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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND2 S* r$ N1 P/ s4 ]4 c& v
GONADOTROPIN* ^8 ?8 S" G; y' y1 a  n! J: f. }
RICHARD C. KLUGO* AND JOSEPH C. CERNY- e. y* z( O$ y8 Z; l3 ^! B
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
; N, N$ ~0 }, t/ b1 y& Y9 _. F( w. XABSTRACT
" y0 V" Y: A5 T5 O  N' W5 BFive patients were treated with gonadotropin and topical testosterone for micropenis associated
$ A( r, k* p: |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 C( w& M8 B) T# y% e5 _& `6 Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. _. q! R/ `( r, i
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! E/ q! i2 X3 f" u  _; E: |
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
; M( ~( I6 q+ cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 t: V8 D7 |" Xincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% x. Y  u& F8 V! V0 U1 ]/ ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
2 U  i5 @* _: j; Z0 vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
" I% v2 p5 f4 V9 jgrowth. The response appears to be greater in younger children, which is consistent with previ-5 c9 g& H/ {0 F' U3 i+ h
ously published studies of age-related 5 reductase activity.7 y+ t5 P& Z+ Q3 x
Children with microphallus regardless of its etiology will
! x" a$ P! {5 \1 j+ irequire augmentation or consideration for alteration of exter-, [6 I# p9 W# l, b4 `- X
nal genitalia. In many instances urethroplasty for hypo-
' ~6 l! r  d' {8 s0 ~6 n3 Xspadias is easier with previous stimulation of phallic growth.
% F5 T9 [" O' ~9 N8 W& _. ?The use of testosterone administered parenterally or topically. G8 ^- @! d; F$ `
has produced effective phallic growth. 1- 3 The mechanism of
6 {8 H7 O. d* ]  L- A! [0 k0 \3 Eresponse has been considered as local or systemic. With this
7 @' b5 r% w; j' |in mind we studied 5 children with microphallus for response
9 P% n- g$ P. _% I( nto gonadotropin and to topical testosterone independently.
8 x& D+ x7 c; y# ?; Y$ K' sMATERIALS AND METHODS
7 Q% ]* ^5 w& m- cFive 46 XY male subjects between 3 and 17 years old were' l( R' Z  A8 g/ B  c* b
evaluated for serum testosterone levels and hypothalamic, [; V$ |+ V( ~* A, Q6 `; l
function. Of these 5 boys 2 were considered to have Kallmann's
) }) q0 `+ ]1 J, osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  D$ ?. T/ y2 q
lamic deficiency. After evaluation of response to luteinizing
; M! a% k1 G/ q0 |7 @hormone-releasing hormone these patients were treated with9 L7 T* L) I3 a; z: D6 M
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
# m& u1 A" A! A% Yafter completion of gonadotropin therapy 10 per cent topical
& k% |- d& O1 Ztestosterone was applied to the phallus twice daily for 3 weeks., z1 T! i+ K8 Z' p
Serum testosterone, luteinizing hormone and follicle-stimulat-
; x/ \1 o/ `3 J% ting hormone were monitored before, during and after comple-
$ W) X( p5 j' C: K3 }( qtion of each phase of therapy. Penile stretch length was
8 F9 n$ k/ u' lobtained by measuring from the symphysis pubis to the tip of  W2 z5 i0 j6 W, N, m: J
the glans. Penile circumferential (girth) measurements were( m$ c8 J) O9 @9 K$ o, X+ s
obtained using an orthopedic digital measuring device (see" P- i- A( k- g2 v/ W
figure).; {- S4 a. V$ e7 A, n' G0 z2 H
RESULTS( @2 _. p) K! Z
Serum testosterone increased moderately to levels between0 R0 [+ z& }; |* z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 z6 N6 Z" X* m4 l7 x9 _
terone levels with topical testosterone remained near pre-2 {- W/ \+ P# ]" u7 R5 Z* x
treatment levels (35 ng./dl.) or were elevated to similar levels
8 Y# a. }$ G# gdeveloped after gonadotropin therapy (96 ng./dl.). Higher
# m& ?- ~: S# [serum levels were noted in older patients (12 and 17 years old),4 D1 H( e& a9 V6 F: G
while lower levels persisted in younger patients (4, 8, and 10( e" f$ M: a$ U9 m6 C- S. O
years old) (see table). Despite absence of profound alterations  Y2 o7 x( K& f" W, E
of serum testosterone the topical therapy provided a greater
3 t/ `( o; k+ C4 C+ lAccepted for publication July 1, 1977. ·" s: e) c- Q& j9 K$ m
Read at annual meeting of American Urological Association,* `/ Z  {1 c: j% Q$ |$ X# [
Chicago, Illinois, April 24-28, 1977.
