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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND: F' q) _  f8 v$ a) u
GONADOTROPIN
. g" V- q+ g3 i, W$ A; kRICHARD C. KLUGO* AND JOSEPH C. CERNY
% E" P/ C6 n/ l2 L; aFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
3 G5 K; O+ t! a! qABSTRACT
/ Q' m( t& e6 O0 K# kFive patients were treated with gonadotropin and topical testosterone for micropenis associated
) o7 `& q. r& a5 d/ F0 [! Q- ]  `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 q/ U0 Q/ R) |1 stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 V) v# \8 h: V  a; s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& {# e5 c! v. j" k6 S. X
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 A3 X; L) @5 O2 T0 ^( l- ]$ Cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
0 z; N+ u; Y2 c  h( H% [increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 z& u# U: F1 l, H0 ]3 Loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 {" r0 Q, U6 q1 @. n" G( Xstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
2 ?3 i; r2 c/ y4 R+ A+ c7 F! y/ Mgrowth. The response appears to be greater in younger children, which is consistent with previ-" z$ d4 u* m  `" }) C1 i4 @
ously published studies of age-related 5 reductase activity.! [5 p+ ]/ ?- k
Children with microphallus regardless of its etiology will
* V; o4 f: s+ L+ L  zrequire augmentation or consideration for alteration of exter-
# x+ m5 S( Z) f2 ~# mnal genitalia. In many instances urethroplasty for hypo-
, J  o% o. F5 _$ Q% d- yspadias is easier with previous stimulation of phallic growth.+ I* Q' h* ~! s  R+ B7 J
The use of testosterone administered parenterally or topically
& {7 @! ]9 r1 f7 q1 Chas produced effective phallic growth. 1- 3 The mechanism of
  ]! u* ?) [1 T7 f" l2 `- j4 d" hresponse has been considered as local or systemic. With this
! e- I7 ]' a( r4 B2 R, e  rin mind we studied 5 children with microphallus for response5 {) T3 S) I; W: F6 \
to gonadotropin and to topical testosterone independently.' y1 N# M+ [* s. k) k# V' i
MATERIALS AND METHODS
! h2 w9 L( Q6 n& o  n8 ?9 R+ lFive 46 XY male subjects between 3 and 17 years old were9 H1 y' |: A1 R% ?# l
evaluated for serum testosterone levels and hypothalamic: U7 O( F2 O( a" L9 f9 R9 T7 w
function. Of these 5 boys 2 were considered to have Kallmann's0 P5 |1 e, E  s4 n% ~
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 |, _! z' Q% ?* ]! J- y6 t
lamic deficiency. After evaluation of response to luteinizing/ t, o$ ^% Q5 B+ |
hormone-releasing hormone these patients were treated with
7 r) v- s2 U8 [3 j8 Q; s1,000 units of gonadotropin weekly for 3 weeks. Six weeks% b. U: N& d. G3 e( A" a1 r4 I- A
after completion of gonadotropin therapy 10 per cent topical
1 @* d- |5 C7 X1 _0 `testosterone was applied to the phallus twice daily for 3 weeks.
/ E* s9 v' f1 J+ YSerum testosterone, luteinizing hormone and follicle-stimulat-
/ ~: z( }6 r9 Ping hormone were monitored before, during and after comple-
- L1 l. |# r1 e6 I( Htion of each phase of therapy. Penile stretch length was
: r' }8 |5 W, Y, h  b% pobtained by measuring from the symphysis pubis to the tip of
) E; P; @( M( D, {: R( j; r% S: ?1 i3 l, Bthe glans. Penile circumferential (girth) measurements were) @, V8 J1 z1 l1 g
obtained using an orthopedic digital measuring device (see
; D5 p4 q  d$ B& E5 V- h- Q* Y! gfigure).
, f0 v7 d+ ^$ z( l1 @RESULTS
8 d% a6 x( C" i+ C: Z# y+ SSerum testosterone increased moderately to levels between8 [5 u1 b& @0 r$ V+ r, ~/ b
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 u2 V$ k6 v( }7 S8 Z" h  q
terone levels with topical testosterone remained near pre-8 e) a6 w1 y& v9 W4 _
treatment levels (35 ng./dl.) or were elevated to similar levels, d/ M- U3 c; o/ |0 h
developed after gonadotropin therapy (96 ng./dl.). Higher# L, }0 T+ ~4 s9 ~- k
serum levels were noted in older patients (12 and 17 years old),$ m+ o, }# j6 U, o
while lower levels persisted in younger patients (4, 8, and 10
. I9 X/ I) e; e; |years old) (see table). Despite absence of profound alterations
" W, G( X; a1 }2 Q- zof serum testosterone the topical therapy provided a greater* o3 p. \) ^' O$ a5 N
Accepted for publication July 1, 1977. ·9 U: c% s+ y) {. G! G/ N
Read at annual meeting of American Urological Association,: r$ y9 e) m/ j; T
Chicago, Illinois, April 24-28, 1977.  `# h4 O' D9 U/ O3 \) R1 U* ?
