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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND. X6 l6 V; T6 E& C: ]* w0 _' e* X
GONADOTROPIN3 Y& @" a3 @. \2 j& G; H
RICHARD C. KLUGO* AND JOSEPH C. CERNY
4 ]/ K" A- {5 h3 l  x: M0 Y% xFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' p: |  @5 f+ r$ U9 |: V6 d
ABSTRACT
  P# [: C' B) j: I- wFive patients were treated with gonadotropin and topical testosterone for micropenis associated$ x1 p" }1 C/ v7 u; H
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: S. f$ w% S$ [( H8 K1 wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 ?! d! E8 O, m( _4 Vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent  N; p! {6 K7 W* p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent& t4 M2 i4 A, S" k" M  }  i
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
' Q6 M4 F9 V$ n$ K# Z9 y# S6 iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
! T3 y5 g" V  l2 ~! E7 Q" noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 _1 z& Y. d! j2 @- Y4 W
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ |: F2 J+ q7 _& y9 T3 `growth. The response appears to be greater in younger children, which is consistent with previ-
9 M8 I8 s: q9 X+ X7 j' iously published studies of age-related 5 reductase activity.6 ^' Q. B7 n' B* p1 i* v
Children with microphallus regardless of its etiology will6 M: f  L: {, H' Z& ~
require augmentation or consideration for alteration of exter-3 a* s6 A1 x" x* p1 y" _
nal genitalia. In many instances urethroplasty for hypo-5 N/ V/ W  E) Y& {) A! X/ Y# \
spadias is easier with previous stimulation of phallic growth.
7 O, G: }  b' s: |! jThe use of testosterone administered parenterally or topically7 v( ~3 t3 ~& X! k, Y3 @
has produced effective phallic growth. 1- 3 The mechanism of/ f7 J" J  j6 v! K$ ]9 M) L6 U
response has been considered as local or systemic. With this
5 e( J, v) m# t0 Jin mind we studied 5 children with microphallus for response% d, T6 Y9 v% @+ T- c0 n( ?# W0 d. Y
to gonadotropin and to topical testosterone independently.6 e$ s/ h9 L3 A; Q( V3 \( R
MATERIALS AND METHODS) \" }- Y, }; G6 X# _) k( F0 E
Five 46 XY male subjects between 3 and 17 years old were% b$ J8 w- K3 j, e* }+ }- D3 T- M
evaluated for serum testosterone levels and hypothalamic# L3 j0 ~. T/ ]; F
function. Of these 5 boys 2 were considered to have Kallmann's( d* j+ P2 R5 m
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-- _# J4 d* c/ r& @* i3 Y2 W
lamic deficiency. After evaluation of response to luteinizing
# I% Y) }( b  O8 A7 `! D2 R/ y7 K7 {hormone-releasing hormone these patients were treated with4 e9 ]* W7 m: U$ Q% L) _: A
1,000 units of gonadotropin weekly for 3 weeks. Six weeks; ?: e/ M5 S+ g, o
after completion of gonadotropin therapy 10 per cent topical( h5 u8 P  l/ g6 x, s, l
testosterone was applied to the phallus twice daily for 3 weeks.
0 ]7 w) H( x' vSerum testosterone, luteinizing hormone and follicle-stimulat-
9 r5 n+ R5 Z/ V% g5 e- d5 Oing hormone were monitored before, during and after comple-
! R4 `, i- H# B' rtion of each phase of therapy. Penile stretch length was
8 |7 Y* u) j, F8 }+ T8 f+ \obtained by measuring from the symphysis pubis to the tip of. C5 o' w  M; ~& j, X
the glans. Penile circumferential (girth) measurements were
9 f5 b% K+ n+ r( O/ R+ f7 robtained using an orthopedic digital measuring device (see6 @! V1 B1 j& c! B! u. W8 u
figure).
% q# |; A7 M" p/ l* `* S+ q; t+ fRESULTS( A$ T; K# G: w2 P5 ?