/ D$ x; b2 d% h  X9 o* Requests for reprints: Division of Urology, Henry Ford Hospital,
; ^! [) T# [+ r: ^" v( H9 n% z4 q2799 W. Grand Blvd., Detroit, Michigan 48202.
) t( I- {* I$ Z5 eimprovement in phallic growth compared to gonadotropin." d/ h8 s# p- x3 F) Q
Average phallic growth with gonadotropin was 14.3 per cent
+ ^7 _- [" W6 d% m% Q3 x# ~7 R8 @increase in length and 5.0 per cent increase of girth. Topical
4 N% g) f5 i* L$ ttestosterone produced a 60.0 per cent increase of phallic length
; m: c2 g+ G6 R9 b, A4 s, G) jand 52.9 per cent increase of girth (circumference). The6 R* W- j% ]' o2 C+ t
response to topical testosterone was greatest in children be-
9 R, D. @8 D) a" e; Ytween 4 and 8 years old, with a gradual decrease to age 17
( [5 D7 Z& m8 ?3 yyears (see table).7 X8 q$ O- k$ g9 b0 J. J7 [
DISCUSSION
2 o# D' u. ]0 S6 |8 sTopical testosterone has been used effectively by other
3 }# v9 S4 u* w7 L% P  m+ u0 lclinicians but its mode of action remains controversial. Im-
6 c( k& ~5 [& N5 Y! S- cmergut and associates reported an excellent growth response
2 \) }$ ?9 U/ q. Y3 l' }to topical testosterone with low levels of serum testosterone,
4 ]9 Z) f$ R$ L* K4 O4 Ysuggesting a local effect.1 Others have obtained growth re-
" i+ r3 d0 D" L( [  Y) [. y  H" X: n# Nsponse with high. levels of serum testosterone after topical" t# v( G: J' h; r
administration, suggesting a systemic response. 3 The use of% J* p2 f, I* V6 x
gonadotropin to obtain levels of serum testosterone compara-
( \1 M6 S/ V, `0 s  X5 Nble to levels obtained with topical testosterone would seem to! w* w1 j" O4 f* c+ v. Q
provide a means to compare the relative effectiveness of
# E% _- h3 X5 G% \$ Ntopical testosterone to systemic testosterone effect. It cer-
' g" Z, ]1 f# Htainly has been established that gonadotropin as well as par-5 R: Y4 w- g* f4 p
enteral testosterone administration will produce genital
1 p  v5 i2 `1 z0 _! E0 Wgrowth. Our report shows that the growth of the phallus was! Q! n; p: ~2 P7 M$ D0 }7 J
significantly greater with topical applications than with go-8 I) v- \8 }( r! N* e0 q7 L* Y
nadotropin, particularly in children less than 10 years old.
3 M% ^0 a8 w/ c/ g! m3 yThe levels of serum testosterone remained similar or lower
4 m! k% ~$ l+ C4 nthan with gonadotropin during therapy, suggesting that topi-
2 R# r( H3 A) \- gcal application produces genital growth by its local effect as5 X7 W- z3 t& u% @) K. `. B
well as its systemic effect.
8 W0 o3 W' h9 W8 T8 V) TReview of our patients and their growth response related to
+ S( a2 Z& |( u0 q+ aage shows a greater growth response at an earlier age. This is. N8 v6 D; n' P
consistent with the findings of Wilson and Walker, who
" L3 W# r- S2 }+ Creported an increased conversion of testosterone to dihydrotes-
/ ^1 [, q# Y+ @9 l2 Btosterone in the foreskin of neonates and infants.4 This activ-5 w7 ]* s) h( j, \, J3 R4 v. [8 \& P
ity gradually decreases with age until puberty when it ap-
! Q! J  @! W( |: |0 N$ V6 Hproaches the same level of activity as peripheral skin. It may0 [& \' r* N2 o+ _; k8 h0 u
well be that absorption of testosterone is less when applied at% N3 ~3 F0 p2 L+ X) u
an earlier age as suggested by lower serum levels in children0 [4 d+ M8 z) ^6 ]
less than 10 years old. This fact may be explained by the
% I$ ]) \7 W; U6 Kgreater ability of phallic skin to convert testosterone to dihy-$ k$ x; N: G  r+ _7 h! @
drotestosterone at this age. Conversely, serum levels in older
5 U' }' I, j9 Gpatients were higher, possibly because of decreased local
3 C3 o: x* E3 u: s667
. Z% ?! ]+ B- I) [2 k668 KLUGO AND CERNY
3 C2 V1 q" g: y- n( X" iPt. Age, ~+ N+ w9 n! R% @& e& \
(yrs.)
