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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& `6 R$ Y& _; _2 F# b- ]GONADOTROPIN
) [0 s! |2 h' ^0 Y( F2 JRICHARD C. KLUGO* AND JOSEPH C. CERNY6 A" P/ U9 L$ `5 V( T$ @% A
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan: ~9 D8 ]" j' {
ABSTRACT
, m9 c% V, N! T! h5 [& YFive patients were treated with gonadotropin and topical testosterone for micropenis associated
0 E& M1 g! i0 g/ T) [) F- jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-. |# y- r5 x) p+ w' Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone( Z, X* Y; Z0 Y) H! v& f2 m/ Y5 k7 B
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent6 o6 G! L/ h! D: Y1 Y6 q0 g
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, F* y5 p* Z; |* v
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; H2 b3 B6 P$ g9 J) _% p7 Wincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response* j! R$ [7 e" V$ ^: Q8 C
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
  m  G- l3 Z% [, {study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% }7 G+ ]" \6 n" Jgrowth. The response appears to be greater in younger children, which is consistent with previ-
1 X1 ^- f1 R) s# Kously published studies of age-related 5 reductase activity.& I# e0 M7 v& f) u5 I8 @
Children with microphallus regardless of its etiology will
' g; t0 K' d0 Qrequire augmentation or consideration for alteration of exter-
9 Z& Q: m' f4 \nal genitalia. In many instances urethroplasty for hypo-
" x2 C% p" c% P0 ~, O7 mspadias is easier with previous stimulation of phallic growth.9 z) W8 \# b4 X
The use of testosterone administered parenterally or topically2 g+ {- T& `; M" M9 L# W7 h0 Q
has produced effective phallic growth. 1- 3 The mechanism of. y6 I* ^8 p* C! n
response has been considered as local or systemic. With this
5 y7 g& f( p4 T. [9 b% E& [. Yin mind we studied 5 children with microphallus for response
# `  L1 |+ x& i1 G6 vto gonadotropin and to topical testosterone independently.
9 ^! _# Y! |0 _, u  ~& g7 D, x* _MATERIALS AND METHODS* D) i; f1 G; I
Five 46 XY male subjects between 3 and 17 years old were# q* [7 u  g1 S( w( e4 T
evaluated for serum testosterone levels and hypothalamic
# f3 @" W- |% a0 i- T, @/ Afunction. Of these 5 boys 2 were considered to have Kallmann's/ \* D: }$ [  `& q; R' i- j; g
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-& D1 a# t$ V& [* S5 n1 F
lamic deficiency. After evaluation of response to luteinizing: F+ `/ x8 r) z# o- i0 ^
hormone-releasing hormone these patients were treated with
" U! f2 _. `8 P; K1,000 units of gonadotropin weekly for 3 weeks. Six weeks
3 x: P7 I& W' q: Eafter completion of gonadotropin therapy 10 per cent topical% U9 p1 l1 E% Q' F4 H/ j. [
testosterone was applied to the phallus twice daily for 3 weeks.
7 z2 w( ?- V" f$ N. j1 QSerum testosterone, luteinizing hormone and follicle-stimulat-
) K( D" y, e9 [3 h+ |7 Ting hormone were monitored before, during and after comple-1 q# q: K7 B1 p, u0 s/ @# \, n
tion of each phase of therapy. Penile stretch length was; k+ A; ?7 W/ L& ~) M) p. Z" ?1 c
obtained by measuring from the symphysis pubis to the tip of
9 a" f* E7 G- c  r8 |& Nthe glans. Penile circumferential (girth) measurements were
" a3 v- j8 R3 ~' kobtained using an orthopedic digital measuring device (see3 r: h: R7 O7 B: d1 u
figure).
& C3 D( Q6 @, T% h& [RESULTS$ ]9 Y% b7 x' F
Serum testosterone increased moderately to levels between
. l7 Y+ v3 V& m; J& k50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 f6 r5 V, j) M8 H! Nterone levels with topical testosterone remained near pre-
) d3 f  p1 t3 h# c. ]* Ltreatment levels (35 ng./dl.) or were elevated to similar levels8 |) F7 y" a, G# T4 E
developed after gonadotropin therapy (96 ng./dl.). Higher
" F* {/ J0 j( G6 Bserum levels were noted in older patients (12 and 17 years old),
( R4 T7 z  g1 [8 }! T. y: Cwhile lower levels persisted in younger patients (4, 8, and 10
/ |/ Z+ N- v7 U$ J0 W) byears old) (see table). Despite absence of profound alterations. b; Q! \) Z) n: a8 h5 {4 X5 S! t
of serum testosterone the topical therapy provided a greater, o: Y* h, s1 O/ w6 O
Accepted for publication July 1, 1977. ·
3 {7 P! C% M* [! n  FRead at annual meeting of American Urological Association,# p' |) L4 Y) W6 u& }+ s
Chicago, Illinois, April 24-28, 1977.