Serum testosterone increased moderately to levels between" o3 Q, }( u5 J. Y- _$ J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
# j6 V/ r$ k! r' O6 X: a6 ~% Pterone levels with topical testosterone remained near pre-
& s5 _. c/ @9 m6 m* O/ r0 C' Otreatment levels (35 ng./dl.) or were elevated to similar levels
" j5 A( Q( P1 D# \3 l, ]" `developed after gonadotropin therapy (96 ng./dl.). Higher- W: a# g- w$ K5 H( H7 e: ^" v
serum levels were noted in older patients (12 and 17 years old),
  R' s* c" N( w* i, c8 y2 z+ `while lower levels persisted in younger patients (4, 8, and 10) F8 P- k8 b- g) q3 G2 ?
years old) (see table). Despite absence of profound alterations
2 r7 v! F6 Q( p3 j0 M7 E# l$ o7 Pof serum testosterone the topical therapy provided a greater
6 }& N9 B/ C# m/ V, ^Accepted for publication July 1, 1977. ·
3 h9 [+ _- r# [' K  q4 U# xRead at annual meeting of American Urological Association,+ {8 h9 ?  H9 }9 \
Chicago, Illinois, April 24-28, 1977.0 E; {* |7 O5 C4 h4 z+ r
* Requests for reprints: Division of Urology, Henry Ford Hospital,
! b/ k7 u, @0 L8 d+ a# v2799 W. Grand Blvd., Detroit, Michigan 48202.
) ]: t2 p. A; R' ]2 Q# Z7 Oimprovement in phallic growth compared to gonadotropin.% c1 n/ E: T& N$ I4 c$ u# i5 b
Average phallic growth with gonadotropin was 14.3 per cent
2 z1 U' J/ e* D+ ^( c5 ]1 rincrease in length and 5.0 per cent increase of girth. Topical  i# m; p( t% _, |) {$ T$ ~$ D" _
testosterone produced a 60.0 per cent increase of phallic length' H. L" M* \2 }' U( x
and 52.9 per cent increase of girth (circumference). The6 o, \/ I3 X* S1 F: K
response to topical testosterone was greatest in children be-
, m/ @2 o" f- o  r7 e. t1 b+ Gtween 4 and 8 years old, with a gradual decrease to age 17
1 A( z# n+ m5 C- y7 |years (see table)., [  N# g- Y6 U
DISCUSSION
+ i$ D8 A- u: F6 N# q9 e1 kTopical testosterone has been used effectively by other
  o1 `# X" U# L5 G1 @9 O2 ~6 Uclinicians but its mode of action remains controversial. Im-
$ M. h3 A7 k& Cmergut and associates reported an excellent growth response
0 P! Q2 S1 Z1 ^! e$ {to topical testosterone with low levels of serum testosterone,
$ q2 s* T. i# I7 W  R9 F% }3 F; usuggesting a local effect.1 Others have obtained growth re-
3 D) D9 A8 o4 Q, U/ d$ d! |sponse with high. levels of serum testosterone after topical( A& Z2 U. I# Z$ |
administration, suggesting a systemic response. 3 The use of
2 }2 ~, [% l% t: `, lgonadotropin to obtain levels of serum testosterone compara-/ c4 ?2 B9 d0 v8 w) }/ f
ble to levels obtained with topical testosterone would seem to( S2 u, k  k$ m+ K3 _5 g
provide a means to compare the relative effectiveness of
1 R( }6 m: T; Ctopical testosterone to systemic testosterone effect. It cer-
. W! |1 Z( T0 ^7 K+ ztainly has been established that gonadotropin as well as par-
% w1 r: i9 C( Z1 u) Nenteral testosterone administration will produce genital
# `( q! l/ O2 y% s# N, z. _, rgrowth. Our report shows that the growth of the phallus was
5 a2 `1 N9 H: H! fsignificantly greater with topical applications than with go-: s) |3 G' D( D
nadotropin, particularly in children less than 10 years old.
