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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" T5 W! ^9 f% d6 m6 t
GONADOTROPIN
, y3 n6 D3 _, g/ [% _  @! I& MRICHARD C. KLUGO* AND JOSEPH C. CERNY
; t' V* V; {. I- OFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' P( f# T  [/ [+ l( Z
ABSTRACT. `9 Z( |( ]2 b
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
. F2 w& {$ ]/ T. J$ pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-* @. C# Z7 o" P6 P/ r* n' O
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ \' Z5 E! p' m
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. E% `9 f2 B1 s
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 V8 M. T8 l$ q/ U
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: X4 r& z. K+ `' N( h9 w- yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
) z0 t8 i. U$ Q: I: y2 M2 L! U0 toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This, X1 s1 T7 }) b7 T" c; ?
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 O$ o: f. J) y) b: Q* ggrowth. The response appears to be greater in younger children, which is consistent with previ-
) N6 s1 {4 Z: Yously published studies of age-related 5 reductase activity., K$ \% P; d' c
Children with microphallus regardless of its etiology will
, U  r# o% D7 G2 Prequire augmentation or consideration for alteration of exter-7 N5 C. W& A0 B0 e/ M) n
nal genitalia. In many instances urethroplasty for hypo-3 E$ A$ ^1 ?9 o$ B5 d, M0 Q: t# z
spadias is easier with previous stimulation of phallic growth.  j7 T6 T0 d. N; Z0 J$ Y0 o
The use of testosterone administered parenterally or topically
: S7 W8 C. k' {3 N9 zhas produced effective phallic growth. 1- 3 The mechanism of
7 I# }! \% C1 h& G6 jresponse has been considered as local or systemic. With this7 s) G4 A8 a" D1 G% ^
in mind we studied 5 children with microphallus for response
' A# z9 T1 [5 H- k1 T; U* W$ kto gonadotropin and to topical testosterone independently.( m( m! R5 p8 f. k8 @
MATERIALS AND METHODS
/ D/ T+ y  I8 ^9 k6 ?Five 46 XY male subjects between 3 and 17 years old were
4 D6 L& q$ C4 qevaluated for serum testosterone levels and hypothalamic
' s1 n7 c! ~  {$ d1 {" ifunction. Of these 5 boys 2 were considered to have Kallmann's
  O, x- \  g0 e2 I- F. l! d8 h3 tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-5 T0 z9 ?" _+ l! V) g7 X8 A* y( ?. ~
lamic deficiency. After evaluation of response to luteinizing
, {  @3 L5 w! [3 Vhormone-releasing hormone these patients were treated with' W/ R* o$ R- U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# w( i  w( h. K
after completion of gonadotropin therapy 10 per cent topical4 G# q+ }! @; \6 E
testosterone was applied to the phallus twice daily for 3 weeks.; ^# p0 J6 Y( g
Serum testosterone, luteinizing hormone and follicle-stimulat-0 J! P5 U& h3 V  e! {( o
ing hormone were monitored before, during and after comple-
( l# M. y. l, r, h: }tion of each phase of therapy. Penile stretch length was
4 w1 R0 t( f# V& Robtained by measuring from the symphysis pubis to the tip of
! I; y: E+ a9 v* J( d& Athe glans. Penile circumferential (girth) measurements were6 ~8 \4 d- ~. K* I
obtained using an orthopedic digital measuring device (see
& x: p4 l( a5 j3 x1 V1 S6 yfigure).
( l7 [$ ]$ u$ X1 Q% E0 g7 A  ^! L: xRESULTS
" V: \  I! F- f# gSerum testosterone increased moderately to levels between: w1 a6 Y. m* _  e: l  U8 ~% K1 }7 I
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 y, t7 z+ y3 E( G$ V& _$ wterone levels with topical testosterone remained near pre-
! r) N$ @9 ]( u! P) `treatment levels (35 ng./dl.) or were elevated to similar levels
5 l- T/ {2 ?2 P5 v( B4 G: F' Qdeveloped after gonadotropin therapy (96 ng./dl.). Higher
/ J( d0 _; ]0 U0 q+ G! C7 Z: p7 ]serum levels were noted in older patients (12 and 17 years old),
7 |1 N' Z, f: z' w, L  s  x* J/ P! c5 T, awhile lower levels persisted in younger patients (4, 8, and 104 B4 I! G% B: S# C
years old) (see table). Despite absence of profound alterations! I  |, m" @% l4 @7 I/ B* O- C
of serum testosterone the topical therapy provided a greater
9 B4 S6 |+ z# s% Z. ^Accepted for publication July 1, 1977. ·$ [! O% i$ e9 t( S) n
Read at annual meeting of American Urological Association,
. l' M3 M% `/ i: E4 l* OChicago, Illinois, April 24-28, 1977.! `. F; O$ w; u& J3 t
* Requests for reprints: Division of Urology, Henry Ford Hospital,
1 D3 K8 X/ ~5 ]0 `4 B2799 W. Grand Blvd., Detroit, Michigan 48202.
+ Z2 K  ~+ Q0 w2 r4 K. x  aimprovement in phallic growth compared to gonadotropin.