9 J/ k, p, }/ Z: R% w2 _* Requests for reprints: Division of Urology, Henry Ford Hospital,
) `0 H+ C0 A4 E' i/ h/ U7 q# b2799 W. Grand Blvd., Detroit, Michigan 48202.9 m; V% Z& r( K
improvement in phallic growth compared to gonadotropin.
2 {1 d8 ^5 H3 T$ l) X& FAverage phallic growth with gonadotropin was 14.3 per cent
! {# s2 l/ f% d6 Xincrease in length and 5.0 per cent increase of girth. Topical
9 g, i) U" X5 B1 B2 `" Otestosterone produced a 60.0 per cent increase of phallic length# t- c0 s0 B" B4 }+ b! S/ Z
and 52.9 per cent increase of girth (circumference). The
) ^' I% d* l4 Y: uresponse to topical testosterone was greatest in children be-' u! ?& b8 v: @2 m' F0 I1 v& V- k2 A
tween 4 and 8 years old, with a gradual decrease to age 17
# `* N+ b6 r, S: T* A4 K8 u+ S4 uyears (see table).
, S1 d7 [: d$ f3 k  yDISCUSSION
0 L2 J9 r8 D; _4 P3 R$ S' |+ hTopical testosterone has been used effectively by other
# C4 ]/ B6 b* ?: Dclinicians but its mode of action remains controversial. Im-
! a" ]) g9 y: Nmergut and associates reported an excellent growth response; m7 v# L. X% M
to topical testosterone with low levels of serum testosterone,
2 P" c) J" @/ G! l9 xsuggesting a local effect.1 Others have obtained growth re-$ ~; P  c, E+ W
sponse with high. levels of serum testosterone after topical
+ U/ ]: C  j5 s5 g, t6 o" ^administration, suggesting a systemic response. 3 The use of! s- D- Z& e- D! W1 A
gonadotropin to obtain levels of serum testosterone compara-
/ W% o+ D  p& W# i- }6 G5 p6 j: xble to levels obtained with topical testosterone would seem to
0 |3 G3 {/ I# ]/ u& O% r% nprovide a means to compare the relative effectiveness of
3 G) E* J# m5 ]; L5 A) [3 |1 Gtopical testosterone to systemic testosterone effect. It cer-
: R) h% d# v2 I# ^+ g( Ftainly has been established that gonadotropin as well as par-
) f/ c" ~6 X# I" uenteral testosterone administration will produce genital
& D: W0 }" z. J1 v4 Z9 Rgrowth. Our report shows that the growth of the phallus was6 f, @" ^# B0 \8 m2 c! u
significantly greater with topical applications than with go-
( E5 c' h3 y" |" p  Fnadotropin, particularly in children less than 10 years old.
  K  g+ U" m- l: ^- ~3 ~2 SThe levels of serum testosterone remained similar or lower+ ^1 r" {6 P: b: W
than with gonadotropin during therapy, suggesting that topi-4 f8 m3 F5 D7 J7 n9 J
cal application produces genital growth by its local effect as
1 H9 O+ Y0 J9 [* \well as its systemic effect.) Y6 E2 m5 L2 ~" T1 {
Review of our patients and their growth response related to2 s7 u' Y3 k' Q/ ^
age shows a greater growth response at an earlier age. This is
  Q* l% }6 ?7 z# oconsistent with the findings of Wilson and Walker, who
9 o* X, G; H( I  P# c' Ureported an increased conversion of testosterone to dihydrotes-. ~' \- r3 ^. @  O% R
tosterone in the foreskin of neonates and infants.4 This activ-% t5 M; k3 l9 Y4 o% V
ity gradually decreases with age until puberty when it ap-
) K+ U7 z3 O8 m" iproaches the same level of activity as peripheral skin. It may  N2 g$ @* y6 R% N& S( J
well be that absorption of testosterone is less when applied at
2 ~! Q, l" t( G$ oan earlier age as suggested by lower serum levels in children* S' P+ e1 G3 K4 g
less than 10 years old. This fact may be explained by the
) c4 E. ], K6 @7 Bgreater ability of phallic skin to convert testosterone to dihy-' E9 e, P: c9 Q; F& ]) X
drotestosterone at this age. Conversely, serum levels in older
% W  g! ^3 ?( [3 d5 p) V4 }5 t0 vpatients were higher, possibly because of decreased local
) E$ G+ z9 }. w; Z6679 D# k6 \# ^4 S3 u7 e9 c" C$ R
668 KLUGO AND CERNY
: ?5 _7 T6 q2 i3 v6 dPt. Age6 |8 p% n& a' o3 A) C
(yrs.)