! M) A! J# M6 u8 r% i- NThe levels of serum testosterone remained similar or lower3 B/ M8 B9 z7 D9 ]2 d& E
than with gonadotropin during therapy, suggesting that topi-
9 `' L5 p6 `% L) g7 k* V& gcal application produces genital growth by its local effect as
) a! b& g& g3 w/ @7 x! x8 U6 Fwell as its systemic effect.2 Y7 ~" r/ d. D* ]
Review of our patients and their growth response related to, \  O! G$ N( N" Y1 T
age shows a greater growth response at an earlier age. This is! {* e  R& O: }* b" L, s( ?/ `
consistent with the findings of Wilson and Walker, who3 E- v& A7 v' c9 r8 n
reported an increased conversion of testosterone to dihydrotes-5 d9 }, Q4 w" w
tosterone in the foreskin of neonates and infants.4 This activ-
; t- V( x* O% _  H' i% M# }: e$ H% Gity gradually decreases with age until puberty when it ap-: C$ k2 P3 Q: x% C9 Y# n6 d3 D
proaches the same level of activity as peripheral skin. It may, A) [/ b! p; M, d+ |6 D
well be that absorption of testosterone is less when applied at
1 ^8 G+ m' f) M( M& ?1 N( s( n- nan earlier age as suggested by lower serum levels in children2 r9 d7 Y# j1 H: c# P
less than 10 years old. This fact may be explained by the' |( c  b1 C. ^7 h5 g
greater ability of phallic skin to convert testosterone to dihy-
1 F( M6 ]' M% J# Mdrotestosterone at this age. Conversely, serum levels in older
+ E% r( l) f% q; y1 j! tpatients were higher, possibly because of decreased local
0 Z  C' E; E" K9 n667
0 G+ E3 s+ n: O668 KLUGO AND CERNY6 r* B5 ^5 I6 ?: H% h5 L) J/ k& L& y
Pt. Age# F+ O# V9 x# D# M4 _5 v% I
(yrs.)6 x: e. p5 O+ I" t% r$ A
Serum Testosterone Phallus (cm.) Change Length
) d5 `7 B9 u0 v3 l. U4 k: R(ng./dl.) Girth x Length (%)
" o; x8 `# o, C6 L5 X4, k) n& |9 ]& x! t) ~
8
/ j1 h) @& P6 v$ g10
( ]+ G3 X' b+ D2 d2 _12
! _& D: l- f0 L5 y6 Z* N; J17
% _. I6 [1 i" h' A* }Gonadotropin3 D3 p  _1 f- S
71.6 2.0 X 3 16.6
! m0 r3 J* Y% ~50.4 4.0 X 5.0 20.0
9 p" p' Q! g$ [22.0 4.5 X 4.0 25.0- x3 |) ~& v0 H8 A. ]
84.6 4.0 X 4.5 11.1
) z/ t! O9 X) F' ~2 E4 ]8 u* X0 Q85.9 4.5 X 5.5 9.0
$ `; k6 q" i8 ~Av. 14.3
1 F, G* S: i9 y6 P/ O  T4
/ m2 e/ a/ ]' d1 d. M8& Z1 N9 I& G5 `5 i9 r
10
0 V, o2 c9 n, H$ @+ q12
7 K0 N1 `* p8 `9 l17' Q4 ^- k3 f' D
Topical testosterone
6 g1 n8 g- z' W5 K0 l34.6 4.5 X 6.5 85
# B5 v+ V& |/ r" }/ r38.8 6.0 X 8.5 70
% L7 Q! n/ }* b. S) [* b" y2 B40.0 6.0 X 6.5 62.5- {+ I3 K: V6 z
93.6 6.0 X 7.0 55.5* X$ N: g, V3 ~1 l( O
95.0 6.5 X 7.0 27.2% H5 F+ x/ Y' f! q
Av. 60.0: q: K2 L& p( {9 l4 \+ l7 d
available testosterone. Again, emphasis should be placed on
5 J' ~9 z- N; ?! `" V- }early therapy when lower levels of testosterone appear to
2 H4 x. u! R1 b1 Iprovide the best responses. The earlier therapy is instituted; I1 n& m$ \4 w" ?
the more likely there will be an excellent response with low  _$ S9 }2 N7 p0 l0 s2 M
serum levels. Response occurs throughout adolescence as9 R8 H0 u9 g& q9 C6 G! \
noted in nomograms of phallic growth. 7 The actual response
, o; Z& l2 j7 g) W: u  `/ sto a given serum level of testosterone is much greater at birth
+ L1 s5 |0 `) Q( |3 ~and gradually decreases as boys reach puberty. This is most
: j/ d1 ~* j) r" F! Tlikely related to the conversion of testosterone to dihydrotes-. G2 x. `) q8 T- E# @' o, \5 {
