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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND# w4 I+ ]: a* G  ]- d
GONADOTROPIN
  I4 b( n* L2 s* j$ \2 e1 v/ k9 b3 TRICHARD C. KLUGO* AND JOSEPH C. CERNY/ S) Z& Y" }2 S0 }! l
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' L0 K" o# Y' @: B
ABSTRACT
, {' Z8 ?% W8 y) D% M. YFive patients were treated with gonadotropin and topical testosterone for micropenis associated
: x5 |  z5 @1 p. w) Qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. c. t/ u4 \2 w; c/ H# g
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, @/ `' R! v" Kcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( o0 y4 Y6 n. i
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 k  c1 i, D# m9 `! p2 cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average" A8 n/ A0 j0 M% V# b6 E8 [  m
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response' A6 g, X4 z- t. B! q5 E9 T; u" P
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# m8 y- }* U, I. o; j+ M2 I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
# I& L  r3 j: [7 Q/ Qgrowth. The response appears to be greater in younger children, which is consistent with previ-
) {5 P8 E+ M# D# Y2 j+ Iously published studies of age-related 5 reductase activity.4 r( K$ }2 y  I3 Y+ J+ j; K) y
Children with microphallus regardless of its etiology will
  o3 |( g  [" Z! W; Y7 G' {! `require augmentation or consideration for alteration of exter-
" H- T9 b, |, U8 ?7 fnal genitalia. In many instances urethroplasty for hypo-
  p+ F3 n0 ~' Z8 c) J3 M% x! Vspadias is easier with previous stimulation of phallic growth.6 v0 u/ B6 _' j; L2 ~
The use of testosterone administered parenterally or topically
) o* o2 |0 S8 i3 Fhas produced effective phallic growth. 1- 3 The mechanism of
: e+ d% z" y/ W" P& p1 Fresponse has been considered as local or systemic. With this& B5 w: r# t* X- B$ m) Z
in mind we studied 5 children with microphallus for response: Z5 b& _% q( z5 Y, f
to gonadotropin and to topical testosterone independently.
3 T/ Y% `& q( J4 l2 rMATERIALS AND METHODS
/ J5 q5 A8 T4 b, ^+ t9 n1 bFive 46 XY male subjects between 3 and 17 years old were
, G  v) a* v' j  L5 v( u9 u% F( R" gevaluated for serum testosterone levels and hypothalamic
5 I7 e- K! \7 o; y' Z  e) v* tfunction. Of these 5 boys 2 were considered to have Kallmann's. p: j$ n4 q) \5 @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, M1 O$ |. T2 h  s2 w1 v# Plamic deficiency. After evaluation of response to luteinizing6 t: N. y1 ?! A
hormone-releasing hormone these patients were treated with% m# p9 o& R  H1 i6 M! t& }
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 {! }6 k, q, P! g9 cafter completion of gonadotropin therapy 10 per cent topical* m5 |% t2 ^  W$ v5 T
testosterone was applied to the phallus twice daily for 3 weeks.
" S/ l# V0 e7 ?Serum testosterone, luteinizing hormone and follicle-stimulat-/ ^1 t4 Z; \+ S# i: M2 X  K! ^
ing hormone were monitored before, during and after comple-
* l( C3 X; P5 i3 Btion of each phase of therapy. Penile stretch length was
3 h; \, l6 F; o8 J2 `obtained by measuring from the symphysis pubis to the tip of5 N9 a) Q5 ?/ d5 K9 V
the glans. Penile circumferential (girth) measurements were# J6 K5 c$ N2 \% \
obtained using an orthopedic digital measuring device (see: I" ], _4 t2 F& T6 S3 d4 |; Y
figure).
& y  D: C% u- _  k7 MRESULTS# B7 i, N) d0 y6 c
Serum testosterone increased moderately to levels between/ Z: E* x9 D8 a. k# B- b- s/ h1 B
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  z+ |. H0 \- ]( Y6 G6 Vterone levels with topical testosterone remained near pre-0 C$ N$ w0 a3 c3 V
treatment levels (35 ng./dl.) or were elevated to similar levels
$ i7 N% d0 ~% r2 E( v5 l) @developed after gonadotropin therapy (96 ng./dl.). Higher
7 T; I; D9 b- G& G4 e' rserum levels were noted in older patients (12 and 17 years old),, \7 M! N0 _; j3 v  J. u
while lower levels persisted in younger patients (4, 8, and 10! q6 j% N4 D3 G$ Z2 I3 ^
years old) (see table). Despite absence of profound alterations
, r, Q6 f9 B: U% d# n1 q$ }of serum testosterone the topical therapy provided a greater
; M$ p  j7 p5 l4 tAccepted for publication July 1, 1977. ·
. Z8 Q7 p% S: P1 j! h$ G0 @! R# ^Read at annual meeting of American Urological Association,
' D8 l+ E( ~! n* Z9 M9 pChicago, Illinois, April 24-28, 1977.
