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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND  }) I* S9 M6 q0 u8 H" G& B) o
GONADOTROPIN, X+ W; {) H8 Q& p
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 c: h/ {/ a8 O7 x/ `
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan: ^% C- F8 W8 K% |7 C/ Z1 l+ B  u
ABSTRACT- S* t- N% K/ u& Y
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
* A; i- _2 U/ D( Q6 J& Q+ dwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-  Q3 J( g' o, E+ u$ V' q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& B% A, e+ `, B6 I  B3 m1 C
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; J+ A' I2 a8 Z$ m" f3 }: j. G# Bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ w3 ~' j% @; A5 Y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
* g; _, o9 F$ E( E9 q0 Dincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 @/ G1 h' H7 }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, {& G+ y7 e! F( \1 y, Kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 i1 d* }$ v' P- E
growth. The response appears to be greater in younger children, which is consistent with previ-
1 y5 U% t% E. K- j2 v. Vously published studies of age-related 5 reductase activity.3 y/ i# W% `! y# N  d% J$ K7 l
Children with microphallus regardless of its etiology will& u% h+ \" _% z: N
require augmentation or consideration for alteration of exter-
, W: d9 b3 ^7 K& f! q6 b3 Xnal genitalia. In many instances urethroplasty for hypo-
8 t& C) m* E3 x( K; Z8 R8 K& M' Uspadias is easier with previous stimulation of phallic growth.
# H6 B! K: k$ M0 S+ T! KThe use of testosterone administered parenterally or topically
1 s) _4 T( \8 L2 ^has produced effective phallic growth. 1- 3 The mechanism of
6 M; V- b9 I( D2 Z1 uresponse has been considered as local or systemic. With this
* `2 x+ M0 C- {/ G7 x% F6 }' a1 Cin mind we studied 5 children with microphallus for response
' O$ t2 K! ~. t7 H" Rto gonadotropin and to topical testosterone independently.
3 y4 v: S6 w8 z6 t( Y! C* \MATERIALS AND METHODS  @2 f  k# U# z
Five 46 XY male subjects between 3 and 17 years old were5 W& p' |$ t- S
evaluated for serum testosterone levels and hypothalamic: H1 E2 D) g+ c% l2 c0 ]' d
function. Of these 5 boys 2 were considered to have Kallmann's0 q: u  N2 @6 C# q' h) I  N
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 L; A% B! x4 ]0 U2 Jlamic deficiency. After evaluation of response to luteinizing6 A2 H* [" F5 }5 o
hormone-releasing hormone these patients were treated with# B, T! g" q* Z3 C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 j/ [) Q1 T8 I  O
after completion of gonadotropin therapy 10 per cent topical5 ^0 G' I# o- z! X" F
testosterone was applied to the phallus twice daily for 3 weeks.  V9 `/ {; a- b: K
Serum testosterone, luteinizing hormone and follicle-stimulat-2 X' h( q, V6 B
ing hormone were monitored before, during and after comple-
! F% c! z* i3 k! \* l6 Qtion of each phase of therapy. Penile stretch length was
, m8 F# B$ j& s8 p8 D# E6 ^1 Eobtained by measuring from the symphysis pubis to the tip of
& k+ B/ a0 y4 D. l- K& w$ }the glans. Penile circumferential (girth) measurements were
5 x' W5 A+ `. q. aobtained using an orthopedic digital measuring device (see! e/ j, |1 m( Y; a: q
figure).
/ a* x" E) {, n% e. l$ pRESULTS
! c* ~& u0 W  N* v; J$ w" v& d1 S; TSerum testosterone increased moderately to levels between
/ H. _9 C; Q  B/ O( A50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- f/ a$ Q3 T  S- u
terone levels with topical testosterone remained near pre-
/ J& }, l$ \, `treatment levels (35 ng./dl.) or were elevated to similar levels6 a4 R6 b& a& ~2 I' r  v9 a# @
developed after gonadotropin therapy (96 ng./dl.). Higher3 d: T1 t( i7 h, l
serum levels were noted in older patients (12 and 17 years old),
5 D7 Q! r, K4 j0 qwhile lower levels persisted in younger patients (4, 8, and 10
/ y5 l4 B: B3 Q2 W1 Y1 xyears old) (see table). Despite absence of profound alterations, F& _( k6 x! m; c# D+ o
of serum testosterone the topical therapy provided a greater
0 w& _/ w8 |+ d; R1 _2 N3 C- WAccepted for publication July 1, 1977. ·
! h) K. W) e4 nRead at annual meeting of American Urological Association,- C- l$ X; Q% u
Chicago, Illinois, April 24-28, 1977.' b3 r# U3 n4 `7 Q2 Y
* Requests for reprints: Division of Urology, Henry Ford Hospital,
' d/ w5 ~2 T1 b2799 W. Grand Blvd., Detroit, Michigan 48202.