/ [/ C! N. g" t2 R$ g1 _Average phallic growth with gonadotropin was 14.3 per cent* k2 M3 `. g1 Y+ ?7 C
increase in length and 5.0 per cent increase of girth. Topical9 P& R5 S4 v* t5 [% K5 v3 P4 P0 r: }" i
testosterone produced a 60.0 per cent increase of phallic length) R2 x: Q. x! _( z6 z
and 52.9 per cent increase of girth (circumference). The- u. G' Y; O" v. ~/ V
response to topical testosterone was greatest in children be-
& Y" x6 n& k+ r8 _* H7 }3 qtween 4 and 8 years old, with a gradual decrease to age 17% r' V2 v" Z" l  W, k
years (see table).$ W. Q8 V/ X# m# O; K! v8 }4 _) I/ H7 g6 Y
DISCUSSION
5 Z+ Y. N/ N) \7 r( o. `" hTopical testosterone has been used effectively by other5 M; Z. Y( O' ^' p! S
clinicians but its mode of action remains controversial. Im-! \- g  g0 z' K! k8 ?
mergut and associates reported an excellent growth response: q  ~# H6 w  M) w& B" D' Z; y& A) n
to topical testosterone with low levels of serum testosterone,# U" C5 v: b' m1 d  r
suggesting a local effect.1 Others have obtained growth re-
. b- O0 n& V$ i% M9 D7 [, K/ osponse with high. levels of serum testosterone after topical. P9 n$ ^0 ^$ H% J$ M. b
administration, suggesting a systemic response. 3 The use of1 x7 i% F1 T: ~. G6 Z( p
gonadotropin to obtain levels of serum testosterone compara-6 w! F/ R1 _. z+ C( L0 {! M/ N
ble to levels obtained with topical testosterone would seem to
( l/ U4 i1 P8 u  Hprovide a means to compare the relative effectiveness of$ N* {) H# r' n+ `: L/ Q
topical testosterone to systemic testosterone effect. It cer-
5 x, \7 j, U- I, U6 f1 `" Stainly has been established that gonadotropin as well as par-
0 i; c. C4 {0 p' Benteral testosterone administration will produce genital8 Y. ~& S  R( s0 [6 p% M
growth. Our report shows that the growth of the phallus was
/ n: g4 k7 D. U$ |significantly greater with topical applications than with go-
. ], Y, h3 t9 N5 I0 N- W0 Knadotropin, particularly in children less than 10 years old.2 ^: ?4 w5 E/ @" m
The levels of serum testosterone remained similar or lower
9 j. A9 l/ v6 a' H' N$ a1 l1 Athan with gonadotropin during therapy, suggesting that topi-
9 r4 G& W, h; ical application produces genital growth by its local effect as
1 ?. y0 `8 R7 @well as its systemic effect.+ |' a  ?' ?6 ^+ j* M! n, |9 a
Review of our patients and their growth response related to
+ r  @! V5 M3 ^age shows a greater growth response at an earlier age. This is6 \- b1 \* y7 m( H* L8 C1 e- y
consistent with the findings of Wilson and Walker, who
' f6 K4 i) H4 O2 S8 ~2 Ureported an increased conversion of testosterone to dihydrotes-
. b  c; ^5 H$ y) U( Wtosterone in the foreskin of neonates and infants.4 This activ-% B" M4 B# `8 q6 {. P
ity gradually decreases with age until puberty when it ap-
; K, n. ]5 J4 T8 @proaches the same level of activity as peripheral skin. It may& W6 @/ c9 W# c: _5 r% R/ ^
well be that absorption of testosterone is less when applied at
! ^- K7 A; S+ Aan earlier age as suggested by lower serum levels in children# z7 ~4 p& d" a2 [3 N
less than 10 years old. This fact may be explained by the; P* q; r# G; D: T3 y
greater ability of phallic skin to convert testosterone to dihy-
: |. g. F! x, q- [: Vdrotestosterone at this age. Conversely, serum levels in older. N- U- V) z1 e9 {- v- F
patients were higher, possibly because of decreased local) _* y/ o4 S) X6 j7 X: |
667( A3 E4 f: o0 i( G! j
668 KLUGO AND CERNY5 ]+ L  f9 `2 [% ]" v1 g5 F  L& i7 \
Pt. Age4 E% H! J9 y0 O/ ^
(yrs.)