; H4 \: P4 r" j3 P5 s0 D: H1 bSerum Testosterone Phallus (cm.) Change Length9 ^& b4 Z& @- ?8 V% s
(ng./dl.) Girth x Length (%)& ?" b, x+ v$ Y: G
4
4 U. O1 `  F5 S# T0 U) S8
' g, [/ ~5 K$ y5 j  L- S101 X, K& N% @# V0 d9 d" L+ w) K
12
& A9 d0 x' B8 a- m) L# I8 L1 M1 T171 o8 }9 e' S- E
Gonadotropin
. f4 U- m7 g2 {  c8 B* d71.6 2.0 X 3 16.6
  Q; c" w) {# e' c7 Q' t50.4 4.0 X 5.0 20.0. ~- ~8 y2 @6 q7 j+ S
22.0 4.5 X 4.0 25.0( K  s! ~4 P$ i+ E3 I5 t
84.6 4.0 X 4.5 11.1
% I: s2 A" d" w3 ]) b$ F2 r* M85.9 4.5 X 5.5 9.0
' v& t! D4 J$ q7 C( _8 \6 L! ^Av. 14.3* A7 L3 d1 K. ?5 k" [+ c
4
: T7 z( \% d$ \8
& x. z) a8 W$ _7 g2 ~10
: h* r& \1 F. S12
5 _9 M. I1 ]9 s2 i& c5 o17
1 m' V" a' B; JTopical testosterone# e( q9 Y) X$ p
34.6 4.5 X 6.5 85
8 v! e$ |" z3 u7 a8 b: L38.8 6.0 X 8.5 70
) x' E+ }% t9 o4 r. p8 B$ t% U! M40.0 6.0 X 6.5 62.5
2 e1 A" P1 h) |- n! r93.6 6.0 X 7.0 55.5+ W: t0 Z5 ?' a3 f* m1 w8 ?
95.0 6.5 X 7.0 27.2
! n; N8 Q8 M+ w% S7 H* J' P- RAv. 60.0: c" t% T- x/ W: _; r) y, a/ a
available testosterone. Again, emphasis should be placed on0 H7 s6 `- S+ _  z9 _
early therapy when lower levels of testosterone appear to
5 J, L' `2 y5 a4 o$ `" A7 pprovide the best responses. The earlier therapy is instituted& W5 b3 Q8 E1 A7 q. D7 P# o; G6 G7 r' |8 ]
the more likely there will be an excellent response with low' l( r# u  g9 O5 V" Z+ l
serum levels. Response occurs throughout adolescence as5 b& V$ k, X) t
noted in nomograms of phallic growth. 7 The actual response
4 m: L  p4 }) Zto a given serum level of testosterone is much greater at birth
$ l* V+ {4 n) G' g# m( T; Q3 p% Eand gradually decreases as boys reach puberty. This is most
- G" t* y8 g+ }. S4 s7 ?likely related to the conversion of testosterone to dihydrotes-2 R7 @7 V" ^' ^( E, \  m8 L
tosterone and correlates well with the studies of testosterone/ w' g5 l' M! ~$ F  V& M8 z
conversion in foreskin at various ages.. t3 A! X5 h: u: ?# Z; I5 A
The question arises regarding early treatment as to whether) ~9 b1 x+ z$ k5 U3 |9 w
one might sacrifice ultimate potential growth as with acceler-
* r/ G/ ~- k7 l% S- }# cated bone growth. The situation appears quite the reverse
  Q3 N# H& Q! z. Cwith phallic response. If the early growth period is not used2 t' q1 K6 t" V. S9 L
when 5a reductase activity is greatest then potential growth
% T# K5 ^$ \& y. |may be lost. We have not observed any regression of growth
2 W3 g" B2 B0 R! a7 H/ Eattained with topical or gonadotropin therapy. It may well
- N3 A# }/ V, |4 d0 l+ C+ E9 D1 zbe that some patients will show little or no response to any
( u5 T% ]' c3 U. P$ m9 F4 k7 tform of therapy. This would suggest a defect in the ability to- Q+ g4 ^) G. A
convert testosterone to dihydrotestosterone and indicate that# t' j+ G) b+ w, j1 l( N! Z: u
phallic and peripheral skin, and subcutaneous tissue should
  e3 E9 H2 X6 }# q0 r- mbe compared for 5a reductase activity.) z: j0 z) |* V! W
A, loop enlarges to measure penile girth in millimeters. B,
* f+ G/ t4 W% p) a; b' b# s5 [example of penile girth computed easily and accurately.
