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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ I6 W7 P* S- H
GONADOTROPIN
5 s0 j% b& b' B- a4 M' w/ P# YRICHARD C. KLUGO* AND JOSEPH C. CERNY
8 R9 B0 C E" gFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' c/ g+ i$ W# f) z% w: R7 v2 |
ABSTRACT
6 \& ^) Z, w$ r% ^0 \Five patients were treated with gonadotropin and topical testosterone for micropenis associated
; _% Y7 W' j( M0 t9 @with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: h' w) | |( ]4 x
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% L1 ~: y# {& U$ I" o) f& Wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# }* n/ ~9 m- S- b8 e8 N! ?
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
, r z% J0 W! P& v1 [- rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
, M$ D; K7 z: a2 \increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response2 c& ^: a* P& o& g4 e
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ M1 k7 A y# ~0 v% @
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" H- c- [, M% p: I- M& w
growth. The response appears to be greater in younger children, which is consistent with previ-
: {$ m+ u% y3 Xously published studies of age-related 5 reductase activity.( I) Y! T* r. a" L2 h9 H% P
Children with microphallus regardless of its etiology will- y4 H) g7 U" D1 @
require augmentation or consideration for alteration of exter-
& w: E/ p# g7 m! A ynal genitalia. In many instances urethroplasty for hypo-$ L) e& |9 U7 a2 y4 J" f: U
spadias is easier with previous stimulation of phallic growth.
9 E# s9 r2 E" L, \The use of testosterone administered parenterally or topically* y% z' [" s" Z% Q* \1 D) R( [/ ~
has produced effective phallic growth. 1- 3 The mechanism of
5 Z& y6 Y$ v, S: _response has been considered as local or systemic. With this" e8 \8 M% C, ^6 o9 _
in mind we studied 5 children with microphallus for response
+ k; d; [& N2 }# }to gonadotropin and to topical testosterone independently.
7 W. N- d6 H. S- D; Q2 gMATERIALS AND METHODS; ?: Y; _. D% E- q6 h1 ]; q! l* c) A
Five 46 XY male subjects between 3 and 17 years old were" }& f3 n9 u' I$ T, r
evaluated for serum testosterone levels and hypothalamic; u/ w( x7 o! R" s9 a+ q$ E8 Z
function. Of these 5 boys 2 were considered to have Kallmann's1 F" ^/ G3 F% `) h6 v
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 X/ L$ z! Z- e4 W8 wlamic deficiency. After evaluation of response to luteinizing1 ~! y" Y' K7 P. [3 r9 C# Q
hormone-releasing hormone these patients were treated with
8 J3 b3 Q; i8 [/ X& `. U1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. K- T) R/ E4 T( H1 c5 j; z+ ?; Z1 gafter completion of gonadotropin therapy 10 per cent topical% C% x0 ]2 T3 V7 ~; h
testosterone was applied to the phallus twice daily for 3 weeks.
( C \! f, M7 n# _" U XSerum testosterone, luteinizing hormone and follicle-stimulat-4 Z4 a5 F0 W: a9 t9 n! R0 e
ing hormone were monitored before, during and after comple-
h* f! w4 h3 u- Xtion of each phase of therapy. Penile stretch length was
; q1 S2 @% o6 r9 Robtained by measuring from the symphysis pubis to the tip of S8 d0 I* g" Y( M2 N- l6 S
the glans. Penile circumferential (girth) measurements were. T+ U6 _) w8 p5 s
obtained using an orthopedic digital measuring device (see4 l( `9 R. f5 a
figure).# d/ Z0 p0 a5 N, c
RESULTS
! C1 B2 h& s0 ~/ ?8 \Serum testosterone increased moderately to levels between
- s4 N: _+ T3 x3 I3 x9 e6 [50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-, f' c& Y8 A# _+ _ E0 y" y K7 C, F
terone levels with topical testosterone remained near pre-
+ f" [/ R( _3 v$ W7 Otreatment levels (35 ng./dl.) or were elevated to similar levels
9 a( w" c H" y4 n8 rdeveloped after gonadotropin therapy (96 ng./dl.). Higher
7 r2 ^; o4 N9 {serum levels were noted in older patients (12 and 17 years old),+ O0 R5 F ~/ a- g. v
while lower levels persisted in younger patients (4, 8, and 10
. C1 ?8 u3 i( J4 r) Xyears old) (see table). Despite absence of profound alterations/ N9 v N1 c* B' l
of serum testosterone the topical therapy provided a greater
- x2 O# g* b2 T( z; X( c. lAccepted for publication July 1, 1977. ·
, p# _ E7 \! p l; W7 j$ CRead at annual meeting of American Urological Association,' E6 O( _$ s2 f8 e
Chicago, Illinois, April 24-28, 1977.