5 y. R/ |2 _: F! dSerum Testosterone Phallus (cm.) Change Length! C3 r) M0 V, M, Z! ?3 i
(ng./dl.) Girth x Length (%)
2 |: r6 H, Y: J) e$ E+ Z5 \0 Z4
! N3 u, G  S4 x: J9 m4 E6 u% P1 h8
0 Z9 _: {4 T- o$ Q* T' a10
" U: G; _8 F3 z0 y- _' {12' {0 T6 B/ L# g0 W2 M7 p9 w
17" q6 K9 A4 R8 W& P6 V! A' e
Gonadotropin
8 V4 I9 k- g1 {71.6 2.0 X 3 16.6
) A5 m6 ~( ?' S* [7 P: x% T# v50.4 4.0 X 5.0 20.07 z# z  _$ [  N% P
22.0 4.5 X 4.0 25.0
9 y) s' @' [! l1 m8 }' z; j84.6 4.0 X 4.5 11.1' p* _) a: e3 f" z/ H
85.9 4.5 X 5.5 9.00 h/ M( e3 H( n  ]- w
Av. 14.3
9 L% D2 W8 V$ i3 W8 L4 [- a46 n$ B' {: R5 W5 F/ f  v/ @- C5 b
8
7 k6 K# `* B/ T& f10
' K9 v3 J7 N/ A7 n129 o) q8 Z8 s4 A9 p; v
17
, |6 g) e9 G; W8 iTopical testosterone) P, `8 H5 o' n& ?) u- S8 \
34.6 4.5 X 6.5 85( w% B. V9 p3 L
38.8 6.0 X 8.5 70
  j- y1 x! S8 D5 ^( _  \40.0 6.0 X 6.5 62.5& w& G2 `! O. L6 C! Y+ E* N  h- R
93.6 6.0 X 7.0 55.5
4 e8 D' i! D/ Z/ z95.0 6.5 X 7.0 27.2
2 L, k$ L% t' t1 p7 }Av. 60.01 T+ ~6 i8 L2 Y4 A, N
available testosterone. Again, emphasis should be placed on5 B) ~: x1 }1 r+ Q% K, V
early therapy when lower levels of testosterone appear to
9 t! ~1 t6 @% u7 c1 J5 W& Fprovide the best responses. The earlier therapy is instituted  N) D3 t* q1 p; d! q5 C" v3 P/ H
the more likely there will be an excellent response with low5 i5 k+ o. K4 F3 K+ _* C, {
serum levels. Response occurs throughout adolescence as" A- v( Q- A  M6 q& w8 J
noted in nomograms of phallic growth. 7 The actual response
! b8 Q3 q, B' X& [, A3 ^to a given serum level of testosterone is much greater at birth, ~0 m2 s* T4 U: P. m' K
and gradually decreases as boys reach puberty. This is most8 {6 J( M5 `' ]& u( v
likely related to the conversion of testosterone to dihydrotes-
) u( h6 B" k+ n- ztosterone and correlates well with the studies of testosterone
* Z# t/ ?- Z  [& M0 y- Z6 ]- @9 Hconversion in foreskin at various ages.3 `. x4 d9 E, [/ X( h# n
The question arises regarding early treatment as to whether
  d$ {& F3 s) @$ H! K" `& vone might sacrifice ultimate potential growth as with acceler-0 G" V' e2 H* W
ated bone growth. The situation appears quite the reverse
# c' _. m4 n1 V4 L0 o  ?  B$ awith phallic response. If the early growth period is not used
# V% @" z+ o6 f8 T" N' kwhen 5a reductase activity is greatest then potential growth
% [! ]* k" K5 d  t! ?0 L  J' D) Vmay be lost. We have not observed any regression of growth7 B! A  G2 b; }6 I% C
attained with topical or gonadotropin therapy. It may well- \# d2 \6 v- V  j6 ?& y% k
be that some patients will show little or no response to any
! s2 o+ c1 m% p" Jform of therapy. This would suggest a defect in the ability to$ L% ^& H' O* @: t7 j$ p- ?' |
convert testosterone to dihydrotestosterone and indicate that
: S+ V; z* D0 |- {* Dphallic and peripheral skin, and subcutaneous tissue should
, F& u' O. r$ j- f9 N% j4 Zbe compared for 5a reductase activity.
( z8 {) Z0 I: j+ DA, loop enlarges to measure penile girth in millimeters. B,
9 t, m  r& D  Z  E" Xexample of penile girth computed easily and accurately.