. X. _' F( K7 n5 [5 S9 Gconversion of testosterone to dihydrotestosterone. It is in this, t, T7 E3 z( D* t) U( b- M" T
older group that others have noted high levels of serum
$ }2 @/ }) f& l4 [  wtestosterone with topical application. It would also appear
6 w) u7 c7 `* b8 c) b( Fthat phallic response during puberty is related directly to the) Z6 Q& i9 S- [5 r7 I1 ?$ D4 `
serum testosterone level. There also is other evidence of local' J0 v: e3 J0 B+ B& k9 T
response to testosterone with hair growth and with spermato-# {( X# m" D/ O1 }
genesis. 5• 6
* G7 o/ D: C$ [" K- uAdministration of larger doses of gonadotropin or systemic! s. ^+ E. ^/ W0 O' B
testosterone, as well as topical applications that produce
- u! K& g# Q9 ?% N7 _: S1 A" s/ Zhigher levels of serum testosterone (150 to 900 ng./dl.), will
2 X9 g7 S! G" k/ ?5 }also produce phallic growth but risks accelerated skeletal
& ]" P1 R' l4 d, J7 t! T/ Z# a" T1 _maturation even after stopping treatment. It would appear
/ H# @; T' U; w0 r; ?that this may be avoided by topical applications of testosterone
. w" F& Z* G" Z- w  q: `/ h  f0 Eand monitoring of serum testosterone. Even with this control+ a2 ~; w  X" w$ E" Y5 Y) h# I
the duration of our therapy did not exceed 3 weeks at any
( A3 D/ N! B: {time. It is apparent that the prepuberal male subject may5 ?  H# r: D4 F# g4 b
suffer accelerated bone growth with testosterone levels near
. j9 t2 p* W* P2 l3 l200 ng./dl. When skeletal maturation is complete the level of# U3 m, o7 d7 A8 E( {
serum testosterone can be maintained in the 700 to 1,300 ng./
( J* |  G! I/ F1 q2 hdl. range to stimulate phallic growth and secondary sexual
2 Z6 s3 f. R+ J$ ?. Pchanges. Therefore, after skeletal maturation parenteral tes-
" D  t1 J/ u6 X9 k5 F7 p/ E9 A5 Z6 jtosterone may be used to advantage. Before skeletal matura-& K0 n" {) g' r) S: [
tion care must be taken to avoid maintaining levels of serum& I/ _* s) m; B- b, {& }: P
testosterone more than 100 ng./dl. Low-dose gonadotropin9 ^9 O6 B' R! r' @+ d* v
depends upon intrinsic testicular activity and may require
, F& {( r1 j3 a% a+ |prolonged administration for any response.) O' a# k' `% c' |: h" \
Alternately, topical testosterone does not depend upon tes-
, C2 \1 Z9 d! t/ Z$ i% f' Cticular function and may provide a more constant level of3 C! U+ x  X% Y; U/ m+ r/ i
REFERENCES% ~; g, b% u' `5 E2 X) t: z1 k
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 t; K7 P) K. B* ]" S4 Q' KR.: The local application of testosterone cream to the prepub-. V6 j/ {0 B$ q! U
ertal phallus. J. Urol., 105: 905, 1971.0 a4 q) F" ^: ?8 d6 e5 f8 O
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& k1 b3 M' J5 ~
treatment for micropenis during early childhood. J. Pediat.,
# l% Y8 \5 K$ G. ?4 O' }83: 247, 1973.
# w5 ~$ ~" p! V# h) e- D3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# p4 S) k5 F3 a9 }, o+ Done therapy for penile growth. Urology, 6: 708, 1975.
/ y- v6 b5 b' s  `' s4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone! r( _( r6 B1 ?# E8 X" Q  @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. R+ E) b7 o- f. r+ Qskin slices of man. J. Clin. Invest., 48: 371, 1969., y2 l' j8 d, A$ I
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# p! v: I! I; ]: R9 d$ @  `" s9 e0 Dby topical application of androgens. J.A.M.A., 191: 521, 1965.; ?1 O$ c2 S' @- N) s- U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ V2 i4 u' x% h' d
androgenic effect of interstitial cell tumor of the testis. J.( A% i; `4 X6 t$ s; l' r
Urol., 104: 774, 1970.
. y$ K3 y5 k( Z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( Z- L+ }2 b. G5 r  ^5 R# H
tion in the male genitalia from birth to maturity. J. Urol., 48:
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