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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 s* z& q' M; z' o5 K( [GONADOTROPIN: _# b3 |$ t( A
RICHARD C. KLUGO* AND JOSEPH C. CERNY5 R( p# `1 R* G' ~ x
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 S0 {# f+ K$ ?1 o9 hABSTRACT
A3 @# _6 N7 E8 K2 HFive patients were treated with gonadotropin and topical testosterone for micropenis associated ^, W O, v9 j1 z' V4 G T3 a
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-0 n7 D' p, h; k/ z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' q$ g& Y+ s- H& o4 S
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& N) D8 ?: \( t p% f3 p9 w
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
$ F7 \% G! X) `* zincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average5 f; O* k& _: D2 C" M* }
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response8 \, H4 r: Y7 o! z. P& Q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 [5 |* N4 c8 X! m* M1 W* kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
Y* n. G! v& g0 F" Wgrowth. The response appears to be greater in younger children, which is consistent with previ-
6 N) v0 g& Z/ F% E+ t5 \; E. bously published studies of age-related 5 reductase activity.. H; u$ J( _' Q7 o: F4 t0 w
Children with microphallus regardless of its etiology will' ~2 D- o* ^; v4 K8 `
require augmentation or consideration for alteration of exter-) }; g) T+ d K- @* k
nal genitalia. In many instances urethroplasty for hypo-' X6 `9 e& K) \. v- X+ Z
spadias is easier with previous stimulation of phallic growth.# ~1 n) [/ }- A2 u
The use of testosterone administered parenterally or topically/ X3 s. Q z2 I, w$ P# H/ T0 D
has produced effective phallic growth. 1- 3 The mechanism of8 g! l: `/ W# g6 C: L, I, @
response has been considered as local or systemic. With this
5 C, D a, G: b" b) o6 a; j$ Ain mind we studied 5 children with microphallus for response
7 ^5 l( G, N3 e4 T; F8 kto gonadotropin and to topical testosterone independently.
1 ]2 O$ f/ @5 B0 u X0 AMATERIALS AND METHODS" R4 m7 v A) _4 \
Five 46 XY male subjects between 3 and 17 years old were
7 x2 I& |7 o% c; Uevaluated for serum testosterone levels and hypothalamic
0 p4 p* S7 E. J* w, a0 c" Jfunction. Of these 5 boys 2 were considered to have Kallmann's
: f) D+ y# L# u, n" Psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-8 p: J8 c0 K$ l1 x9 P
lamic deficiency. After evaluation of response to luteinizing' D0 D" Y0 s* Y# }
hormone-releasing hormone these patients were treated with4 i4 t5 c5 z b% [* o0 _! n8 C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
* z' l. M) q5 p7 c; ^5 F' W7 pafter completion of gonadotropin therapy 10 per cent topical2 S# v! y% Z v( A3 n- k+ G+ K
testosterone was applied to the phallus twice daily for 3 weeks.0 E4 n; R: c6 ]
Serum testosterone, luteinizing hormone and follicle-stimulat-* K- u# ^, U( i$ c* x
ing hormone were monitored before, during and after comple-
: v s3 M) O/ k+ P; ~! I5 [ }tion of each phase of therapy. Penile stretch length was3 M; S e" W7 }+ X* m* r7 L
obtained by measuring from the symphysis pubis to the tip of
7 M o! I0 D; h* E2 @# W6 |the glans. Penile circumferential (girth) measurements were, j5 C1 N( }9 a* a! A
obtained using an orthopedic digital measuring device (see
& V3 P, B" K! p# I9 X+ R+ o `4 Q5 Ifigure).
; W+ F- L+ O% Q6 E/ I! wRESULTS3 o( C- C) A! V) `
Serum testosterone increased moderately to levels between
8 }; }( c q" R4 ?- ~! Y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ L; _' K, N" D. s j; Iterone levels with topical testosterone remained near pre-, W% [ e$ `% Z/ }3 R2 U
treatment levels (35 ng./dl.) or were elevated to similar levels
1 [6 @8 z* h# [5 w( ?developed after gonadotropin therapy (96 ng./dl.). Higher
1 w1 D4 ?1 L* o9 D: V7 W1 s# `serum levels were noted in older patients (12 and 17 years old),
+ t/ X6 \, u0 m/ xwhile lower levels persisted in younger patients (4, 8, and 10
$ T4 ^5 M% Q# \years old) (see table). Despite absence of profound alterations
0 y: _5 s7 x# v9 ^. p+ P6 vof serum testosterone the topical therapy provided a greater
$ }, c7 x2 Y6 k% }, FAccepted for publication July 1, 1977. ·( Q! w2 R R, E4 o) Y! i% b" B3 p
Read at annual meeting of American Urological Association,& s8 j- v1 \% y4 `6 M& j
Chicago, Illinois, April 24-28, 1977.