* Requests for reprints: Division of Urology, Henry Ford Hospital,: N: P' }4 T5 z
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 y) R+ M6 U" e( ~improvement in phallic growth compared to gonadotropin.* G. B1 s+ V, e1 S) \( r6 Y4 p9 ^* @
Average phallic growth with gonadotropin was 14.3 per cent
# _9 }8 g% C2 x+ Q3 }& a" x" N8 R: `9 aincrease in length and 5.0 per cent increase of girth. Topical
) `/ e2 K+ O5 ^* e/ N$ R5 Ztestosterone produced a 60.0 per cent increase of phallic length' h6 r9 W# Y0 k; R9 H5 t% c! h
and 52.9 per cent increase of girth (circumference). The2 v$ N$ f! h. Z$ B" I) v" F( ~) n
response to topical testosterone was greatest in children be-3 x0 w. P. W. W* u+ M3 B
tween 4 and 8 years old, with a gradual decrease to age 17
; _. l2 s& B4 F2 f; @! s- x5 J' ?, ~years (see table).+ T4 ~+ x3 v% }& {+ B
DISCUSSION
# k* E$ H9 n+ j% i. M0 vTopical testosterone has been used effectively by other
8 X( v  d- w: u1 wclinicians but its mode of action remains controversial. Im-/ D* d; }# y: h  V
mergut and associates reported an excellent growth response+ K" I+ ?; S$ w' x0 ?
to topical testosterone with low levels of serum testosterone,( ]" _% C# j8 q+ c% \; G3 d
suggesting a local effect.1 Others have obtained growth re-$ W8 q9 z  c3 y+ S% j, p
sponse with high. levels of serum testosterone after topical* _1 e- Y% |2 o
administration, suggesting a systemic response. 3 The use of
7 e7 A  `& g# G0 \- [gonadotropin to obtain levels of serum testosterone compara-
8 ?( ^' \7 c0 k* `1 Q" V1 K/ kble to levels obtained with topical testosterone would seem to- b# ]8 n9 Z. g( |, ^2 A, ]
provide a means to compare the relative effectiveness of
7 q: R" p. ~  U5 F% ztopical testosterone to systemic testosterone effect. It cer-. Q! D: o# s% j0 J& c) w
tainly has been established that gonadotropin as well as par-
- M* e. _% H, Z) V, m# ?4 b; Genteral testosterone administration will produce genital) @  O- T/ M8 C0 B% ^
growth. Our report shows that the growth of the phallus was  {. ]' G  r2 w# w  z& Z* U
significantly greater with topical applications than with go-
4 q7 E& G- _: E% V* `4 ~nadotropin, particularly in children less than 10 years old.
2 a$ V$ O; o# w& X: ?. I$ @The levels of serum testosterone remained similar or lower
$ _% ?8 g* J/ C; sthan with gonadotropin during therapy, suggesting that topi-
4 q" `& Q9 ?- B" K- K; A. n* @' Fcal application produces genital growth by its local effect as
" L9 E: H, o. i2 Pwell as its systemic effect." Y) d' K1 @/ J: c5 m% j
Review of our patients and their growth response related to4 `, T: d/ _. K4 L" _4 x, {
age shows a greater growth response at an earlier age. This is% p) v$ |; B, f& p+ K6 Z& H# ]8 F
consistent with the findings of Wilson and Walker, who5 x8 W1 m* f8 k& A- e5 I+ @( H
reported an increased conversion of testosterone to dihydrotes-
' C. z5 A$ l1 K& d6 s  j' @tosterone in the foreskin of neonates and infants.4 This activ-9 c7 Y( p8 \" B! _- W! a- o$ Q
ity gradually decreases with age until puberty when it ap-
/ l3 q  X  _0 D* f% X# aproaches the same level of activity as peripheral skin. It may) ?$ k+ `, E4 O1 F
well be that absorption of testosterone is less when applied at
1 H& F6 H+ M- tan earlier age as suggested by lower serum levels in children& A3 M/ B/ r6 \: j/ x
less than 10 years old. This fact may be explained by the' o5 Q$ A5 `+ u. T7 ^, n
greater ability of phallic skin to convert testosterone to dihy-0 V% P2 F0 p$ S" g$ Y' \& `: P
drotestosterone at this age. Conversely, serum levels in older
1 m5 m# _9 @* n. P5 Spatients were higher, possibly because of decreased local
1 k: E6 O5 H: g4 a8 K2 h" q  m667
) a0 Y' B4 D8 v# w' u0 g668 KLUGO AND CERNY9 x1 _$ M$ p* S; E" y
Pt. Age
% r7 c# u2 j. L) f, R(yrs.)
