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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- p5 c4 c" f' y/ k3 WGONADOTROPIN, Y7 @ C1 L" w+ K
RICHARD C. KLUGO* AND JOSEPH C. CERNY$ Z G6 @7 W+ t4 ]
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ Z, w3 ^. E- r6 E5 @# V
ABSTRACT
1 d+ ]8 J1 K2 G, x* @" }8 J9 vFive patients were treated with gonadotropin and topical testosterone for micropenis associated- \6 [0 H; i% c6 V
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' n$ W* |. }# X
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; h' Y3 l6 F) R2 S) o$ C, U8 U1 pcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" Q5 J3 @/ S" C* b! F8 h cfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 Z$ G/ G) B+ I2 v$ k; y, N
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ o: e' i1 n; W
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response# b- P7 Z2 H7 {8 t9 k: S9 @
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
. x, |/ `# d6 N f8 B/ Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, l4 ` T% A8 G" W
growth. The response appears to be greater in younger children, which is consistent with previ-, r& y- ]8 K9 t: G* w
ously published studies of age-related 5 reductase activity.& O" r2 h, W# A
Children with microphallus regardless of its etiology will
, _6 G" T' G% M' N: X( ^# ]& s. wrequire augmentation or consideration for alteration of exter-: u& n8 ?9 Q' p! }* W1 O
nal genitalia. In many instances urethroplasty for hypo-* r4 e* v; D; D1 H) p+ Y* `
spadias is easier with previous stimulation of phallic growth.3 z- x) ]8 @3 a. \! {
The use of testosterone administered parenterally or topically0 A" f- Q/ P9 H
has produced effective phallic growth. 1- 3 The mechanism of
6 ^$ @* r1 ]* ~) h R3 }7 ^response has been considered as local or systemic. With this" _( n4 n! p/ ^1 \3 C
in mind we studied 5 children with microphallus for response9 H8 y1 v& H+ e0 `" P
to gonadotropin and to topical testosterone independently. P( h+ _; B+ r% C2 J. b
MATERIALS AND METHODS' m2 u! k0 x, F9 v8 ~6 @
Five 46 XY male subjects between 3 and 17 years old were" S: b4 ?# W+ r
evaluated for serum testosterone levels and hypothalamic) A& M/ m/ U4 w3 f- o
function. Of these 5 boys 2 were considered to have Kallmann's- A& X* f7 d' d. u( c4 o: T" t! X
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-) @7 F k( p% `6 J( g
lamic deficiency. After evaluation of response to luteinizing
0 j' Z. D: o: W+ r6 w' j7 Ahormone-releasing hormone these patients were treated with" w! W t% V" G! I6 G/ e8 ~
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ t6 s& K% c8 V' R, M( ]9 g+ [
after completion of gonadotropin therapy 10 per cent topical, Y" M: m: |( \8 c0 K
testosterone was applied to the phallus twice daily for 3 weeks.
. p% x+ q* S5 N8 zSerum testosterone, luteinizing hormone and follicle-stimulat-
% e, p* w4 J1 |# G% l$ Y' jing hormone were monitored before, during and after comple-* Y: S, K" f4 O
tion of each phase of therapy. Penile stretch length was. N, U9 U: T! i* S e" _7 @$ t
obtained by measuring from the symphysis pubis to the tip of/ r3 i7 U& A& U$ V8 z$ W
the glans. Penile circumferential (girth) measurements were* ]) B9 i7 d# o1 W4 p" [8 s3 T
obtained using an orthopedic digital measuring device (see9 c& ]% Q: S/ I6 N8 v+ p8 f* r
figure).
9 k& L( s& W, r u. H/ uRESULTS" Y- i$ X2 N7 {& X" {
Serum testosterone increased moderately to levels between
" Z7 |" E" c6 z. Z. Q! Z1 e50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" o7 _; F n* C$ u! F! ]# P( t% ]
terone levels with topical testosterone remained near pre-$ P5 E" B& A% q+ |5 Z: Q2 y
treatment levels (35 ng./dl.) or were elevated to similar levels
" a/ }# x1 N9 Y3 r F2 d: Q1 `' cdeveloped after gonadotropin therapy (96 ng./dl.). Higher4 C& q/ `- V' _. h
serum levels were noted in older patients (12 and 17 years old),
. _9 t2 h3 B+ t- Z) a. q! r! owhile lower levels persisted in younger patients (4, 8, and 10% \6 y" P9 G3 K* y- d3 p3 A: H8 X
years old) (see table). Despite absence of profound alterations
0 D+ [- _# z' I; J. T. Q6 E* ^of serum testosterone the topical therapy provided a greater2 l, v: z: R, r( f9 Y+ {# u* P% n( J
Accepted for publication July 1, 1977. ·
) n# X1 |% d4 Y$ s5 o1 r% NRead at annual meeting of American Urological Association,( @( i! f& @, e8 x1 t
Chicago, Illinois, April 24-28, 1977.9 A" u& u6 S, _/ S
* Requests for reprints: Division of Urology, Henry Ford Hospital,5 T- P" K5 |! D7 X5 ?2 v2 _% C/ Y7 P
2799 W. Grand Blvd., Detroit, Michigan 48202.
, H. r8 `5 H% K. e \, Vimprovement in phallic growth compared to gonadotropin.
