~1 m' @
greater ability of phallic skin to convert testosterone to dihy-
. |/ U, {# X! o9 mdrotestosterone at this age. Conversely, serum levels in older
* u7 |) V. k0 L% }patients were higher, possibly because of decreased local
& j$ A0 `# y& }* b. B667
5 ~0 N. B" ]$ {( J4 y/ c668 KLUGO AND CERNY
7 j1 A3 e5 J4 O5 R1 UPt. Age3 p; z! \7 X! ^! c0 j% k. C' @, I
(yrs.)4 R, r. G3 q$ T, Q7 }/ u2 e
Serum Testosterone Phallus (cm.) Change Length
1 g! s/ d# S- m4 g/ ](ng./dl.) Girth x Length (%)2 x0 z5 f5 m6 p2 g" n, E
45 b# {# w5 r2 x$ U
8% U) u8 i$ D7 ]
10: d9 [3 v" n* }- p) p6 I
121 N, ]. X* R" l7 Q$ J1 Y
17' t( C, h' \* F+ `% I. i o( ?0 t
Gonadotropin- E: x. B; {; u2 D7 W
71.6 2.0 X 3 16.6
1 Z- a5 A9 C5 U: t3 M50.4 4.0 X 5.0 20.0; ?) _ g. V( {5 R
22.0 4.5 X 4.0 25.0! y" W* @$ o- H- x/ p. B) J7 Y4 A5 `
84.6 4.0 X 4.5 11.16 ?- F$ s' }; |9 V; U
85.9 4.5 X 5.5 9.0) ^6 D& E* [, Y- s
Av. 14.3
/ @: I6 i o: a" _40 M4 E- @6 Q, M6 B; K
8
* ^% {- l# ~0 r. y6 q+ s10
5 w. |& B6 t2 k3 W4 B12
* Z4 r. m8 E$ ~17
7 m5 i( Q5 n6 Z) z5 p. o( v0 hTopical testosterone5 S6 M2 n" x4 v0 j% B* `
34.6 4.5 X 6.5 855 ^" v5 M8 M0 B \; K3 T4 b$ T( a
38.8 6.0 X 8.5 706 o& J+ h% ^. N
40.0 6.0 X 6.5 62.5 ?) m @9 B7 s! l# k
93.6 6.0 X 7.0 55.5
) n3 ]; V% S2 Q4 ]95.0 6.5 X 7.0 27.2' q9 d" g+ o8 R: E, u7 J
Av. 60.0
1 G; T# G5 G" r% k3 A$ Uavailable testosterone. Again, emphasis should be placed on8 T& q- B) h9 l p- j8 y! _
early therapy when lower levels of testosterone appear to% h. F0 Q1 {; n
provide the best responses. The earlier therapy is instituted
& h9 h( |* \0 V$ ~0 G- Othe more likely there will be an excellent response with low& O2 n4 q% g( }3 ^# s1 y4 Z/ l
serum levels. Response occurs throughout adolescence as* A9 ^+ ^9 Q+ i5 O
noted in nomograms of phallic growth. 7 The actual response
' d4 ]5 H' |+ q8 F7 G& h/ Mto a given serum level of testosterone is much greater at birth
7 G! C2 ^% K# t) v, O2 uand gradually decreases as boys reach puberty. This is most
; m b8 T; v6 t0 b% g3 R0 P, ]likely related to the conversion of testosterone to dihydrotes-5 R0 l$ w% C6 m, ^6 h, O
tosterone and correlates well with the studies of testosterone
0 i* H. Z; l4 G4 }. {( \conversion in foreskin at various ages.
, n% m( ~+ O ?The question arises regarding early treatment as to whether
# a/ j& j c- p5 M1 O; ^one might sacrifice ultimate potential growth as with acceler-# O" X1 q j* P0 A
ated bone growth. The situation appears quite the reverse
3 |! O" v' [ `# L# _2 d( Pwith phallic response. If the early growth period is not used
1 N4 X( X% A3 t) ^: k3 Jwhen 5a reductase activity is greatest then potential growth# r2 @; K" ^( n$ f0 i& Q2 }0 _
may be lost. We have not observed any regression of growth
' D/ B+ U% Q% C! W6 t! X2 P9 qattained with topical or gonadotropin therapy. It may well
; w& M/ S- \; L# Qbe that some patients will show little or no response to any/ ~" r- ^" a6 O0 w r& i
form of therapy. This would suggest a defect in the ability to
F1 @% Z8 f# G% R* `) }convert testosterone to dihydrotestosterone and indicate that6 v, |( S: Z( m# r: I4 A- j
phallic and peripheral skin, and subcutaneous tissue should; ^) Z5 _% a3 h! I& u$ p( N
be compared for 5a reductase activity.+ R2 o b0 ]8 A
A, loop enlarges to measure penile girth in millimeters. B,: y# W* H9 h) |/ U1 u) @
example of penile girth computed easily and accurately.
