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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 @3 g; R9 S1 ^' e
GONADOTROPIN
0 }! r1 W9 A) M$ f8 C# ]RICHARD C. KLUGO* AND JOSEPH C. CERNY& X) e, P% p8 ^4 n
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
) ]' S: T: C) X4 y6 s+ oABSTRACT
# @* K  E' d. m$ g4 RFive patients were treated with gonadotropin and topical testosterone for micropenis associated
2 K+ z$ F4 X5 p- ~% vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 U7 b, A+ u9 ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' a- y; |) a, R  ?) z/ a, P2 dcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! H# ?4 d3 A- I2 m
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent" C7 g' H: D3 n) p
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
7 d- N& m6 d0 v" R8 n; D8 t8 qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& J; s+ V7 P% e: N5 U. i6 k* doccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This; A/ A* F; ^0 C) H
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile3 U& [+ b1 Q5 F7 n7 u: p. M) f- B
growth. The response appears to be greater in younger children, which is consistent with previ-
, @/ |4 O) {; Hously published studies of age-related 5 reductase activity.
) z' f1 w1 n! Y' fChildren with microphallus regardless of its etiology will) |& L1 H3 Q. }
require augmentation or consideration for alteration of exter-- G8 [  J# I" F  j2 O- s
nal genitalia. In many instances urethroplasty for hypo-7 S' |4 w5 `, s* H
spadias is easier with previous stimulation of phallic growth.& g$ w" B& B* I  `* V7 A4 l- m
The use of testosterone administered parenterally or topically
$ ^5 q, o9 Z9 r9 r6 xhas produced effective phallic growth. 1- 3 The mechanism of: u" Y4 T. S: L- [, h2 t- L' w' p0 U
response has been considered as local or systemic. With this" l8 h" Q: d5 B0 u# `$ A
in mind we studied 5 children with microphallus for response
  {5 `& H2 |+ `: B# M! M+ ?* D! mto gonadotropin and to topical testosterone independently.
% c& G. C* ?+ e- G. _+ hMATERIALS AND METHODS
# d3 d0 u$ k1 }: ?, N$ {Five 46 XY male subjects between 3 and 17 years old were( f$ ^; t' \: n& C* {' {, c* }5 p
evaluated for serum testosterone levels and hypothalamic* p4 k8 R5 w* \( i2 V0 x
function. Of these 5 boys 2 were considered to have Kallmann's
; w6 [! }# w8 X! v8 lsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
( p+ T7 g3 g& G% B: |8 Klamic deficiency. After evaluation of response to luteinizing: D' ]! e! U+ N% A2 D( E8 E- e5 `+ t
hormone-releasing hormone these patients were treated with
' L, e% r) A. M4 H# m1,000 units of gonadotropin weekly for 3 weeks. Six weeks) d. I! u- s& h* e# ^
after completion of gonadotropin therapy 10 per cent topical
  P- T% {/ W) }0 y* W+ _. @testosterone was applied to the phallus twice daily for 3 weeks.- y4 ^0 X" U; V7 I/ ?, t: y# U4 G
Serum testosterone, luteinizing hormone and follicle-stimulat-
  Z* g' c/ k" eing hormone were monitored before, during and after comple-3 }5 |2 b( e. q& j. v
tion of each phase of therapy. Penile stretch length was
; s) y6 ]( P' J; @* w1 Mobtained by measuring from the symphysis pubis to the tip of
* r2 m+ b! S8 F1 c# l7 o6 Z) {the glans. Penile circumferential (girth) measurements were
! Z; L7 I% G, \1 p/ p6 }obtained using an orthopedic digital measuring device (see
7 Y+ y7 V* B8 afigure).
9 W; @' \* N% G$ V1 ]; HRESULTS6 I3 a' h2 p  H6 ^
Serum testosterone increased moderately to levels between
% \& ]. N) n+ E4 {6 n50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 ~, l7 ?$ q2 f. _7 Oterone levels with topical testosterone remained near pre-
7 V* N0 u. l; D" @treatment levels (35 ng./dl.) or were elevated to similar levels
/ l4 j9 ?; \9 D9 n& y; N( ^developed after gonadotropin therapy (96 ng./dl.). Higher
$ l  O0 `" m/ V* ^& p1 Gserum levels were noted in older patients (12 and 17 years old),
: G7 L2 g5 G" l9 p1 Ywhile lower levels persisted in younger patients (4, 8, and 10
8 r$ I1 I' R  \+ gyears old) (see table). Despite absence of profound alterations
0 O' q! R2 E3 Nof serum testosterone the topical therapy provided a greater4 ^- w, Q1 y$ Z2 q+ x( R
Accepted for publication July 1, 1977. ·( F5 h  v9 S! o. L# x; B
Read at annual meeting of American Urological Association,
* ~/ A2 |' `! _- B2 N5 A4 ~/ i# B3 QChicago, Illinois, April 24-28, 1977.. }: q5 `0 u+ R$ \4 s& r
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 [" Y6 N1 w2 X: l  f+ D
2799 W. Grand Blvd., Detroit, Michigan 48202.1 `" Z+ ~7 N$ ]5 D5 O- d
improvement in phallic growth compared to gonadotropin.