- W0 i; m- _( J5 O+ h8 n2 k8 qAverage phallic growth with gonadotropin was 14.3 per cent4 B9 i! b+ T# Q+ C" c, ]7 L. R
increase in length and 5.0 per cent increase of girth. Topical
3 t. m d+ l- a7 U- I/ Wtestosterone produced a 60.0 per cent increase of phallic length3 [/ i i% R+ M6 V$ ~0 @1 Y
and 52.9 per cent increase of girth (circumference). The+ i N/ U7 {$ }& u
response to topical testosterone was greatest in children be-7 E3 n( `5 q2 P, a' [: v: k* N
tween 4 and 8 years old, with a gradual decrease to age 17/ o: d/ J0 I1 r, [. O
years (see table).
) L5 ^4 y) R4 }* P3 q+ `! zDISCUSSION
. |9 k; G( u4 L/ YTopical testosterone has been used effectively by other: s" ~ @( x5 A1 x- s6 I5 _
clinicians but its mode of action remains controversial. Im-1 [# C& [- m# \
mergut and associates reported an excellent growth response
6 ?( i% P: E: |2 T; L2 gto topical testosterone with low levels of serum testosterone,7 v6 I5 V5 E4 a/ `: }8 ]4 u! J' D
suggesting a local effect.1 Others have obtained growth re-) F& t# a$ j: j
sponse with high. levels of serum testosterone after topical
6 s" `6 I3 _3 }) K' T9 xadministration, suggesting a systemic response. 3 The use of6 F4 v* O! W% u# C8 D# g
gonadotropin to obtain levels of serum testosterone compara-+ s7 ^( U' V8 L6 B
ble to levels obtained with topical testosterone would seem to$ Q- \$ p ?+ S* f. z' ^+ f3 E' I {* k
provide a means to compare the relative effectiveness of
, l$ U8 {, _7 r- v) \topical testosterone to systemic testosterone effect. It cer-# u& `7 D; K. F" S" B* n
tainly has been established that gonadotropin as well as par-
2 _7 ^9 a' g6 A. }$ t3 xenteral testosterone administration will produce genital
; e) u6 y0 I* l9 O5 k* J3 ?5 Agrowth. Our report shows that the growth of the phallus was
7 v6 G/ ]5 M" @- Msignificantly greater with topical applications than with go-* Y! f* R2 m+ Q
nadotropin, particularly in children less than 10 years old.
3 v* d4 Z ]: B) X# `1 h8 e; L$ KThe levels of serum testosterone remained similar or lower. v2 u. L+ U0 [7 r# D* s
than with gonadotropin during therapy, suggesting that topi-
. Y* q( d) Y4 T; t+ a. S' g2 Hcal application produces genital growth by its local effect as
% D, n) v' J2 ~& s9 Nwell as its systemic effect.
0 t$ s* `/ C0 C, nReview of our patients and their growth response related to
9 Q$ \8 E9 Z1 H2 b" R4 O: Hage shows a greater growth response at an earlier age. This is
& ]4 f5 q" _1 s5 Mconsistent with the findings of Wilson and Walker, who
- K7 K2 A! `6 N! vreported an increased conversion of testosterone to dihydrotes-+ M. C$ y( D3 x T0 T: L
tosterone in the foreskin of neonates and infants.4 This activ-
4 T* G4 s e9 O# D( n4 vity gradually decreases with age until puberty when it ap-% T5 h9 f- h( n/ {1 c0 F
proaches the same level of activity as peripheral skin. It may% K1 f$ |1 [$ }' g/ v+ l7 u: W- w+ t
well be that absorption of testosterone is less when applied at' T' }$ C* \& y: _3 j2 g, \: S
an earlier age as suggested by lower serum levels in children& l$ l% m- b/ @" X7 u6 K
less than 10 years old. This fact may be explained by the6 `' Y: E, }* X. O4 B, i+ G) F! ?