' {7 n( X% x1 A3 [. M: |4 `Serum Testosterone Phallus (cm.) Change Length5 p# b2 Y/ f% e6 ^" \
(ng./dl.) Girth x Length (%)& n' E9 e# v- }9 k9 w: v* B8 m& r
4
0 m" L1 T4 ?4 j/ w  \3 M7 m: C* W8
7 i8 }: n3 M. A7 K7 N% ?1 u% O, O. q10
+ v) g1 U0 U- o: s; r9 h124 G! t: \0 s9 D$ V2 }
17' ^$ [* p$ r6 q# g7 A
Gonadotropin8 K& [# W: g) y, ?
71.6 2.0 X 3 16.6, Z3 j  N# ~. }
50.4 4.0 X 5.0 20.0
! }5 s* \1 T% X% `& Q$ Z, s22.0 4.5 X 4.0 25.0
" X4 l1 G' e+ x; G3 i5 L84.6 4.0 X 4.5 11.1) Y, Y7 {; o" j
85.9 4.5 X 5.5 9.0
' x# @! U! H$ v5 A  |6 A8 B' xAv. 14.3
) r- l) m0 h+ g5 S) I& \) A42 R: P9 p* O, ^, _4 ^5 t4 u
8
1 d3 g+ ~2 V5 H7 Y9 a3 j2 Z10" f$ k% z3 U; F- v
12. B# E: V1 a$ V1 X4 O
17# `3 T5 j; p) N
Topical testosterone0 U, a6 s( j5 a2 V. R# x9 s" v
34.6 4.5 X 6.5 85# E1 E  `4 w* @6 `  ?# Y% K  W5 B
38.8 6.0 X 8.5 70
' _8 K2 B+ M" f/ n! ^! `* l40.0 6.0 X 6.5 62.5
  \$ o: W( ~3 d. y93.6 6.0 X 7.0 55.5  b6 d1 r8 e( W
95.0 6.5 X 7.0 27.2- V# w4 H/ e: e/ q
Av. 60.0
' t3 m2 G& x0 R' Wavailable testosterone. Again, emphasis should be placed on( n5 e; A( g6 |- A  j
early therapy when lower levels of testosterone appear to" _* D" f9 E+ {
provide the best responses. The earlier therapy is instituted
' B/ W  d0 W8 D0 \6 r  ithe more likely there will be an excellent response with low9 L/ ?# H' G: v8 F, R
serum levels. Response occurs throughout adolescence as/ u4 s) B* ~0 D5 [
noted in nomograms of phallic growth. 7 The actual response
  l  N7 k5 T1 t8 T% f: Fto a given serum level of testosterone is much greater at birth
" P9 K9 |7 ]/ F; {$ ?; Eand gradually decreases as boys reach puberty. This is most# a( o% D, y& Q
likely related to the conversion of testosterone to dihydrotes-# W- [  y# R5 B
tosterone and correlates well with the studies of testosterone
+ h9 Y4 {+ t9 b; V2 Sconversion in foreskin at various ages.3 j+ d' F$ w$ T  J5 [
The question arises regarding early treatment as to whether' j" k/ N4 Y, g% c
one might sacrifice ultimate potential growth as with acceler-% F$ w3 A' s5 T6 R  R
ated bone growth. The situation appears quite the reverse4 g- ]0 }1 Q3 @7 y& M7 g: Y
with phallic response. If the early growth period is not used% Z3 G! L2 u: d' e
when 5a reductase activity is greatest then potential growth: B; M: {- X4 K% k* y0 z
may be lost. We have not observed any regression of growth0 _  b  {+ ]# ]  q
attained with topical or gonadotropin therapy. It may well: A" d2 Q$ U5 j7 D9 B. Q1 b
be that some patients will show little or no response to any% ?. E( O$ G9 v/ Q
form of therapy. This would suggest a defect in the ability to
, n( P/ J5 {6 c. kconvert testosterone to dihydrotestosterone and indicate that8 y1 ]: K# f. c4 H/ R$ [
phallic and peripheral skin, and subcutaneous tissue should
& y5 Y3 k% e1 f8 Qbe compared for 5a reductase activity.$ ^$ R  V. d+ K; U7 i* F# T2 G
A, loop enlarges to measure penile girth in millimeters. B,
7 j8 n) M# Q( ]# y% c- cexample of penile girth computed easily and accurately.* z  P4 D  Z4 B& }( b
conversion of testosterone to dihydrotestosterone. It is in this5 r3 w" I6 S, r% [
older group that others have noted high levels of serum+ A/ d- ^6 h' ]1 I' L3 A4 z
testosterone with topical application. It would also appear
+ y1 ^" N+ T$ d4 H) X  @that phallic response during puberty is related directly to the
* O& |% d3 O7 R  g" Bserum testosterone level. There also is other evidence of local