) r' j; G" p4 gAverage phallic growth with gonadotropin was 14.3 per cent
9 z5 m/ i% t/ k/ Mincrease in length and 5.0 per cent increase of girth. Topical4 e" A& h, ^9 M; u
testosterone produced a 60.0 per cent increase of phallic length
( T! X" |, E6 ]& ~$ |, ~1 tand 52.9 per cent increase of girth (circumference). The
& X9 w6 A' B4 Kresponse to topical testosterone was greatest in children be-
" z& e1 h& x8 I1 |" ~1 htween 4 and 8 years old, with a gradual decrease to age 17/ ]* c3 [. ~  v0 u: w" I
years (see table).
/ A4 [7 U9 u0 ]( P. G: R; XDISCUSSION
, H9 c0 N) u: M1 p! {6 c( ]' u/ \/ YTopical testosterone has been used effectively by other
% b" j. g/ m% S. s& f2 T5 f6 R: ~clinicians but its mode of action remains controversial. Im-
! U2 m- w# }' v3 V  P4 c+ q7 @/ Mmergut and associates reported an excellent growth response
* f+ E0 N! X8 ^/ g. ?& i) r7 pto topical testosterone with low levels of serum testosterone,
$ w4 K- C  \( Zsuggesting a local effect.1 Others have obtained growth re-
6 n5 P* \5 Q! R- w; i1 m1 i) Ksponse with high. levels of serum testosterone after topical
  e; [4 k" l8 d0 ^5 e+ \administration, suggesting a systemic response. 3 The use of4 s( O! u2 d. |4 n; B
gonadotropin to obtain levels of serum testosterone compara-* K) }% u" n/ c- T6 X+ s
ble to levels obtained with topical testosterone would seem to
. ^" k, o) F" \! f& s: x& I& |6 F; u! Mprovide a means to compare the relative effectiveness of
2 i+ }# S, N) J& R" s1 Atopical testosterone to systemic testosterone effect. It cer-  K# C! T% V( `. g- J$ o
tainly has been established that gonadotropin as well as par-) u7 b' K6 W" b7 U( u
enteral testosterone administration will produce genital& F1 b+ N- w* A
growth. Our report shows that the growth of the phallus was
* L  a" \; m$ I- T# K& u4 Zsignificantly greater with topical applications than with go-
& U9 e* ~# d' ^nadotropin, particularly in children less than 10 years old.
' [. H. d  Q* ~. v; j4 ^, Q0 R$ lThe levels of serum testosterone remained similar or lower
4 _+ H1 P$ L9 Sthan with gonadotropin during therapy, suggesting that topi-
. @1 R$ p" M( L% r4 Ccal application produces genital growth by its local effect as