greater ability of phallic skin to convert testosterone to dihy-
0 \+ _+ @7 D" ?+ k. f7 qdrotestosterone at this age. Conversely, serum levels in older4 H: b6 _7 F0 c. m0 B7 G
patients were higher, possibly because of decreased local
\- v# {0 J# e& z+ n667
6 q! p: Q, B5 |" d668 KLUGO AND CERNY
; M4 o) L! x* R' K! z9 ^4 \( [3 @Pt. Age
2 g2 N4 {3 j) l# b/ ]8 Z(yrs.)0 F {% q( { a0 Y% S7 C2 H
Serum Testosterone Phallus (cm.) Change Length
' U2 _" [* ? G4 E$ m4 ](ng./dl.) Girth x Length (%)
: Z" a. n' f7 C) i9 Y4 d4
0 g! D% ^ D: }' S9 T) j0 O5 T# U8
5 a/ H4 S+ A" O! B. [7 V. D1 u10! R1 ^) Y+ ^6 w8 D6 \
12
1 N# \1 C" U4 Q4 ]& a, D; l175 s$ D8 C c. f3 P1 b; c5 c
Gonadotropin! Q1 X3 C0 b2 U' M% d0 P
71.6 2.0 X 3 16.6/ Z2 ]7 S2 u. s# ^) ?) w2 w
50.4 4.0 X 5.0 20.0/ u9 a$ k5 V) ?2 T2 {: u6 V! K
22.0 4.5 X 4.0 25.0/ W: a% e2 F) h4 @& \4 e
84.6 4.0 X 4.5 11.1
1 o1 |* y) w0 H; A& t& _; q: j85.9 4.5 X 5.5 9.0* \0 o$ A* i. i* b
Av. 14.3
; V/ m4 J/ ?' U6 l4
) [! m4 x$ t' R5 i8+ N5 n/ L" l4 ?
10
% W7 b6 M3 U1 Z! ~$ f. i12
: O8 A6 l g1 f. h7 G* W17
0 r8 X+ r2 O5 A. N- Z: M) [+ [Topical testosterone
& a9 M& @7 p: N7 h4 V0 W! b+ s0 l34.6 4.5 X 6.5 85* y+ p( S2 D/ z1 X
38.8 6.0 X 8.5 70
+ y3 ^- j0 Y/ h3 O' X40.0 6.0 X 6.5 62.5
9 |0 W! c3 X: I6 m4 p6 R( Q: l, r93.6 6.0 X 7.0 55.5
5 ]& ? F" r9 u" Q' V95.0 6.5 X 7.0 27.2
/ s" J% g+ X- V l+ _Av. 60.06 F) g/ N% d' O6 A. t ?
available testosterone. Again, emphasis should be placed on
9 W0 E. v m- c0 L6 O# ~early therapy when lower levels of testosterone appear to: T. i% j* {! n$ ~
provide the best responses. The earlier therapy is instituted* y$ T. F y' e+ x$ o
the more likely there will be an excellent response with low# g0 W% h1 ]! \) k
serum levels. Response occurs throughout adolescence as a, D# M* U! E% T9 [* U
noted in nomograms of phallic growth. 7 The actual response
8 Q- o7 @/ r1 V- W# |# B* zto a given serum level of testosterone is much greater at birth. H' b; v* g: I" U1 ?) f6 C
and gradually decreases as boys reach puberty. This is most( b0 v. V9 N6 @3 X i( s
likely related to the conversion of testosterone to dihydrotes-
! f3 a2 ?% w6 M7 mtosterone and correlates well with the studies of testosterone$ b, r7 A2 h- M( t4 |
conversion in foreskin at various ages.
' _! [1 M$ P" f- U7 UThe question arises regarding early treatment as to whether3 ]8 ]/ P2 s V0 ~# A1 J: Q
one might sacrifice ultimate potential growth as with acceler-
' p Y1 Z% ]/ I0 mated bone growth. The situation appears quite the reverse
! }- A; E* p- J* M9 p0 G( Z6 A. C4 Lwith phallic response. If the early growth period is not used
3 h) H S1 h$ G9 h+ B: ~when 5a reductase activity is greatest then potential growth/ Y& U. T) X: Y( U: @+ c F
may be lost. We have not observed any regression of growth
. W* ?& P9 E. h( H+ k6 Hattained with topical or gonadotropin therapy. It may well
, b/ T0 S. \: w% Ube that some patients will show little or no response to any5 R# m G7 A, U5 _1 R1 Q
form of therapy. This would suggest a defect in the ability to
1 s8 P& ?/ k4 q: z( t3 u6 a$ Pconvert testosterone to dihydrotestosterone and indicate that
9 h1 G$ u( `# I* s7 U$ {4 `* K% Sphallic and peripheral skin, and subcutaneous tissue should
8 [2 M/ K5 ]# d) Nbe compared for 5a reductase activity.