tosterone and correlates well with the studies of testosterone
7 C2 ^* G( V! ~$ V# ^/ tconversion in foreskin at various ages.
- A6 T1 O( u6 e' k2 h, xThe question arises regarding early treatment as to whether+ l% X7 z7 T  O& T
one might sacrifice ultimate potential growth as with acceler-" l+ p& X$ {0 Q+ k- @
ated bone growth. The situation appears quite the reverse% t( F: S; ]3 q
with phallic response. If the early growth period is not used
  x7 u% ]2 S4 x; l! a! pwhen 5a reductase activity is greatest then potential growth  x7 P$ l* ?& n' Y4 G' ~* F
may be lost. We have not observed any regression of growth
9 g- {/ n8 P# A! @1 q/ R: S1 Hattained with topical or gonadotropin therapy. It may well
2 G1 Y+ D! s' Nbe that some patients will show little or no response to any- k  k7 g5 ?1 o' p' v+ @3 E
form of therapy. This would suggest a defect in the ability to0 x2 f) h7 S9 m6 Z( }
convert testosterone to dihydrotestosterone and indicate that* {5 T8 z" F4 r: o
phallic and peripheral skin, and subcutaneous tissue should; K9 B' {; J- T4 A
be compared for 5a reductase activity.' m! \0 O7 B' _& R& ]6 Y
A, loop enlarges to measure penile girth in millimeters. B,
& W! `  P& g$ ~example of penile girth computed easily and accurately.* A/ m- G1 e1 m* w
conversion of testosterone to dihydrotestosterone. It is in this
2 J; P1 ]! K+ v, }" ~1 `1 polder group that others have noted high levels of serum: n& O; H+ y+ |$ o
testosterone with topical application. It would also appear
/ X( K+ H6 x. q* S# O# B4 Rthat phallic response during puberty is related directly to the- Q1 z2 G: k+ w
serum testosterone level. There also is other evidence of local' b3 L! J) M% b$ H) h
response to testosterone with hair growth and with spermato-
: _( T" i2 D+ z+ [2 o* _) Bgenesis. 5• 6/ e  Y3 f. r% ~5 S& i& `1 h, v' R+ T
Administration of larger doses of gonadotropin or systemic' ^2 J" f4 E, z7 i/ I% u
testosterone, as well as topical applications that produce  ]5 s4 _+ C9 t. p9 C2 U
higher levels of serum testosterone (150 to 900 ng./dl.), will
3 n! K/ m# m1 o$ C" Ualso produce phallic growth but risks accelerated skeletal* Y$ o4 i# B/ c
maturation even after stopping treatment. It would appear4 d. |/ n2 l! O5 A
that this may be avoided by topical applications of testosterone( l  v5 J( J* B. |; K$ g
and monitoring of serum testosterone. Even with this control
7 I" A  C" ?, F+ c7 q5 X% E& z& @the duration of our therapy did not exceed 3 weeks at any- j1 D9 Z8 o4 m' }
time. It is apparent that the prepuberal male subject may2 y) Q# j/ V; ~8 D6 O) w5 i
suffer accelerated bone growth with testosterone levels near, F. |4 H. b4 q; s% T. g
200 ng./dl. When skeletal maturation is complete the level of- }7 I! F2 `% e/ J6 u! @
serum testosterone can be maintained in the 700 to 1,300 ng./
. b, |0 B. V6 I  xdl. range to stimulate phallic growth and secondary sexual- g& Y$ }. g  v3 c1 R
changes. Therefore, after skeletal maturation parenteral tes-# o8 b' F2 R/ d+ f: U9 E9 f
tosterone may be used to advantage. Before skeletal matura-
0 K) }, k8 L8 e9 ]tion care must be taken to avoid maintaining levels of serum
( Y3 I% Q2 L* v5 O6 Z. jtestosterone more than 100 ng./dl. Low-dose gonadotropin! E6 w4 S2 e4 j5 F! }5 r
depends upon intrinsic testicular activity and may require5 a- Y! C! Z) d9 O: }# n
prolonged administration for any response.
- E0 C+ Z, V9 l4 N/ Z* V  v, EAlternately, topical testosterone does not depend upon tes-
3 d* D& H$ l3 a. kticular function and may provide a more constant level of
- M) c; l, Y  H$ G1 MREFERENCES+ p7 m  K* [: s+ V; l
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
5 p- T$ A  N. I$ Y! V3 ?3 l% gR.: The local application of testosterone cream to the prepub-
5 V6 }$ A% s$ G. w$ \, k; J8 Oertal phallus. J. Urol., 105: 905, 1971.0 C! J- S& r  {! w% J; \5 r
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" O' A/ E9 o' B  y5 Mtreatment for micropenis during early childhood. J. Pediat.," z  S) w- Q6 m
83: 247, 1973.! E" a+ @: w* W5 n  L' l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
. e0 c$ Y3 v) l8 p: `one therapy for penile growth. Urology, 6: 708, 1975.
0 S7 r# o/ [3 }2 U0 c- ?0 X4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
' X0 G% R" G+ ?2 Y# o- q& Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 {  e/ W4 c1 s5 _+ a
skin slices of man. J. Clin. Invest., 48: 371, 1969.8 s0 G. `. k, @  b1 v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
& M: D/ x( K: N9 s7 cby topical application of androgens. J.A.M.A., 191: 521, 1965.; F9 Q1 {* x: M: g/ |5 N4 b8 V
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local/ H) }6 b  k1 O, _- V( f
androgenic effect of interstitial cell tumor of the testis. J.
2 Q8 B2 V1 E+ G5 l' Q. I8 CUrol., 104: 774, 1970.
. |/ O1 D- p% M9 j8 P1 S) q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) n! {0 m3 b& n) x7 n
tion in the male genitalia from birth to maturity. J. Urol., 48:
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