2 P$ j" J& ?" o+ C' [7 J0 ?well as its systemic effect.
4 g: |0 U3 M) C; ~, ~2 U; oReview of our patients and their growth response related to+ V) c! ~, }( c% m% `$ H
age shows a greater growth response at an earlier age. This is+ c/ h4 ]3 v3 e8 S
consistent with the findings of Wilson and Walker, who, P: r4 |( d& G; v& a# x4 F
reported an increased conversion of testosterone to dihydrotes-0 X% J! k9 A) {+ b- u0 [9 M
tosterone in the foreskin of neonates and infants.4 This activ-: @5 f- R, l& j0 S, h7 `
ity gradually decreases with age until puberty when it ap-
2 x2 C* Y2 w; a, }, g, nproaches the same level of activity as peripheral skin. It may+ \8 p: h* \% Q2 }
well be that absorption of testosterone is less when applied at, f. X( ~  _2 \; Z+ `( P& f1 W4 X# E
an earlier age as suggested by lower serum levels in children
; u" [, H. \/ D% p' b8 n- Cless than 10 years old. This fact may be explained by the& i- h: h' k3 Z' |' N( }7 ~
greater ability of phallic skin to convert testosterone to dihy-
9 A* T0 q1 ?2 Z% j; idrotestosterone at this age. Conversely, serum levels in older
: a/ `9 c! s3 I+ j0 Zpatients were higher, possibly because of decreased local( y' h2 R/ ^, D# c7 Y3 S
667
: v+ N" w, T$ ^668 KLUGO AND CERNY
" f% N' g1 ?0 J! V" W% kPt. Age( {5 j' f8 X# @0 O  ~, a
(yrs.)8 w! \7 W6 g- J, c6 N) g0 C, J% o% c
Serum Testosterone Phallus (cm.) Change Length3 A. B, B' d" b" P
(ng./dl.) Girth x Length (%)
% H5 F+ k1 x0 X' M4
+ ?, x& ]: T2 `: @6 P8 ~& _8
4 [8 \/ ~5 e4 `  K" V0 s+ S- N10
$ l. E1 N( n, T& o0 m) \" }) W12( g9 d1 }6 X7 n' ^
17
. }, U$ W3 ~( e' I+ }Gonadotropin% ]5 `! n8 w) m
71.6 2.0 X 3 16.6
2 k' i1 _5 V& N# c3 P50.4 4.0 X 5.0 20.0
' y: O% l( H7 V6 r, y* Z5 g22.0 4.5 X 4.0 25.00 K" y" Q4 N! C9 E& i5 T" i
84.6 4.0 X 4.5 11.1( K1 i+ t7 R0 c9 @
85.9 4.5 X 5.5 9.0. l9 ^8 B  j, f% {% u8 i( E7 n  d1 `
Av. 14.31 h2 v6 ^- M+ r. _# d9 c2 ]
4
+ \" O! z, l+ Q8
+ K1 u9 P" s$ L  f" j. X7 B  y10
' P) d- W& ~( J% |, K5 I' x+ u! \12: b  |5 y" f! v5 Y0 c
17, j& G4 l) U3 y! q" y( t/ p
Topical testosterone
2 T- i/ n2 ^0 I: w  z34.6 4.5 X 6.5 85
' K# T0 Q' y- s: b$ e38.8 6.0 X 8.5 707 e' s) ?. l4 i5 K5 p3 Y: j
40.0 6.0 X 6.5 62.5  Y' W) m- T1 C0 Z% D7 i$ p
93.6 6.0 X 7.0 55.5
4 K( ^0 @4 r, C5 |; x95.0 6.5 X 7.0 27.2
4 C% e; `. s+ v1 E; n+ ZAv. 60.08 n1 y" J  r3 u6 d, O3 j
available testosterone. Again, emphasis should be placed on7 ?/ b/ B' `5 O* P; R5 u3 I
early therapy when lower levels of testosterone appear to/ n9 e6 B. d; p3 s, U. F4 }2 q
provide the best responses. The earlier therapy is instituted5 s( ]. M3 O& a; y# r, K5 B- m5 h; V
the more likely there will be an excellent response with low
# e7 U2 D6 w: Y' ]serum levels. Response occurs throughout adolescence as
1 F) o' i! K; xnoted in nomograms of phallic growth. 7 The actual response
& x( i1 o  P( Cto a given serum level of testosterone is much greater at birth
9 X: n4 j! v/ m7 U7 W- Kand gradually decreases as boys reach puberty. This is most2 ~! y$ p7 B9 o. Q
likely related to the conversion of testosterone to dihydrotes-2 Q& G8 D3 I; ^( x$ h
tosterone and correlates well with the studies of testosterone
5 _# |. M& F" g/ Wconversion in foreskin at various ages.
0 |8 n, M/ t/ T7 K+ U) EThe question arises regarding early treatment as to whether
2 O5 C' h5 O, l* {7 o1 \$ Fone might sacrifice ultimate potential growth as with acceler-: @# J$ k, C. A' }0 m
ated bone growth. The situation appears quite the reverse
( g4 W1 p, q6 l" @' Qwith phallic response. If the early growth period is not used1 @+ {, ^# r0 z8 M5 n& V- y% ?
when 5a reductase activity is greatest then potential growth& c0 u3 d, _% c' ]" P. Q
may be lost. We have not observed any regression of growth
5 n5 S  t% G; V7 ?5 {5 P8 nattained with topical or gonadotropin therapy. It may well$ x  U+ n- p; ~5 b% D9 I2 b! M6 M$ v
be that some patients will show little or no response to any$ r6 h# R0 l/ @
form of therapy. This would suggest a defect in the ability to
4 m% Y# D1 I& E+ A( A" N0 W1 k% Lconvert testosterone to dihydrotestosterone and indicate that4 f3 H$ Z9 j* r% L* _" c8 j) G& i+ \
phallic and peripheral skin, and subcutaneous tissue should) H* B# X* |9 M
be compared for 5a reductase activity.1 U4 A: x! V( ?3 K9 U7 ?