! H( g$ B( K, `improvement in phallic growth compared to gonadotropin.7 k8 r% d2 l5 _; A7 [& x) _1 T
Average phallic growth with gonadotropin was 14.3 per cent
0 Z. `; R0 p: f" ~$ f- j" kincrease in length and 5.0 per cent increase of girth. Topical
8 B6 u# E: o2 y' ztestosterone produced a 60.0 per cent increase of phallic length
) ?/ j  }4 g( K) \, Dand 52.9 per cent increase of girth (circumference). The
: P; r" l. e- Qresponse to topical testosterone was greatest in children be-1 u: M9 d% o. L3 c  x9 ~
tween 4 and 8 years old, with a gradual decrease to age 17( K9 l* @& `' Z% p  a
years (see table)./ J; X4 M9 g) c8 o! `2 m$ L- C0 o
DISCUSSION
8 m# T+ c1 `7 b) Q3 {2 ^9 UTopical testosterone has been used effectively by other# E5 \& |5 A$ t  m2 J$ W
clinicians but its mode of action remains controversial. Im-. b6 v% y8 O0 u  f$ ]0 J
mergut and associates reported an excellent growth response% ~; P; _  s8 d* V- ?
to topical testosterone with low levels of serum testosterone,* A6 s" J4 ?0 p# h1 H) D5 \. R
suggesting a local effect.1 Others have obtained growth re-
; U. |: d4 }6 xsponse with high. levels of serum testosterone after topical9 n' l" D/ n6 y& Z3 N; ^
administration, suggesting a systemic response. 3 The use of
+ O; H4 ~# {5 }gonadotropin to obtain levels of serum testosterone compara-# N; E8 Z6 g5 C# M$ b
ble to levels obtained with topical testosterone would seem to
* K) S! M5 j% L0 W" {9 P) q, jprovide a means to compare the relative effectiveness of" }; W, O5 X* E; v
topical testosterone to systemic testosterone effect. It cer-, }, W# X# u1 t4 m& @5 \7 h
tainly has been established that gonadotropin as well as par-
3 {; C7 Z! p. s& f% wenteral testosterone administration will produce genital) N- e7 Z0 W4 a9 R- @
growth. Our report shows that the growth of the phallus was
  u  t) f. H4 `: s5 X7 ksignificantly greater with topical applications than with go-
3 |$ r  E; q7 c5 I  @9 hnadotropin, particularly in children less than 10 years old.
" p5 y; M% J9 ?The levels of serum testosterone remained similar or lower' }. H' H4 M& ^0 m1 A0 S3 w
than with gonadotropin during therapy, suggesting that topi-6 {* ?# a& |9 @* u
cal application produces genital growth by its local effect as% g, u. B8 ]- m- N
well as its systemic effect.
3 l# s" m* l8 v5 CReview of our patients and their growth response related to
' H/ k3 [$ ^- Y$ ^& ?2 o5 qage shows a greater growth response at an earlier age. This is8 u/ v; Z' p: J8 S3 Y0 u4 l
consistent with the findings of Wilson and Walker, who* y5 q! U- E8 ^  A
reported an increased conversion of testosterone to dihydrotes-
4 |! ]" d2 ]/ i( n$ j; Jtosterone in the foreskin of neonates and infants.4 This activ-, S1 k2 G; y  e7 v& \
ity gradually decreases with age until puberty when it ap-1 S" |0 G* d" L/ T9 d
proaches the same level of activity as peripheral skin. It may5 `" C) j1 Q) S1 A8 J" O8 x
well be that absorption of testosterone is less when applied at' Z, P4 b" H0 I4 d; i2 n, z
an earlier age as suggested by lower serum levels in children
# s; J4 b3 V4 O0 v$ \* s$ sless than 10 years old. This fact may be explained by the
6 F; k" w' {1 ~" {3 w# Cgreater ability of phallic skin to convert testosterone to dihy-
9 `' ~5 d5 m. p; Fdrotestosterone at this age. Conversely, serum levels in older. V) O/ X0 Z) l) ~: I- G
patients were higher, possibly because of decreased local9 c0 C8 `2 I1 w6 a5 a6 E. G/ \- d2 O, }( \
667; D! H3 }8 \  r& n7 k9 Z( r
668 KLUGO AND CERNY2 U0 L2 @# O. K% F1 g3 g
Pt. Age
4 ?( u2 n' `4 s# g+ |7 @4 j(yrs.)