, U3 r1 g& \1 x5 I1 X- z* Requests for reprints: Division of Urology, Henry Ford Hospital,4 m& R  c2 a+ D6 P' s, k! E" D- B5 q
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 q: D( I0 l9 l  Kimprovement in phallic growth compared to gonadotropin.
* L! A4 @' Z6 x4 |Average phallic growth with gonadotropin was 14.3 per cent
5 W& ~# O: ~" E  o6 K* aincrease in length and 5.0 per cent increase of girth. Topical# n& p. O# c  A" H  a. C: r
testosterone produced a 60.0 per cent increase of phallic length& n: ~4 U) G. J/ G
and 52.9 per cent increase of girth (circumference). The( p+ s8 o. H# L+ [7 ~  ^- {
response to topical testosterone was greatest in children be-2 O/ N8 Z8 [2 o# ^' `4 A0 m
tween 4 and 8 years old, with a gradual decrease to age 17
$ S( |4 T; F8 Hyears (see table).
) ?. p7 ?; \# C- l9 k! q# qDISCUSSION
- ?! v: s2 }7 N# x/ O9 [7 A+ QTopical testosterone has been used effectively by other2 ]& n8 |! c) H- y
clinicians but its mode of action remains controversial. Im-* ]* O9 e( D, B0 X* Z
mergut and associates reported an excellent growth response
8 D2 \' }: \0 \to topical testosterone with low levels of serum testosterone,! F- C; G$ P- }
suggesting a local effect.1 Others have obtained growth re-
3 i4 y; j: n9 k! \/ f' Gsponse with high. levels of serum testosterone after topical0 Z/ m) o9 H* _3 D
administration, suggesting a systemic response. 3 The use of/ c# H. A2 Z, q6 X" ]: ~
gonadotropin to obtain levels of serum testosterone compara-; \* ?% V' @" g' p/ R/ Q3 n
ble to levels obtained with topical testosterone would seem to
! K% m9 a- X$ |2 ^) z' ~provide a means to compare the relative effectiveness of4 M- {9 O1 ^/ H
topical testosterone to systemic testosterone effect. It cer-
# m) i9 q3 P3 {tainly has been established that gonadotropin as well as par-5 _" D+ i/ L. L4 g8 n. S
enteral testosterone administration will produce genital
& ?# T! b9 b" Ygrowth. Our report shows that the growth of the phallus was
4 h; w$ z- d9 W8 L; M: hsignificantly greater with topical applications than with go-
) ]# Y8 u9 |2 ~' \nadotropin, particularly in children less than 10 years old.$ t# Y* Y( r3 y  c2 ^' \; {5 V
The levels of serum testosterone remained similar or lower6 W4 A" \2 y9 l! ^# S
than with gonadotropin during therapy, suggesting that topi-$ Z; m9 ], U8 \- D' L6 a* [
cal application produces genital growth by its local effect as
6 K6 U3 e) h4 \' ~well as its systemic effect.
4 C  R/ M8 m$ n8 R/ x; s- eReview of our patients and their growth response related to
  {4 h; B- F8 m# K8 L5 Lage shows a greater growth response at an earlier age. This is
4 B  \3 w; K# D: ?9 Hconsistent with the findings of Wilson and Walker, who% X) K  R9 z; u# K) O
reported an increased conversion of testosterone to dihydrotes-
& X  ]# k" Q) Vtosterone in the foreskin of neonates and infants.4 This activ-
! {& S# h2 F1 H" m& Vity gradually decreases with age until puberty when it ap-
! S0 e: \/ b2 g! Zproaches the same level of activity as peripheral skin. It may
; z5 R% x  u, gwell be that absorption of testosterone is less when applied at
- y( t6 {0 l% x, t" m. F! J. O+ zan earlier age as suggested by lower serum levels in children* m+ c) O! m9 C9 w6 l/ Y
less than 10 years old. This fact may be explained by the
, b0 w$ h( X( A5 B. bgreater ability of phallic skin to convert testosterone to dihy-+ }* W; z9 e: L8 C* _  Y, j- z: d
drotestosterone at this age. Conversely, serum levels in older
9 @1 s9 W9 A0 Y2 D& q/ Vpatients were higher, possibly because of decreased local7 @% k2 Q0 z5 o8 F+ A4 }; x
667: |8 ?/ E/ f) c' Q( ?