" b$ v7 i( L. j( ySerum Testosterone Phallus (cm.) Change Length
. q) _; D; t2 h(ng./dl.) Girth x Length (%)9 j' `5 e: D( J0 M/ j1 L1 `
42 F% h) O: A) ?, T- h  n( Z0 V
8& V4 W. t  _7 {; S, p
105 l3 j- K' V+ E, x/ j
12
7 q  E$ @! S; i! U17
7 G0 j+ J0 p* x: @1 BGonadotropin9 ^: G! w- a- J) y* E) a0 Q
71.6 2.0 X 3 16.6
6 s; Y: H$ m) l7 y50.4 4.0 X 5.0 20.0
* c- ~4 f8 `: R6 m  H$ l$ \* ~; a22.0 4.5 X 4.0 25.0' |* G  ~/ Q- d& `1 |# \0 }  J7 g
84.6 4.0 X 4.5 11.1# k' C4 D/ S9 j8 v
85.9 4.5 X 5.5 9.0
, C8 d; v  e7 iAv. 14.33 h' M' t$ Q, }' z4 M0 m' F
4
# u( }) q/ K5 m4 K4 ^/ {+ }* N8
9 P. q" i: @3 o  _  j9 m5 ]10( w5 e$ l2 p- j, ]( a. n  `, p
12! K- U. j% G+ k; x+ N+ H% l
17
- ?, J" u! d0 C2 @) Q2 M4 \& Q2 @Topical testosterone
7 c: Q$ w0 M  I; J/ z34.6 4.5 X 6.5 855 C7 H9 w/ r; c; a/ v5 d/ n- u
38.8 6.0 X 8.5 70
' K4 b7 d* M8 @$ Q40.0 6.0 X 6.5 62.53 |4 Z9 h/ ^; }, E6 Z, K
93.6 6.0 X 7.0 55.5
7 h: C% `1 K0 x5 U' o- _7 s95.0 6.5 X 7.0 27.2
5 U9 T2 L( j6 H  Z7 i! o3 OAv. 60.0& f- X9 u; b5 I% V
available testosterone. Again, emphasis should be placed on; I* s6 y2 c3 M* r! z9 D( A+ Z
early therapy when lower levels of testosterone appear to4 H/ |9 X/ a- e* k) q5 w; ~
provide the best responses. The earlier therapy is instituted8 k$ O9 Y+ |  `: m
the more likely there will be an excellent response with low
4 ]" V. k! v/ S) T0 x3 W9 Q8 {' pserum levels. Response occurs throughout adolescence as
+ Q# F9 d- s/ |) O9 W- W$ Onoted in nomograms of phallic growth. 7 The actual response. }# t9 l0 O1 z2 O! S. ?  t3 M' o
to a given serum level of testosterone is much greater at birth8 N4 m, q8 Q9 s& r
and gradually decreases as boys reach puberty. This is most
4 A$ i; w% E+ O- F& T! a/ Blikely related to the conversion of testosterone to dihydrotes-
2 j% h2 ^% ~* O3 j4 W& q* j! h3 Otosterone and correlates well with the studies of testosterone: C6 z/ @3 {. P) N
conversion in foreskin at various ages.9 K" g  o& E9 f! l8 v  o7 j
The question arises regarding early treatment as to whether4 X  p# L/ b' q2 m5 \
one might sacrifice ultimate potential growth as with acceler-
, g5 L* ^5 m/ h* j; Nated bone growth. The situation appears quite the reverse
3 h* C! a+ u. h& M9 Z# i- X8 l; dwith phallic response. If the early growth period is not used
! f4 @) G. h  j5 E. Mwhen 5a reductase activity is greatest then potential growth* P3 ~. l- L3 [5 A4 F
may be lost. We have not observed any regression of growth/ }8 W- e7 \& L
attained with topical or gonadotropin therapy. It may well
/ i6 e9 }, N% a4 zbe that some patients will show little or no response to any
  A" [0 ~! x4 t! T# j4 Xform of therapy. This would suggest a defect in the ability to
; [7 m( Q3 X% P0 ]convert testosterone to dihydrotestosterone and indicate that( R2 j5 z% D4 H
phallic and peripheral skin, and subcutaneous tissue should
; ?. v, |' g2 u$ @9 _be compared for 5a reductase activity.) t1 [9 ^0 p% Y. s+ g9 H$ @
A, loop enlarges to measure penile girth in millimeters. B,* n+ ]: h) |  o9 l+ l: X
example of penile girth computed easily and accurately.  L" p) e8 r' V- h) A3 s* j& l2 B
conversion of testosterone to dihydrotestosterone. It is in this
5 Z- S, l4 u) Folder group that others have noted high levels of serum
2 u2 r6 p* H9 X2 L/ W. \testosterone with topical application. It would also appear# c! c. ]; R3 f& C- C: O
that phallic response during puberty is related directly to the