, C, M9 K: c0 Q* Requests for reprints: Division of Urology, Henry Ford Hospital,* H# l% c7 \- N2 ^0 b
2799 W. Grand Blvd., Detroit, Michigan 48202.7 Z& ?% t! K1 ]0 F
improvement in phallic growth compared to gonadotropin.) a5 L- A: ~4 o! z3 a: E7 {
Average phallic growth with gonadotropin was 14.3 per cent1 a6 R6 \- r2 M( j u
increase in length and 5.0 per cent increase of girth. Topical
& Q/ t9 H0 X xtestosterone produced a 60.0 per cent increase of phallic length E+ \; ?6 `. E& b* S
and 52.9 per cent increase of girth (circumference). The3 ?" H6 t! w. s! x
response to topical testosterone was greatest in children be-
# X4 t4 a$ K( r4 W( Rtween 4 and 8 years old, with a gradual decrease to age 17- A F+ j$ C2 b0 b) {% k1 R4 Q K
years (see table).( {9 ? E, X, m9 U8 M! B
DISCUSSION8 f$ P) C- j0 A0 P/ ^0 ^
Topical testosterone has been used effectively by other
' A; o$ F8 o5 h% hclinicians but its mode of action remains controversial. Im-' p7 N3 _: F1 T' h( Q
mergut and associates reported an excellent growth response
3 o% Q G! u" _9 i$ o4 Tto topical testosterone with low levels of serum testosterone,; x& l3 Q5 q% d, h
suggesting a local effect.1 Others have obtained growth re-4 a. w7 v$ ]$ |6 S% d
sponse with high. levels of serum testosterone after topical( m7 v F; q% e) @% ]7 x( H7 n
administration, suggesting a systemic response. 3 The use of; P3 H" X ^, `' ]
gonadotropin to obtain levels of serum testosterone compara-4 z' t# w: b- K9 q' N( W7 y! V% F
ble to levels obtained with topical testosterone would seem to
' H# Y7 i _' B v! F; s% rprovide a means to compare the relative effectiveness of
. d0 ?% E* a2 M6 U( ~0 g" n9 j7 Z6 {topical testosterone to systemic testosterone effect. It cer-
3 h4 z9 D! [* q/ I: H* e" p0 stainly has been established that gonadotropin as well as par-
* v: v/ {# K0 `6 Z8 a% Wenteral testosterone administration will produce genital+ x$ e5 p1 C! P' o- ]* ^
growth. Our report shows that the growth of the phallus was" H+ n3 H9 b: z8 m$ Y4 q$ h
significantly greater with topical applications than with go-1 P2 a6 Z8 b2 k# P# Y
nadotropin, particularly in children less than 10 years old.
2 c ^5 E' b; ~ K8 q" L- q- O4 p. PThe levels of serum testosterone remained similar or lower
" h6 n( s6 r; M1 I; }than with gonadotropin during therapy, suggesting that topi-- E+ U# K. z! E- _2 L3 K
cal application produces genital growth by its local effect as9 z& [0 }3 i6 K
well as its systemic effect.; b. }( _. e# o9 d7 G! K
Review of our patients and their growth response related to
: ?1 h* \% |; uage shows a greater growth response at an earlier age. This is
7 f; e- ^5 W& _$ J: u0 Oconsistent with the findings of Wilson and Walker, who' e( H' i w/ k6 h
reported an increased conversion of testosterone to dihydrotes-7 l! r+ ]# I5 x7 {1 g
tosterone in the foreskin of neonates and infants.4 This activ-
3 o/ d3 |8 |% ?& V _ity gradually decreases with age until puberty when it ap-, v: x. {* o# E9 A: T. G- t( L c5 S
proaches the same level of activity as peripheral skin. It may
: V( |0 w% m0 _: [/ Kwell be that absorption of testosterone is less when applied at
8 i$ L2 e5 Z# R" t- s; R4 ?% s' Man earlier age as suggested by lower serum levels in children