M; s$ v' R: T* Requests for reprints: Division of Urology, Henry Ford Hospital,
4 P' W: A# ?8 Q% H% ^) K8 |. S. x6 I2799 W. Grand Blvd., Detroit, Michigan 48202.$ v1 D; G) K! N. i6 `1 c
improvement in phallic growth compared to gonadotropin.
2 f0 o9 K" @: f, j I7 aAverage phallic growth with gonadotropin was 14.3 per cent8 ?# m$ L9 `$ o/ _5 l
increase in length and 5.0 per cent increase of girth. Topical
6 i6 A9 {# u9 @$ `' e6 g7 vtestosterone produced a 60.0 per cent increase of phallic length; ^& P% F) R1 {* F0 B7 Z
and 52.9 per cent increase of girth (circumference). The
) k5 d( o% H; d$ W0 cresponse to topical testosterone was greatest in children be-/ I/ Z( Z/ o. d8 D
tween 4 and 8 years old, with a gradual decrease to age 17
6 A3 Z3 U/ G0 }& F/ l9 Lyears (see table).: s' R0 ]2 P) B4 V
DISCUSSION! }% Z6 C% c+ J4 j# W
Topical testosterone has been used effectively by other
, U1 h5 A' R O& @clinicians but its mode of action remains controversial. Im-
4 t9 ~. C7 `, dmergut and associates reported an excellent growth response
/ s; h1 W6 r) T, R2 f# \/ mto topical testosterone with low levels of serum testosterone,5 o' [3 L1 C! _. O0 a( W8 G
suggesting a local effect.1 Others have obtained growth re-
8 ^0 b# V K; \6 s' w2 ksponse with high. levels of serum testosterone after topical
% Z2 s7 x0 b2 S- e2 m& oadministration, suggesting a systemic response. 3 The use of2 v/ z5 R! g; }' ]
gonadotropin to obtain levels of serum testosterone compara-/ {" j, P$ }+ I. k! H: y! n( o
ble to levels obtained with topical testosterone would seem to: l0 r% L* ?* i+ B4 s
provide a means to compare the relative effectiveness of
. k$ r4 k5 ~* f9 Y# y9 Qtopical testosterone to systemic testosterone effect. It cer-
, n; ?6 S5 W" T6 ftainly has been established that gonadotropin as well as par-5 I9 _* s% D& N: P7 }1 l1 W
enteral testosterone administration will produce genital
- y9 R4 i. B$ _, X |growth. Our report shows that the growth of the phallus was
5 t# l# N& Q% [5 D ^+ l) c& x$ Osignificantly greater with topical applications than with go-
9 G0 x, ?3 g w5 e4 k% p# s: ynadotropin, particularly in children less than 10 years old.
3 w: G+ w% b6 k- p6 ]. X$ `. {, c( ~The levels of serum testosterone remained similar or lower4 T8 R* L; U: N9 B( r
than with gonadotropin during therapy, suggesting that topi-$ X+ D" N4 |- O; i+ y- l
cal application produces genital growth by its local effect as
6 n) e1 \0 d9 o; X# ]: T# B) Xwell as its systemic effect.