3 O/ W; `" N! o6 `; Gserum testosterone level. There also is other evidence of local5 [8 O/ A& n$ [
response to testosterone with hair growth and with spermato-* g; W! J! N* c/ G3 B! V
genesis. 5• 6( B9 r, J" {  e7 h
Administration of larger doses of gonadotropin or systemic
' z: z& L4 p# s4 R4 h. xtestosterone, as well as topical applications that produce, _6 K+ R& G; {' U
higher levels of serum testosterone (150 to 900 ng./dl.), will( B; Q: s# X: ~+ Y$ [; g4 t
also produce phallic growth but risks accelerated skeletal/ K. B0 u5 M8 A. R- E/ g  b7 K
maturation even after stopping treatment. It would appear
0 G, |1 \& P* J! |9 }& ^5 Sthat this may be avoided by topical applications of testosterone
" `- O! U1 e) B$ m) o) u& Y. g- Oand monitoring of serum testosterone. Even with this control
0 O( ~8 t4 \' I+ O/ ithe duration of our therapy did not exceed 3 weeks at any5 H1 T0 M; f3 `
time. It is apparent that the prepuberal male subject may6 y3 l+ A2 m+ _4 l
suffer accelerated bone growth with testosterone levels near! o2 R6 u, h7 c( }
200 ng./dl. When skeletal maturation is complete the level of3 ?3 B7 x% w! m; }4 X7 \8 C; n, m
serum testosterone can be maintained in the 700 to 1,300 ng./
. J6 V" a: E& O. R1 sdl. range to stimulate phallic growth and secondary sexual, G, }4 a0 B) y+ y1 F
changes. Therefore, after skeletal maturation parenteral tes-/ @( I6 P' y( Q* N3 M/ @1 c5 o) U
tosterone may be used to advantage. Before skeletal matura-
: O. o, `$ q; S; |5 Ktion care must be taken to avoid maintaining levels of serum5 n# ]" p- [; ?+ ]+ H9 X
testosterone more than 100 ng./dl. Low-dose gonadotropin
9 q/ p. e8 S7 k" [9 o6 Y  vdepends upon intrinsic testicular activity and may require
# h% w) X2 i9 z6 J4 v1 V7 U  bprolonged administration for any response.
& j  c4 K2 K/ U1 t# _; X) |Alternately, topical testosterone does not depend upon tes-
+ |4 a2 j& ?' m! w- r6 ]ticular function and may provide a more constant level of/ m7 l; ?/ m' f- S, ^
REFERENCES
" N7 C" m: e! [6 a6 B  R1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,2 v- {- L% O3 e9 A) s* e. l
R.: The local application of testosterone cream to the prepub-
- e0 ?1 y, c3 xertal phallus. J. Urol., 105: 905, 1971.
, l0 f, n( e" n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 k7 ^1 m1 z: W1 ttreatment for micropenis during early childhood. J. Pediat.,& x" C4 ~( p) P  ]
83: 247, 1973.
: ~* s) F7 V6 R" t3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
& O/ ~/ Y8 c1 }$ \2 bone therapy for penile growth. Urology, 6: 708, 1975.
2 K/ j- X/ {0 E* l# n4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: |" i% m  d% k4 ?0 u) Xto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% e2 F, ~9 V5 ]9 H0 T
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 \2 [+ R5 @' }/ P5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% r$ ~4 r: ^6 }5 ~% i, U( o
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; h* s* c0 k& k2 k, E6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
  I# c& [+ f1 I9 Y# sandrogenic effect of interstitial cell tumor of the testis. J.
  Y- u/ s. j( C5 ~) _9 c  rUrol., 104: 774, 1970.
1 `' o* d/ ^5 K4 k7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
5 q$ v6 L# |3 [1 N; {tion in the male genitalia from birth to maturity. J. Urol., 48:
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