! S) X+ B4 w9 ^: D9 i6 aless than 10 years old. This fact may be explained by the
8 I8 D# H; ?9 D2 o& dgreater ability of phallic skin to convert testosterone to dihy-
3 g2 }0 m" w# `% f0 Edrotestosterone at this age. Conversely, serum levels in older
( P& ~; E& X/ z6 k' wpatients were higher, possibly because of decreased local9 Q, \/ w4 H* j. E# R4 t+ C
667
1 }5 C z6 V% y# A8 ~4 Q; j668 KLUGO AND CERNY
" P1 L5 C& w$ X) c7 w" r8 bPt. Age
9 z3 L \4 [5 w& E' ]$ i! E3 v7 b0 M. Q(yrs.)4 M% f! ]3 R1 [
Serum Testosterone Phallus (cm.) Change Length% `7 F& W. P$ ~" X
(ng./dl.) Girth x Length (%)
$ ?7 o+ [5 J+ p4, }0 x% m3 v1 @+ Z" r
8
# y' @$ I5 n5 c+ C$ d10
# O9 l+ ?/ C* ~8 O: p128 n# y4 @' p- R0 ]& S' _& {! {
17* O% T) v/ o. i ^: x! O4 x$ r" M2 R
Gonadotropin% {& j( @: k1 ]& D" y5 r% C2 b
71.6 2.0 X 3 16.69 V- H2 b+ [* t* c B
50.4 4.0 X 5.0 20.0
^4 l. ?. a, k1 Z4 I) w22.0 4.5 X 4.0 25.0
# q4 [, H: [" y4 E0 e84.6 4.0 X 4.5 11.1
' Z6 a6 ]* l! E+ v/ \85.9 4.5 X 5.5 9.03 W3 u, h2 S# C
Av. 14.3
. }" c3 A+ v b F3 z4 A |4
0 i( V& M% v( x* r6 C/ R8
2 @+ U: i7 D# W- a# I+ O1 Q10
" Q4 |6 k) |( q/ w' i# @( d12
( L4 x2 F3 J9 C# P7 `174 `% n& D3 C2 A! B3 p
Topical testosterone
& z2 A1 T5 i8 Q; l7 U34.6 4.5 X 6.5 85( X4 E# k& n! G
38.8 6.0 X 8.5 70
+ l% L' a9 S2 X40.0 6.0 X 6.5 62.50 v& z' `8 H0 t. N
93.6 6.0 X 7.0 55.5
# _" \1 p- p0 p9 v! P) P95.0 6.5 X 7.0 27.2$ X9 l' _- E( C
Av. 60.0
' n: i4 V Q% l5 d E6 Aavailable testosterone. Again, emphasis should be placed on
/ u _+ X9 u' l3 Q/ T/ u3 M2 mearly therapy when lower levels of testosterone appear to
4 O- ?- W8 x- b) aprovide the best responses. The earlier therapy is instituted
3 |9 d8 W6 a4 o; c* x! B5 t7 M2 Othe more likely there will be an excellent response with low/ @/ `, I& W* F8 J' ^. m1 W
serum levels. Response occurs throughout adolescence as
' M( R' @! D0 r6 E7 Qnoted in nomograms of phallic growth. 7 The actual response
% P9 i* b; I; y3 f3 D, sto a given serum level of testosterone is much greater at birth
# ^4 @7 h0 [2 b2 zand gradually decreases as boys reach puberty. This is most
# M1 w) N( t, l E( f! J. G; xlikely related to the conversion of testosterone to dihydrotes-
. s/ j9 a2 b8 `* P8 Ktosterone and correlates well with the studies of testosterone9 j( }* w$ k+ j2 s- ~1 Q5 r
conversion in foreskin at various ages.- X" h- u7 K" ^+ i3 Z
The question arises regarding early treatment as to whether
8 \+ T+ T- Y6 ]" [& eone might sacrifice ultimate potential growth as with acceler-
8 [( p! N' M) x( d/ Sated bone growth. The situation appears quite the reverse/ }" a6 }) a( _6 i
with phallic response. If the early growth period is not used
$ |* x0 k/ H. fwhen 5a reductase activity is greatest then potential growth
. I+ r; w4 X" imay be lost. We have not observed any regression of growth
. P% ]' Q( E, c; C, c2 }attained with topical or gonadotropin therapy. It may well
9 _+ \# Q. _& f/ h mbe that some patients will show little or no response to any& P; N/ j7 H4 z, \
form of therapy. This would suggest a defect in the ability to: A, {, |$ G5 W1 ^1 d
convert testosterone to dihydrotestosterone and indicate that
+ w' h/ a0 l& h/ ?# K5 o' E) ephallic and peripheral skin, and subcutaneous tissue should
0 ^$ ?( q& _% O" J) ~be compared for 5a reductase activity.