8 ~; ]6 _7 z, ]* N! z: NReview of our patients and their growth response related to
; K2 N7 B9 o$ Q Z9 w# dage shows a greater growth response at an earlier age. This is
- a7 H6 o% v" pconsistent with the findings of Wilson and Walker, who
( ~4 d" E0 w0 o! u) Wreported an increased conversion of testosterone to dihydrotes-
& B/ _6 B$ Q4 W9 ~! O* ^tosterone in the foreskin of neonates and infants.4 This activ-) W5 i4 q- t& E- r$ P' X) B
ity gradually decreases with age until puberty when it ap-
5 X6 j7 D& p$ |5 ?0 vproaches the same level of activity as peripheral skin. It may3 B6 u1 D+ A* j4 E" E
well be that absorption of testosterone is less when applied at: h' e2 Q' B( e: y ?2 z
an earlier age as suggested by lower serum levels in children6 I. |1 E0 m) F
less than 10 years old. This fact may be explained by the
s6 y: B1 L! a. ngreater ability of phallic skin to convert testosterone to dihy-8 c$ F. | y6 ]. e, _
drotestosterone at this age. Conversely, serum levels in older. D, { |5 F" w% s
patients were higher, possibly because of decreased local
* r! i/ \9 n4 O* b& d. z9 O667
# R# j% x* Y% G1 L8 _* _668 KLUGO AND CERNY
6 d% ~. v( J. p4 MPt. Age
/ J6 g2 g5 E, K: U(yrs.) e7 n3 `: W* Q
Serum Testosterone Phallus (cm.) Change Length" j2 [ b' M! j: G
(ng./dl.) Girth x Length (%)0 k, H. |. ^1 W3 N! [' g
41 @/ z4 [3 Y. }& P" H: N }
8
; L5 q2 ~/ F4 J10 r0 c& s+ L+ J% t7 e2 V
12
" t$ h2 O3 p8 K17# @3 M& A7 y3 n# \4 B. K) a
Gonadotropin& e( [6 U$ y" I* D9 H% Z
71.6 2.0 X 3 16.6$ n9 _, Y* R& u t( d9 P7 M
50.4 4.0 X 5.0 20.0- A* k+ P0 a# q/ P
22.0 4.5 X 4.0 25.0
' p! Y" ?) a/ q" q' v e1 K84.6 4.0 X 4.5 11.16 X# ~5 X1 ~) C- \- n8 V
85.9 4.5 X 5.5 9.02 M$ P) L9 h8 K; y; q# F1 E/ Y
Av. 14.3
! r- h0 W3 L6 }# W44 q' T7 y" V$ E* p
82 l( b3 W" {. Z8 u
10! k: j3 t, f; I+ r& M
12# @6 L, p7 x9 Q% g: N# I; H
17* t y: g; M& \3 Z+ P+ _
Topical testosterone
, \, n2 i. }( u3 E* e9 ~4 t8 R34.6 4.5 X 6.5 85
0 m% E8 q; {* s8 Q( t2 K7 h! V38.8 6.0 X 8.5 70- v+ g. [, R% |
40.0 6.0 X 6.5 62.50 { ?9 ?. \# ]' S+ n9 X2 ?+ b5 ~
93.6 6.0 X 7.0 55.5
6 K( {* O0 D; e& y _( I6 ~95.0 6.5 X 7.0 27.20 W9 r5 c7 M$ i2 ~- G. X4 C
Av. 60.09 ~% K6 d# ?+ p* }) N/ N9 u3 e
available testosterone. Again, emphasis should be placed on- R* D* n; F/ h* ^1 z3 F
early therapy when lower levels of testosterone appear to
8 O% X3 O6 d# _5 l9 q/ }provide the best responses. The earlier therapy is instituted
* w& L) \0 T tthe more likely there will be an excellent response with low
+ z4 O3 K7 |4 G+ Y& a: Sserum levels. Response occurs throughout adolescence as
4 A% a1 c* H. Cnoted in nomograms of phallic growth. 7 The actual response
* }$ u$ O; W2 C Q$ b Jto a given serum level of testosterone is much greater at birth
/ }0 F$ Y6 N% x2 pand gradually decreases as boys reach puberty. This is most
# q& ?2 ~/ x! _. a5 blikely related to the conversion of testosterone to dihydrotes-
i8 H% g7 y+ I' _tosterone and correlates well with the studies of testosterone
$ ]2 I# P- y5 ~+ { J/ W* oconversion in foreskin at various ages.