3 Q( l1 D' F" v7 P1 k8 C4 F3 W5 X. k4 tresponse to testosterone with hair growth and with spermato-
3 o8 b( T0 m2 p: y" V- |' Sgenesis. 5• 6
, Y  \( J9 o2 ZAdministration of larger doses of gonadotropin or systemic
: g3 @  R! P6 atestosterone, as well as topical applications that produce9 ^1 S/ F3 J: S9 h3 J
higher levels of serum testosterone (150 to 900 ng./dl.), will
# \& a) R3 z( v2 @) l3 z2 \0 qalso produce phallic growth but risks accelerated skeletal) v. O, n7 |7 ^& [2 q" S
maturation even after stopping treatment. It would appear  {, S7 P+ T9 P# F! q; ]( R
that this may be avoided by topical applications of testosterone  u. d/ ?& @4 l5 M/ ^% B3 T
and monitoring of serum testosterone. Even with this control3 s& H: X1 Y: D4 k7 p" z  X  g
the duration of our therapy did not exceed 3 weeks at any" V2 O. {2 _; D+ o; f, f3 @
time. It is apparent that the prepuberal male subject may/ E% ?1 K  ~' y" H, A
suffer accelerated bone growth with testosterone levels near
; [  D, J) W* W: F/ y200 ng./dl. When skeletal maturation is complete the level of$ G; `: O) Q6 P. y) t
serum testosterone can be maintained in the 700 to 1,300 ng./, Q4 p  D9 `  U7 p3 |
dl. range to stimulate phallic growth and secondary sexual' E/ B4 {. z& w5 H" _1 [0 H
changes. Therefore, after skeletal maturation parenteral tes-' _# j2 y- V. @* Y
tosterone may be used to advantage. Before skeletal matura-# z% u' X3 e( }& }; `0 Y
tion care must be taken to avoid maintaining levels of serum
# w! ~4 E( X: n9 L: v/ _$ j# Ktestosterone more than 100 ng./dl. Low-dose gonadotropin7 Z. x8 v2 B+ x' w9 a# [8 @- |
depends upon intrinsic testicular activity and may require
: M! H+ b: r3 Wprolonged administration for any response.7 P7 a1 I8 n3 P% C5 K; I
Alternately, topical testosterone does not depend upon tes-
+ K% R8 P) h& N7 n9 vticular function and may provide a more constant level of$ ^+ w( v5 g# }- Z9 J; s
REFERENCES
* n8 v* a: O, ]/ {5 Y' ]; d9 N1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
! N4 M7 [+ Q: I: t- |( JR.: The local application of testosterone cream to the prepub-
6 [6 X/ F. U* Mertal phallus. J. Urol., 105: 905, 1971.' a8 \# O7 x* a  e% p; l
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" ]" U0 X4 ?/ o* Itreatment for micropenis during early childhood. J. Pediat.,5 ~+ N+ t' |! C( l3 |/ C- R
83: 247, 1973.( I& l+ \9 a( ^8 l: m6 _
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
! f' A8 P) j+ e% k4 H: |3 T# x2 Eone therapy for penile growth. Urology, 6: 708, 1975.
4 l! i$ q$ M  v3 p4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
+ F% {7 g' N) M) ^2 H; X* N- A- y9 `to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 |2 v7 f2 b( C2 D; s8 gskin slices of man. J. Clin. Invest., 48: 371, 1969.
3 L5 X$ G; |% w5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- f3 l. ]' v# Lby topical application of androgens. J.A.M.A., 191: 521, 1965." z/ S9 Z  @" e* S8 t3 r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ A& B/ A  u2 O; Fandrogenic effect of interstitial cell tumor of the testis. J.0 O; l2 P& {' j5 p4 x8 B8 {
Urol., 104: 774, 1970.
  ]" _. }* A0 O: k5 x7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  s4 k& m  u9 r& m: Ktion in the male genitalia from birth to maturity. J. Urol., 48:
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