8 k. |4 B. e- {) h& d9 M: bA, loop enlarges to measure penile girth in millimeters. B,
# Q; K6 B4 q2 k# K: G; F) A* bexample of penile girth computed easily and accurately.
/ ^4 v: M6 V* ~5 Pconversion of testosterone to dihydrotestosterone. It is in this
4 ~, @6 N2 U! Y; `/ Y: r! |older group that others have noted high levels of serum8 X8 f2 `1 f8 A! j- |5 l
testosterone with topical application. It would also appear
) q$ g0 H0 D( X5 T; Nthat phallic response during puberty is related directly to the4 z9 M* O% V* m
serum testosterone level. There also is other evidence of local3 ^0 C/ v/ q y. }
response to testosterone with hair growth and with spermato-
' \* L% A/ D/ y& H; [genesis. 5• 6
) F4 m, a6 K- n0 V/ ]Administration of larger doses of gonadotropin or systemic* e2 g. R: J" K$ ]6 ?8 w
testosterone, as well as topical applications that produce
6 T$ H* B) u1 Q; \0 z! ?3 \+ ]$ hhigher levels of serum testosterone (150 to 900 ng./dl.), will
% a. {/ d- r; C( a9 f0 u8 Ualso produce phallic growth but risks accelerated skeletal
$ b1 C0 Q$ ]( F# p6 S$ {/ C, g: amaturation even after stopping treatment. It would appear
* l- Q. }9 C5 N* ~! _" ?% Rthat this may be avoided by topical applications of testosterone" F$ o1 ]: A9 l8 }
and monitoring of serum testosterone. Even with this control
: e$ F( J, r. v* T# k* Sthe duration of our therapy did not exceed 3 weeks at any. q1 |- G1 Y* F6 ^+ k
time. It is apparent that the prepuberal male subject may
& w* j C, O5 Z- \& f3 wsuffer accelerated bone growth with testosterone levels near
' T- A. u0 H) Z' O' a2 Z* ^- O/ J200 ng./dl. When skeletal maturation is complete the level of3 ^( S. s& i" R# _+ B6 [' O
serum testosterone can be maintained in the 700 to 1,300 ng./
& i( h+ b. T4 B, F( ~- tdl. range to stimulate phallic growth and secondary sexual- f z+ E/ _9 u9 W
changes. Therefore, after skeletal maturation parenteral tes-
+ f6 T& n: @/ U) ^$ E- G dtosterone may be used to advantage. Before skeletal matura-# p( B- C2 L, M: J1 m
tion care must be taken to avoid maintaining levels of serum
. {: ]4 ?* Z% C0 a5 @+ ~4 J- ttestosterone more than 100 ng./dl. Low-dose gonadotropin
, M- Y7 i# k# O, Tdepends upon intrinsic testicular activity and may require' ?1 W' N7 J$ a2 S1 P- \- t
prolonged administration for any response.
7 W3 B/ }. P9 A0 [1 rAlternately, topical testosterone does not depend upon tes-
* C/ I- O$ _; T+ `+ |; mticular function and may provide a more constant level of. o8 d7 R4 q1 N$ e6 j! @
REFERENCES" a7 g. N/ A) @% ^, g' Q$ Z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 d$ J9 `/ f! o% d% r
R.: The local application of testosterone cream to the prepub-4 O$ N& Q# i& B! f) M6 Z. g
ertal phallus. J. Urol., 105: 905, 1971.
9 K6 d) T& {2 n2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone% ^) J: }# s7 r0 P
treatment for micropenis during early childhood. J. Pediat.,
" M8 w9 A) N0 |$ M83: 247, 1973.7 M t" Z# i0 h' U0 e x
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 w+ ]& B; F. K$ s5 E$ J
one therapy for penile growth. Urology, 6: 708, 1975.: V6 `6 r0 [6 {- J% E6 u, B) K
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) y+ Z5 i, x7 i- O" G) q
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
7 w) Y4 A) z7 Z& Iskin slices of man. J. Clin. Invest., 48: 371, 1969.! F- z- R. a1 w
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth% l9 A; j: Y3 l, D6 B# c
by topical application of androgens. J.A.M.A., 191: 521, 1965.. c d' C* C, e0 B" G3 O5 f/ U
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- _9 U/ L3 h( }( v7 Z
androgenic effect of interstitial cell tumor of the testis. J.
2 c" g. U+ t: c$ h& _, NUrol., 104: 774, 1970.
3 `$ V+ W0 K8 \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-' t- ]$ y# \& H1 B5 L; b
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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