/ H( |# Y1 P9 ]  JSerum Testosterone Phallus (cm.) Change Length2 Z2 I* @* J2 P9 T
(ng./dl.) Girth x Length (%)
1 z2 |0 {/ p! n# Z. |4
1 o9 [( \  T! {; _, V0 P, Y/ b8
9 X, p2 g  ?% q5 L; V8 G10  s7 C4 V& P0 L$ O
128 h5 |! C& z8 g+ Z! g2 p* m
175 M0 f$ a' T, h) N, k) [
Gonadotropin8 b! T. U3 a/ |& K+ Y# E
71.6 2.0 X 3 16.6
% Z5 y; z: i7 b6 x) F50.4 4.0 X 5.0 20.0
2 Y( d, b' {( m' W+ m# c22.0 4.5 X 4.0 25.08 C* L8 i% W; {% h2 r; t
84.6 4.0 X 4.5 11.16 L" d. ^& S) _9 A0 |  X) x
85.9 4.5 X 5.5 9.0
: B$ {# h- O8 x, K0 l( CAv. 14.3
  U8 L, U+ \2 X! T4 d4; }! i) W- R/ s% V% t# _
8
& t- B- B3 x' t2 W9 N$ I" u3 H/ S10. A( R% Q5 q+ R
127 x' G8 \3 K( v
17/ ^( B3 p5 @, z7 ^
Topical testosterone) S8 w+ I, R+ z# ]9 s
34.6 4.5 X 6.5 858 F% q% F" v2 v8 ~; J$ o$ J+ S
38.8 6.0 X 8.5 70
$ o  v" D8 E, e/ s2 R40.0 6.0 X 6.5 62.58 V* V/ W" a( Y4 I$ l* t, V7 Q: S- F
93.6 6.0 X 7.0 55.5) ^( Z" R$ V, W" |7 Z' h) m
95.0 6.5 X 7.0 27.2
5 p* f8 J6 C7 T' ~" K" RAv. 60.0
* |& ?. ^" Z. Ravailable testosterone. Again, emphasis should be placed on% Q# @7 o- j" P8 V3 d; f* y
early therapy when lower levels of testosterone appear to) N4 C3 H# B  y$ l
provide the best responses. The earlier therapy is instituted
, _2 Y9 t3 G2 m, T+ C( fthe more likely there will be an excellent response with low! k- E3 ~" _9 ]  f- I
serum levels. Response occurs throughout adolescence as9 ?, W8 j' e4 _3 \4 i- o; M
noted in nomograms of phallic growth. 7 The actual response. G2 v- x3 ^- k1 i
to a given serum level of testosterone is much greater at birth
2 E) l- U" A3 k. S- j! o9 \: r1 Rand gradually decreases as boys reach puberty. This is most
* Y$ P0 Q  w5 ]- O7 O7 h2 z5 alikely related to the conversion of testosterone to dihydrotes-- m# T7 F4 n5 z
tosterone and correlates well with the studies of testosterone
' {  j! L2 f0 F) a. Lconversion in foreskin at various ages.8 g* O( Y$ O) s$ z* `# h* z
The question arises regarding early treatment as to whether
( ?4 E7 t" @- C: Kone might sacrifice ultimate potential growth as with acceler-8 V6 f; J% B, Y: I# @! |6 b/ `
ated bone growth. The situation appears quite the reverse7 B7 z7 K5 q+ R4 |
with phallic response. If the early growth period is not used
8 b3 w/ R6 T8 ?; Cwhen 5a reductase activity is greatest then potential growth& X/ B5 W( I2 Q6 t- m5 v
may be lost. We have not observed any regression of growth
$ z; f5 m* y1 F. E2 k( F& c( ^& ~attained with topical or gonadotropin therapy. It may well
! q, \  K# o  n" g' i$ E* Zbe that some patients will show little or no response to any
1 v  m7 J, X$ }7 ?! ?form of therapy. This would suggest a defect in the ability to! ?! F- J! R; H2 R& b) \
convert testosterone to dihydrotestosterone and indicate that
' \" x& ^$ ]) S& i5 Kphallic and peripheral skin, and subcutaneous tissue should
/ j* v) ^3 d8 r( y4 \- Ybe compared for 5a reductase activity.