668 KLUGO AND CERNY
0 D' X1 f$ [5 z5 ^* pPt. Age$ o. u% @  Q7 {# E8 @
(yrs.)
, ?1 A$ U1 T6 d/ c$ }* b8 fSerum Testosterone Phallus (cm.) Change Length) D/ h6 q5 b/ {7 m6 C8 [
(ng./dl.) Girth x Length (%)+ E' a: \/ y( S5 Z$ A: z
4
) x7 z: U6 k6 M8 `4 V; a8
; _  p! Q$ R3 f10% c3 j) l: w5 C: V4 Z6 v4 p
123 ?' V4 \7 _' m1 f& ?# |4 e; G' G
17
+ H0 x" g- Z& V% WGonadotropin
) I5 J1 _" o. K71.6 2.0 X 3 16.6( _5 ?, g) ~, L* u( u# F, j
50.4 4.0 X 5.0 20.07 j# d% q& u) C0 g5 ^4 I
22.0 4.5 X 4.0 25.0: W- E: ~; x; u% l, ]; y
84.6 4.0 X 4.5 11.12 r: ]9 {1 O! B9 Z6 v4 n. I/ i% `) Q
85.9 4.5 X 5.5 9.06 g0 ~- s0 r8 ^  S
Av. 14.3
2 g0 M$ {9 j- v  Z! K4- s. B& D! }0 ^! k1 u
8
& Z5 E7 h9 K/ ?! Y10' {/ S% V0 l& B% X3 d
12
: F) t! ]: [( {17
/ }0 g; X3 m" T8 l3 N4 f6 y3 ~Topical testosterone
; ~/ i6 L% X; l  ]8 X" p/ s7 p! M1 u34.6 4.5 X 6.5 85
' U( e$ d2 G9 z8 a: h7 U" u38.8 6.0 X 8.5 70# \0 t* n6 ?( t( Z( k8 B) ?2 k
40.0 6.0 X 6.5 62.5
2 w! t4 B) @8 L- G- r+ v93.6 6.0 X 7.0 55.55 p8 R! e2 E/ J, l
95.0 6.5 X 7.0 27.2: U. r3 [: q/ m
Av. 60.0
4 z; e, I" S5 vavailable testosterone. Again, emphasis should be placed on
0 j# ^4 d' a0 J  ^6 ]. K! U" ~0 kearly therapy when lower levels of testosterone appear to
' ~3 E3 [3 K) {4 A; I' cprovide the best responses. The earlier therapy is instituted, p) w- C  \# Y. }* B
the more likely there will be an excellent response with low9 r: g: |" d* x2 b
serum levels. Response occurs throughout adolescence as
; k/ o- e# y6 Z7 C3 vnoted in nomograms of phallic growth. 7 The actual response) o+ E, O! b+ D5 A
to a given serum level of testosterone is much greater at birth
: K2 Q, D8 D' zand gradually decreases as boys reach puberty. This is most, `* {- W! l6 F! [
likely related to the conversion of testosterone to dihydrotes-- U, a# _3 m/ F) r% k4 u
tosterone and correlates well with the studies of testosterone
% w; q) X% a% E2 [1 z" q8 Bconversion in foreskin at various ages.* W0 n) z3 ]! V1 @
The question arises regarding early treatment as to whether4 f" H; X: w0 e* B
one might sacrifice ultimate potential growth as with acceler-0 Z$ O& r: ?5 q( _( p! F
ated bone growth. The situation appears quite the reverse
. D+ m$ w7 O/ k6 @% |with phallic response. If the early growth period is not used
0 q- k2 x3 \/ |& X" Hwhen 5a reductase activity is greatest then potential growth
) X  w/ x7 G. U' C1 w/ ?" Lmay be lost. We have not observed any regression of growth2 P9 d2 n6 l1 s( @7 m9 H* ^1 q+ B2 v
attained with topical or gonadotropin therapy. It may well
/ a% N0 i( W! a: E, L  Hbe that some patients will show little or no response to any/ e% m8 p# w- V0 y: R) z
form of therapy. This would suggest a defect in the ability to, j; Z- @" d" g$ F; [
convert testosterone to dihydrotestosterone and indicate that
7 T& m1 `( _3 s! Wphallic and peripheral skin, and subcutaneous tissue should
: y8 D- C) q5 t( r1 K. ~be compared for 5a reductase activity.