. n0 T& q; K+ Z5 h- bconversion of testosterone to dihydrotestosterone. It is in this+ l! t, ?) A. G h2 f
older group that others have noted high levels of serum
# o6 q) z6 d' f; i$ u8 }' a. z* Htestosterone with topical application. It would also appear5 o8 f6 G Z2 R8 i( H/ C. m
that phallic response during puberty is related directly to the, h; W# ]5 x3 P* q* J
serum testosterone level. There also is other evidence of local
% s2 Q/ G8 H8 T( G L+ Kresponse to testosterone with hair growth and with spermato-0 F2 _8 d. M* V# X3 A
genesis. 5• 6! [; E1 [8 [0 j% b, N
Administration of larger doses of gonadotropin or systemic
. D/ I% ]& y9 c/ J, Gtestosterone, as well as topical applications that produce
4 C K, g/ ~5 U' S6 Whigher levels of serum testosterone (150 to 900 ng./dl.), will! u* I8 t9 D, ?" Q
also produce phallic growth but risks accelerated skeletal
+ g7 i! ]1 m( w3 n; }- Wmaturation even after stopping treatment. It would appear% @* e ^+ N) D0 @7 J1 q5 @
that this may be avoided by topical applications of testosterone
( n* `2 r/ g, |1 Qand monitoring of serum testosterone. Even with this control4 B- X/ Q! P' d2 T
the duration of our therapy did not exceed 3 weeks at any
- g& C* o# n, f/ Z6 X. itime. It is apparent that the prepuberal male subject may8 Y$ u t( }) E' `( \0 z5 H+ H
suffer accelerated bone growth with testosterone levels near
/ J' m) }0 B8 f* h* D3 P9 C3 n200 ng./dl. When skeletal maturation is complete the level of
5 q0 z% m; A( ~) [9 f6 |: Gserum testosterone can be maintained in the 700 to 1,300 ng./7 k1 x9 i5 ^* K! |6 ~/ `0 v x
dl. range to stimulate phallic growth and secondary sexual$ y1 H! |0 T. \9 d
changes. Therefore, after skeletal maturation parenteral tes-
; O; L% s4 N; ~8 y. P; x- @$ n) q' etosterone may be used to advantage. Before skeletal matura-
2 i1 G, o* @$ j$ \6 `4 A% X8 H7 B7 S( ption care must be taken to avoid maintaining levels of serum4 m B d4 a( y0 @6 |
testosterone more than 100 ng./dl. Low-dose gonadotropin4 \; j, F' w) a/ q: E: e
depends upon intrinsic testicular activity and may require
/ Q: v' Q+ z+ S) g+ Z hprolonged administration for any response.
5 s" H- [- d7 \$ g$ E/ @$ b% u% ^0 JAlternately, topical testosterone does not depend upon tes-
1 b' \2 D6 e- V/ Z* L6 oticular function and may provide a more constant level of5 A- P6 y5 c% s1 o; K. f
REFERENCES
1 ?4 C( ?: G2 e9 I1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
- ?2 t- o& \( T% ER.: The local application of testosterone cream to the prepub-& W/ E/ N: I! J1 `
ertal phallus. J. Urol., 105: 905, 1971.
& L( A8 S" j) _$ w8 O2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( b7 ]2 y' j ?( N6 k* V+ O, h$ J$ h
treatment for micropenis during early childhood. J. Pediat.,
# ^4 e3 D" c. B/ c, F83: 247, 1973.: S0 j# k2 N$ P/ h! H: t" L
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: k; Q! n+ Q7 t( rone therapy for penile growth. Urology, 6: 708, 1975.
! c& N4 Q! ?/ L5 Y! W8 P" i) m3 Q [4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* s3 P+ B# u5 C4 v! `to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by- r: H: F6 N6 H4 r+ z3 N
skin slices of man. J. Clin. Invest., 48: 371, 1969.
3 q6 Z$ Y8 ^' d7 T/ b% j9 \; H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth/ y# |9 z6 `1 e7 Y. ^/ I: Q
by topical application of androgens. J.A.M.A., 191: 521, 1965.0 K/ i" p Q7 o5 f
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local9 ]1 d5 M0 R5 U" ~; K+ Y
androgenic effect of interstitial cell tumor of the testis. J.
. c* |% }& m+ c$ l) a1 {, ?Urol., 104: 774, 1970.
; p3 X. J; N# m' {+ r$ w# \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-5 P. Q; \/ J; M5 o0 @
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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