) d. ~5 z3 o, s0 X( g! |' UA, loop enlarges to measure penile girth in millimeters. B,, x* L$ r. q6 Q, C, ]
example of penile girth computed easily and accurately.8 @+ g0 @7 j: {
conversion of testosterone to dihydrotestosterone. It is in this- ?! \: I/ k; n. h* [+ v, t
older group that others have noted high levels of serum
0 C/ M3 Q- y+ u+ ~& I {1 Atestosterone with topical application. It would also appear: |* J, u% b# `4 F9 r
that phallic response during puberty is related directly to the
3 D4 F: ]0 Y0 @serum testosterone level. There also is other evidence of local
+ Z# j3 S" ^* F. presponse to testosterone with hair growth and with spermato-8 r" d$ c* T% z+ T
genesis. 5• 69 `- n i4 y5 k G
Administration of larger doses of gonadotropin or systemic
% ~ r! X( M0 V+ R6 Otestosterone, as well as topical applications that produce
$ m# b: r! d0 q. Yhigher levels of serum testosterone (150 to 900 ng./dl.), will
! h5 K% S. u0 k% c% W1 halso produce phallic growth but risks accelerated skeletal, e* d& S7 P, D8 C: q( Z
maturation even after stopping treatment. It would appear
, }9 u6 D f7 E, t. f: {that this may be avoided by topical applications of testosterone5 t8 B7 w2 C( i- h0 K8 q
and monitoring of serum testosterone. Even with this control/ Q |9 y4 U* v* q4 O4 \3 W+ z
the duration of our therapy did not exceed 3 weeks at any8 o% ~! E* T% e# \
time. It is apparent that the prepuberal male subject may- s% _9 u a7 P8 Y* K) e* E( r- e S
suffer accelerated bone growth with testosterone levels near
( ^/ V. o* k4 S u) o& z* V( L& l200 ng./dl. When skeletal maturation is complete the level of
% \# l3 q' D& tserum testosterone can be maintained in the 700 to 1,300 ng./* v3 _ D* v0 u/ K$ \: q2 k" }
dl. range to stimulate phallic growth and secondary sexual
+ _8 G/ C8 E- b h, Kchanges. Therefore, after skeletal maturation parenteral tes-& b9 E y/ g7 B+ a. U) `5 y+ c
tosterone may be used to advantage. Before skeletal matura-) Z+ s4 n) I3 `6 R6 B Z: B8 C% ?+ @
tion care must be taken to avoid maintaining levels of serum. }" Y: S2 j* x% ?
testosterone more than 100 ng./dl. Low-dose gonadotropin2 a7 M1 p( U* t, l* n" L
depends upon intrinsic testicular activity and may require% w. U2 H N, g# R, ?4 F ^% w
prolonged administration for any response.% W% A0 j! R% q* _& T
Alternately, topical testosterone does not depend upon tes-& ~, b+ M4 L j& d
ticular function and may provide a more constant level of* [1 P6 ~+ D4 k6 w& N5 w; q L! c
REFERENCES# @ B* t) a2 S/ Z4 H j
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 \! a% j. r) Q0 WR.: The local application of testosterone cream to the prepub-
+ ]/ U9 Q" V- `* rertal phallus. J. Urol., 105: 905, 1971.4 {- W. W2 J+ Y9 Q0 D! I. B; W
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ Y! \; ?5 c, b! G5 wtreatment for micropenis during early childhood. J. Pediat.,& j; V* ^4 U. s* |$ J1 |
83: 247, 1973.: t' s7 S: }/ }: t; F ^; n
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& V5 S8 L+ A1 n; Q
one therapy for penile growth. Urology, 6: 708, 1975.9 j8 v# K2 l5 B- d/ v% A4 E
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone9 e. D! Q7 B; O& Y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 B) ^5 p# E( F3 z* t0 Vskin slices of man. J. Clin. Invest., 48: 371, 1969.
! k1 `6 Q; u0 F1 i2 ]5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! t6 Q% d y t" \. g8 e- `
by topical application of androgens. J.A.M.A., 191: 521, 1965.7 |! H; ^* G2 D) {( w, e
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 k8 w9 K- ^7 n" T( c3 q5 [, Yandrogenic effect of interstitial cell tumor of the testis. J.) _7 o ?& p3 ~( \ v
Urol., 104: 774, 1970.
# s0 X% n l$ n7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-' o- D' C4 j; J# k# X$ g! A
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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