- U5 c  V* B& \, d4 ^conversion of testosterone to dihydrotestosterone. It is in this7 }4 ~3 M6 y8 F$ P' H
older group that others have noted high levels of serum9 N' Z$ ]6 v- U. V
testosterone with topical application. It would also appear/ g6 `6 R3 [0 Q' X/ P
that phallic response during puberty is related directly to the
4 h$ [  Y1 d: `* t, ~2 Tserum testosterone level. There also is other evidence of local% F) {1 o! @9 Q3 a0 D
response to testosterone with hair growth and with spermato-
0 J! J. k! s* }, A# Ugenesis. 5• 6
9 _% G; S3 u9 |* AAdministration of larger doses of gonadotropin or systemic
- X, Z% `! b& k, `4 s$ \# s4 N0 }testosterone, as well as topical applications that produce  D9 \1 D# p0 s4 ]% ?6 J- ?
higher levels of serum testosterone (150 to 900 ng./dl.), will+ D$ Q2 j& @6 u: g( g/ G# ^+ Z- W; d
also produce phallic growth but risks accelerated skeletal
' ?% b( _: n+ v4 s& I2 Smaturation even after stopping treatment. It would appear% f. J4 T2 g* I, z# {) X3 U
that this may be avoided by topical applications of testosterone
9 V3 t) \5 m8 x3 D: q, @6 Aand monitoring of serum testosterone. Even with this control
2 j) `* u% j$ r) l- w* E/ `the duration of our therapy did not exceed 3 weeks at any6 D- S- d9 s9 I! @
time. It is apparent that the prepuberal male subject may$ z" B$ e- Z  e, U8 M% O% i% B
suffer accelerated bone growth with testosterone levels near  p, [' R& ^2 v: ]+ @* }5 i
200 ng./dl. When skeletal maturation is complete the level of$ T: u3 ~. Z1 P& L  g
serum testosterone can be maintained in the 700 to 1,300 ng./# W! V1 g1 b, F6 A0 V$ j& S$ k, a
dl. range to stimulate phallic growth and secondary sexual
. ]3 S# n1 U* m% @5 o5 |& |4 N( `8 rchanges. Therefore, after skeletal maturation parenteral tes-
2 t% @( A# S' O$ G" x8 N; {) ltosterone may be used to advantage. Before skeletal matura-
/ Y: H6 \% n0 t% ition care must be taken to avoid maintaining levels of serum
0 d1 E7 q" ~2 ], g( ntestosterone more than 100 ng./dl. Low-dose gonadotropin& \: x: P: h+ x4 W+ Q8 v# e! a
depends upon intrinsic testicular activity and may require
  c# X. M2 x7 E$ Qprolonged administration for any response.  p( z, H. X8 S* z" [( Q2 }
Alternately, topical testosterone does not depend upon tes-
6 c( G8 g2 W! ^9 Y: zticular function and may provide a more constant level of
2 P# m9 A3 I+ |' Z5 y( s/ ?REFERENCES
9 h$ w, H4 m0 A) |5 B# v5 U1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ L& N) j, S2 Q; j$ P$ T. \
R.: The local application of testosterone cream to the prepub-' T+ m5 u  G; o# _$ d0 ^* _- o, b$ P
ertal phallus. J. Urol., 105: 905, 1971.
  ?! ]0 u' ]6 ~2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 E  G, t* C, l  b% Y2 {& J: l* H$ Gtreatment for micropenis during early childhood. J. Pediat.,4 y2 `5 t+ g5 G) z8 H( ^2 E
83: 247, 1973.! G, H9 z& c0 T/ e! p% ]) V# j3 V
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" O4 M. q8 O) o# S* p! ]one therapy for penile growth. Urology, 6: 708, 1975.. L/ E7 @2 m" ?
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! }; H) D& m9 [2 `* v: Qto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 s- V0 ]! ?% T2 q: @# V( {: V! A
skin slices of man. J. Clin. Invest., 48: 371, 1969.
- h/ S' ^4 U9 C1 R5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- C0 G) H7 x: _. B0 A4 g. h9 }  gby topical application of androgens. J.A.M.A., 191: 521, 1965.
1 Y* q0 \3 p! u+ {& S$ c- [6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ W  o. [: F8 q$ w/ n) }androgenic effect of interstitial cell tumor of the testis. J.9 n- S+ q! \+ n6 t
Urol., 104: 774, 1970.
: _2 t+ L  R' _. O: p. o) `7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-6 _/ Q- q! @, i2 |
tion in the male genitalia from birth to maturity. J. Urol., 48:
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