/ u  K1 B. }! l2 G3 o! c3 ^3 AA, loop enlarges to measure penile girth in millimeters. B,# A8 b! x# T8 Y) g, r( D* ?
example of penile girth computed easily and accurately.
8 f9 g6 |" H+ T; mconversion of testosterone to dihydrotestosterone. It is in this+ J4 p6 H) n9 r( H
older group that others have noted high levels of serum8 D/ D' I+ V* S- r" `
testosterone with topical application. It would also appear
1 s  t/ o8 c5 d* z" Q: tthat phallic response during puberty is related directly to the+ U- `/ O9 q+ a) E& T7 ]( N4 X
serum testosterone level. There also is other evidence of local7 `/ r: s  Y5 y3 u* d4 o
response to testosterone with hair growth and with spermato-
2 g  O# y3 ~/ G# Q; Rgenesis. 5• 6
1 u; B, j2 H* A% w: J. I; f4 }Administration of larger doses of gonadotropin or systemic
% {1 {0 Q8 f: ]; J7 i! I+ j+ Ktestosterone, as well as topical applications that produce
4 F2 C0 g/ Z1 D( |  shigher levels of serum testosterone (150 to 900 ng./dl.), will
* o: W/ l9 T6 X) j: E9 Y9 jalso produce phallic growth but risks accelerated skeletal
3 A0 G( G* Q4 f: L& hmaturation even after stopping treatment. It would appear
& O) _* B8 x8 x: J  @' y* ^0 R& ~that this may be avoided by topical applications of testosterone
7 {3 W& W/ n. l' Y: E6 d3 Cand monitoring of serum testosterone. Even with this control  c, v3 o, p6 c) R0 ^* B* u; I+ N
the duration of our therapy did not exceed 3 weeks at any0 T8 \6 e3 R5 W2 u' @1 N. Z0 x
time. It is apparent that the prepuberal male subject may) \7 X( ~8 [- m- o
suffer accelerated bone growth with testosterone levels near
' A2 C. x! `; n% C$ k$ k200 ng./dl. When skeletal maturation is complete the level of
/ W" R. J9 h- oserum testosterone can be maintained in the 700 to 1,300 ng./
" |0 E8 E5 w  }6 P* }, Fdl. range to stimulate phallic growth and secondary sexual) Z' i1 }% w# f( Z" f
changes. Therefore, after skeletal maturation parenteral tes-; \  A. `; s# o' X; C0 ]# ^& v
tosterone may be used to advantage. Before skeletal matura-' H( @, a- W$ |
tion care must be taken to avoid maintaining levels of serum! J0 s0 A/ z) w, v) C4 M7 W/ W: D. J
testosterone more than 100 ng./dl. Low-dose gonadotropin
/ y- A. s( p! V" U; Vdepends upon intrinsic testicular activity and may require
/ {0 `5 \/ ^' nprolonged administration for any response.5 Y# _! T2 z( [2 k
Alternately, topical testosterone does not depend upon tes-
- [, R; q7 a% M+ iticular function and may provide a more constant level of
% H$ Y! u5 Q6 LREFERENCES
- T0 F, M; K! c7 E& H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 N$ \4 l8 v: z$ z6 L! IR.: The local application of testosterone cream to the prepub-
* j! e4 |# u% Mertal phallus. J. Urol., 105: 905, 1971.- X6 L4 Y; F3 w% h9 Y. j
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# y7 p1 r' i3 w3 e4 s
treatment for micropenis during early childhood. J. Pediat.,
' N' T7 C. d' {1 T" R* A; I) N! B83: 247, 1973.. H7 f1 Y) L+ Y9 x
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# ^, u1 O: l: L. G! xone therapy for penile growth. Urology, 6: 708, 1975.4 L8 d- p# @9 a9 B9 L
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! M# d5 H8 j: T5 P0 \0 hto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 q# S) W" A1 S3 E( C& t
skin slices of man. J. Clin. Invest., 48: 371, 1969.
7 t; B  Y3 }% g6 M0 x5 ?& R5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 y9 x0 G1 Y4 x9 ]/ ?by topical application of androgens. J.A.M.A., 191: 521, 1965.
! X6 G0 D# q2 Q9 F4 W: h6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
# ?0 K4 g1 {- Z3 m/ P9 L( dandrogenic effect of interstitial cell tumor of the testis. J.. s. p9 U9 Y! E! `% x
Urol., 104: 774, 1970.
4 @* p; q3 f) M0 N1 V+ ~& J' y$ a7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-5 M5 `5 o4 U" G2 F7 a9 }2 }% S, e
tion in the male genitalia from birth to maturity. J. Urol., 48:
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