, ^1 u$ P3 j0 @& z* g+ g. n4 UThe question arises regarding early treatment as to whether
1 u! W3 l$ V# U3 Uone might sacrifice ultimate potential growth as with acceler-1 f) E3 A' u! b3 @* k( }
ated bone growth. The situation appears quite the reverse
9 Q4 q- N6 y9 s! f _4 Q9 f3 L# Zwith phallic response. If the early growth period is not used
5 V8 J: k, v2 r; Vwhen 5a reductase activity is greatest then potential growth
6 j7 y& Q( C7 ~may be lost. We have not observed any regression of growth
! T+ y5 p7 F+ n+ L c9 pattained with topical or gonadotropin therapy. It may well
5 ~) J$ F$ h Rbe that some patients will show little or no response to any+ ~0 u1 e! q" M6 z' V
form of therapy. This would suggest a defect in the ability to
1 m/ O: C0 M+ [. T6 M1 zconvert testosterone to dihydrotestosterone and indicate that
& K+ l- F% J. Z7 W* x$ T' l( qphallic and peripheral skin, and subcutaneous tissue should5 V( N& i2 R( q/ H. r
be compared for 5a reductase activity. ^2 _) p. A3 K: b, n
A, loop enlarges to measure penile girth in millimeters. B,# I4 w9 i( l: O1 Q
example of penile girth computed easily and accurately.& {: z$ M0 ^% v Q& E/ Z5 F7 f
conversion of testosterone to dihydrotestosterone. It is in this" K7 K E- X1 j/ t1 A/ Z0 O
older group that others have noted high levels of serum
. {- E. g/ z3 G! jtestosterone with topical application. It would also appear$ H6 e; H( O: L y g$ o
that phallic response during puberty is related directly to the3 V& H1 L% \, a# q0 }) l, U
serum testosterone level. There also is other evidence of local
; T8 i. M# |4 s. N5 Rresponse to testosterone with hair growth and with spermato-
- E& | V9 X4 ugenesis. 5• 63 R, v5 Z5 R- C% c, ?8 z
Administration of larger doses of gonadotropin or systemic
( x) @: m @$ G& u% ^8 U' gtestosterone, as well as topical applications that produce$ E- O; ]1 b6 K; y, u4 P$ I) S
higher levels of serum testosterone (150 to 900 ng./dl.), will+ D( r: f% s. `! G `' U5 r) k
also produce phallic growth but risks accelerated skeletal
$ f- [% }+ X' r$ q( k: Zmaturation even after stopping treatment. It would appear7 A8 ^$ t) |5 v3 E
that this may be avoided by topical applications of testosterone
0 u# D( b0 w3 |! p- L( Sand monitoring of serum testosterone. Even with this control* K. z B6 N0 M) W5 P# l
the duration of our therapy did not exceed 3 weeks at any
) u0 m$ Q% N- O: P0 b; S3 j8 R- Otime. It is apparent that the prepuberal male subject may
! h" h+ d/ E" B% m1 @4 d1 @$ v8 R& wsuffer accelerated bone growth with testosterone levels near
/ d- J7 D J1 ^* A3 y/ m; f/ Y/ k200 ng./dl. When skeletal maturation is complete the level of
- r9 Q' h5 l3 }; w0 {- oserum testosterone can be maintained in the 700 to 1,300 ng./
3 i$ _. p) \6 G' vdl. range to stimulate phallic growth and secondary sexual7 V( z x! `3 x. j* z
changes. Therefore, after skeletal maturation parenteral tes-1 e% I) @# p5 p8 Q) |1 q
tosterone may be used to advantage. Before skeletal matura-, S9 Z. E4 l. b0 t- M2 V
tion care must be taken to avoid maintaining levels of serum* h' m1 m o. z+ d0 h) b6 `( R' y
testosterone more than 100 ng./dl. Low-dose gonadotropin
. G8 \$ ?# P3 n2 `# Udepends upon intrinsic testicular activity and may require
( e5 i! g' S% t% d2 ], oprolonged administration for any response.! k' R% F, ^7 J5 Y2 J3 W& e
Alternately, topical testosterone does not depend upon tes-3 f$ t( y$ ^3 t/ S3 M9 z
ticular function and may provide a more constant level of* C# }6 l" G! r5 @; Q* n
REFERENCES* e" P- d& @, D H% O
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; F! i F$ z4 u& K) iR.: The local application of testosterone cream to the prepub-& a" y7 O6 W$ h8 q
ertal phallus. J. Urol., 105: 905, 1971.
+ u9 b- `: s3 ]2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 q1 f: v5 E1 H5 [' utreatment for micropenis during early childhood. J. Pediat.,. R/ y1 b' m- M9 j6 a; ^
83: 247, 1973.6 ~ t/ B4 {7 G, r
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# g2 O1 ~3 _7 p, V7 ^one therapy for penile growth. Urology, 6: 708, 1975.
, m! N: K. I: k. Z# m$ M8 V# {, P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! t3 F) [* j" d% `' ^to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( [# ^3 f, \ L% x$ O
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, G t9 W* Y+ h5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( m/ y1 o" [6 Z+ f5 j" G9 a/ jby topical application of androgens. J.A.M.A., 191: 521, 1965.
9 w6 M" Q1 ]: b: [% F6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
1 ^. o- i' X3 g% z. handrogenic effect of interstitial cell tumor of the testis. J.. [) m% u! a/ \ o6 {0 q( q
Urol., 104: 774, 1970.: f. u6 s/ ?/ \% U
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 |& b$ l! V9 e) ~: v; N" W+ i htion in the male genitalia from birth to maturity. J. Urol., 48: |
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