A, loop enlarges to measure penile girth in millimeters. B,) w8 `" L6 Y& I) G1 X+ M9 J# d6 H  F2 B
example of penile girth computed easily and accurately.
0 b$ T7 {$ p: D6 z( @1 M& W' a0 pconversion of testosterone to dihydrotestosterone. It is in this- r! G& A! N, q. B. d, n! U2 S
older group that others have noted high levels of serum. b( A/ I5 L( i& M$ N
testosterone with topical application. It would also appear- G" d2 \" d4 i+ Z
that phallic response during puberty is related directly to the
& _3 ^+ b/ Y# B! V2 r& p4 a" S  [5 Lserum testosterone level. There also is other evidence of local& w" j/ r/ V1 w& Y
response to testosterone with hair growth and with spermato-
5 U! K; Z1 T! i9 Q2 x0 K3 b1 r+ \genesis. 5• 6
- m# f9 }7 A  x& X8 I. s. N! pAdministration of larger doses of gonadotropin or systemic
) n- @8 r, U' s0 X3 Ctestosterone, as well as topical applications that produce) Y& O3 {5 c5 ]0 d
higher levels of serum testosterone (150 to 900 ng./dl.), will) A/ d! |' M& `6 a, l  i
also produce phallic growth but risks accelerated skeletal
1 H% w9 D9 V3 Cmaturation even after stopping treatment. It would appear
6 O; M8 m2 {! o" J- F5 l7 bthat this may be avoided by topical applications of testosterone. U* j, Y" I) H' C! T( G& G
and monitoring of serum testosterone. Even with this control3 G! E1 ~$ u  I3 ]. C) @
the duration of our therapy did not exceed 3 weeks at any
9 k: _1 Q- W2 o. t$ n+ ttime. It is apparent that the prepuberal male subject may
( c' T6 G- X4 W6 {- |$ ssuffer accelerated bone growth with testosterone levels near
& h4 }' ?& N& f( C  y200 ng./dl. When skeletal maturation is complete the level of
( `' R, y9 o1 ^  c* P% n2 ]serum testosterone can be maintained in the 700 to 1,300 ng./
0 r6 X4 C$ o' A/ cdl. range to stimulate phallic growth and secondary sexual
5 O# P/ b" z- R) P" k" w- D* {changes. Therefore, after skeletal maturation parenteral tes-
7 d1 [- a" m7 R! Z: ytosterone may be used to advantage. Before skeletal matura-
0 g$ d+ f2 V/ s3 ?' \& ]# f4 x5 Jtion care must be taken to avoid maintaining levels of serum
$ G' W  Y/ D% h! I( C( @testosterone more than 100 ng./dl. Low-dose gonadotropin
! {3 F( e& l# Cdepends upon intrinsic testicular activity and may require* G5 C2 [9 G/ w7 W# C" ]7 t
prolonged administration for any response.& R8 X) c+ @/ a8 m) H, Q! k7 u
Alternately, topical testosterone does not depend upon tes-# D6 u. _; [& Z' p1 b0 q  S! B
ticular function and may provide a more constant level of
+ M5 y: v: S3 ?& R* d0 pREFERENCES
3 e+ r" Y  c, \- D1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; u8 B; \8 m  o& F. @0 LR.: The local application of testosterone cream to the prepub-4 Z0 m) B& p: Y& y% I- Q" i
ertal phallus. J. Urol., 105: 905, 1971.
9 o! {! J6 u1 Y& r8 i  E2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, D" K7 f  [0 l" s( h5 U  Q! ctreatment for micropenis during early childhood. J. Pediat.,
+ `4 p& A  X$ x8 ~) h  b& i83: 247, 1973.; d# X7 U6 \+ D# c
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 ~/ q+ [" V- t6 }; |" Z% i
one therapy for penile growth. Urology, 6: 708, 1975.) A' V8 M' F6 N' \& `
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 _% w$ p, P6 D- @' k7 rto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by# \/ h% a! J, N0 S: p7 j
skin slices of man. J. Clin. Invest., 48: 371, 1969.
) q) n& j4 T: A" A$ a: d, d0 G5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% t* g7 _3 L$ M& r. {
by topical application of androgens. J.A.M.A., 191: 521, 1965.
7 Z( e* k8 k3 l& x& N% u1 F& b  n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; l: r1 J4 [. n* F% L1 V( L( O
androgenic effect of interstitial cell tumor of the testis. J.
' m4 w6 V+ F' U! P5 E, ~5 }Urol., 104: 774, 1970.$ ^9 A! M* L. e
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
4 X6 u8 V1 J8 E: U' Stion in the male genitalia from birth to maturity. J. Urol., 48:
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