7 f: X3 J) H! T3 yA, loop enlarges to measure penile girth in millimeters. B,
1 U) I* A! D, {+ }9 z: o7 C5 uexample of penile girth computed easily and accurately.; O2 r3 A9 K, g4 R# A9 F3 R
conversion of testosterone to dihydrotestosterone. It is in this1 O4 C. z) J& |8 |, Y% z1 G% T2 D
older group that others have noted high levels of serum
3 k& v( p; p! Z8 Ttestosterone with topical application. It would also appear* i4 {+ K- x9 C6 ]5 D- x
that phallic response during puberty is related directly to the/ G- H* U9 V, q2 y7 r
serum testosterone level. There also is other evidence of local
& q. V5 C/ r3 l: J4 H# U" @response to testosterone with hair growth and with spermato-
9 c- G- l( A  i- `genesis. 5• 6/ v) i2 f* F8 j9 e* n$ a
Administration of larger doses of gonadotropin or systemic
' F; L- `2 q0 n' g! btestosterone, as well as topical applications that produce
  ~/ G4 S7 s$ F% m4 Lhigher levels of serum testosterone (150 to 900 ng./dl.), will3 j3 f1 P) ]7 ~9 L
also produce phallic growth but risks accelerated skeletal
2 _: ~- h3 g5 e& k; l! Ematuration even after stopping treatment. It would appear1 t# j* Z/ Q; b7 m% {4 d2 Y' p0 U
that this may be avoided by topical applications of testosterone
& N! K  x' X1 K* s& O+ M' Z' Pand monitoring of serum testosterone. Even with this control
2 X  t, P# t! z0 vthe duration of our therapy did not exceed 3 weeks at any
, {: E. T/ K9 jtime. It is apparent that the prepuberal male subject may4 _& Y& r  C( K3 D
suffer accelerated bone growth with testosterone levels near
% S8 T, D  W; N5 R' K  z# m  W4 N200 ng./dl. When skeletal maturation is complete the level of2 F3 N+ a$ F( o& `
serum testosterone can be maintained in the 700 to 1,300 ng./
2 h! x* z  H( _' g1 ?- D  }dl. range to stimulate phallic growth and secondary sexual
2 h- ]* ~$ Y: K' Zchanges. Therefore, after skeletal maturation parenteral tes-) [7 U/ _) \0 b" U
tosterone may be used to advantage. Before skeletal matura-
4 X& C8 T1 `7 F3 o  L: `2 |9 jtion care must be taken to avoid maintaining levels of serum
& {7 `6 }$ S7 t5 y# vtestosterone more than 100 ng./dl. Low-dose gonadotropin
, c' |8 H! T- `( h, F+ W) N. Jdepends upon intrinsic testicular activity and may require) \, W% W2 u9 N  h0 z
prolonged administration for any response.1 z; P" ^7 `+ g* l* D
Alternately, topical testosterone does not depend upon tes-
3 o) u2 X" o8 [ticular function and may provide a more constant level of
2 f/ Q8 s! Y  s; S/ ~. F: BREFERENCES
$ u$ [. v2 N. y/ V* K3 V0 J2 q1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 U" W2 F% c* [* I4 H: n! J' QR.: The local application of testosterone cream to the prepub-1 l- d8 z2 _7 U$ }1 @1 T: U. [8 Y- r7 @
ertal phallus. J. Urol., 105: 905, 1971.
- x' x2 H7 H8 s" t2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 d5 \$ V2 _# U, Z6 y$ g# {
treatment for micropenis during early childhood. J. Pediat.,
2 q4 V* l6 T7 M1 ^+ i$ X83: 247, 1973.
2 f9 \! R( R3 z5 N; \* o2 R# k2 A& e7 |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* @  A% e; s+ E8 [6 l4 x$ F* ]
one therapy for penile growth. Urology, 6: 708, 1975.
) @6 P$ D) c( ^, O, B* t% V7 S5 |4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone5 W& V7 \9 ^  |% v& c/ x5 q; p& W
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" W! O0 |0 _/ A; z3 y0 Vskin slices of man. J. Clin. Invest., 48: 371, 1969.% n. [) j6 g1 {/ x7 G; ^+ n5 L. \7 f
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ }4 K3 Q9 `- Jby topical application of androgens. J.A.M.A., 191: 521, 1965.& X7 a) q8 L' S$ D7 W1 l$ }+ }
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
  [+ N* w# U5 ~: M4 M! fandrogenic effect of interstitial cell tumor of the testis. J.
2 I; g, Y% c0 ~; l. C1 R: LUrol., 104: 774, 1970./ D/ n( F& ~* d+ O( \2 P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ C+ p! e$ Y0 F5 G- p& V+ {3 h; gtion in the male genitalia from birth to maturity. J. Urol., 48:
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