Testicular Modulation of Luteinizing Hormone ...

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Aug 20, 1986 - hormone. (LH) and follicle-stimulating hormone. (FSH) to chronic gonadotropin-releasing hormone-agonist. (GnRH-A) treatment is substantially.

BIOLOGY

OF

REPRODUCTION

36,

309-313

(1987)

Testicular Modulation of Luteinizing Hormone Response to GonadotropinReleasing Hormone (Gn RH )-Agon 1st Treatment SHALENDER URIEL

BHASIN,’

THOMAS

A. SOD-MORIAH,

and

Division

S. SWERDLOFF

of Endocrinology

Department Harbor-

J. FIELDER,

RONALD

of Medicine

UCLA

Torrance,

Medical

Center

California

90509

ABSTRACT We hormone

and

others (FSH)

ferent

in normal

have observed that the response to chronic gonadotropin-releasing

of serum luteinizing hormone-agonist

compared

These

to hypogonadal

the gonadotropin response mediated by products of

to GnRH-A. the interstitial

with

selective

of interstitial,

were

divided

bilaterally

impairment into

five

cryptorchid;

impairment

of

Unlike treatment,

impairment GnRH-A tubular

the

function),

testicular the tubular

behaved that

modulation compartment.

1)

or both

castrated;

while

ketoconazole injections 4 wk.

which animals

showed showed

regulate

of gonadotropin

intact

castrated

analogs of gonadotropin-releasing have generated a great deal

of

GnRH-A

the course in man, cancer,

of other we noted who tend

studies with these that older patients to be hypogonadal

of

have

mature

of

an

patients. following determine

tubular

August 20, 1986. April 21, 1986. requests.

selective compartments 309

shown

the

5 groups GnRH

IV, to

was

have

divided

agonist,

suppression T biosynthesis

elevation

of

LH of

at least

in part,

to GnRH-A status of

D-

modulation products

GnRH-A

GnRH-A by

and

products

of testes.

2) of

(Heber et a!., to suppressive hormone-agonist

(LH) that

than younger the difference

be attributed function

to the of these

prompted us to ask the Does testicular function to GnRH-A? 2) If so, is

of

we assessed experimental of the

after

of LH response of the interstitial

compartments

impairment

of LH after and intact

women sensitive

could gonadal

These observations questions: 1) the LH response

the testicular mediated by

agonist with as a

rats

implants;

a potent

administration

mediated,

in LH response pretreatment

effect is states Wistar

(T) been

and post-menopausal were much more of gonadotropin-releasing

hypothesis, rats with Accepted Received Reprint

sexually

dif-

determine

concentration after 4 wk of GnRHbaseline. Animals with preferential

chronic be

testes

(GnRH-A) on luteinizing hormone male volunteers. We hypothesized

because of their potential as male contraceptive agents (Linde et al., 1981; Schurmeyer et al., 1984; Bhasin et al., 1985) and as treatment for a variety of hormone-sensitive disorders such as prostate cancer (Warner et al., 1983), precocious puberty (Crowley et al., 1981), endometriosis (Meldrum eta!., 1982), and polycystic ovarian disease (Steingold et al., 1986). During analogs prostate

to may

group, 1981) effects

hormone interest

Each

LH below

the

testosterone

1 jig

demonstrated

response to

male animals

or serum

of

+ T) also showed significant animals (with inhibition of

and

INTRODUCTION Agonist (GnRH)

saline

of basal suppression

animals

100 20-mm

Ciyptorchid

follicle-stimulating is substantially

determine whether this To create experimental

to

compartment. with

(LH) and treatment products

T biosynthesis.

either

gonadotropin response

designed

castrated

inhibits

an elevation significant

that

compartments,

III,

of

(cryptorchid and the ketoconazole-treated to

suggested

animals.

daily for

similarly testes

tubular, II,

data

studies were or the tubular

ketoconazole-treated

function

of tubular function treatment. However,

treatment. We conclude

V,

to receive N-ethylamide,

intact animals, the castrated

The present (steroids)

1, intact;

and

tubular

into 2 subgroups leu6des-G1y10GnRH A

groups:

males.

hormone (GnRH-A)

the

gonad?

the LH response lesions designed tubular,

interstitial,

to GnRH-A (steroids) or To to

test

this

of

male induce

or both

310

BHASIN

MATERIALS Study

AND METHODS

hundred into

male sexually mature 5 groups: I, in act;

H,

Wistar rats castrated;

were III,

castrated animals with 20-mm testosterone (T) implants; IV, bilaterally cryptorchid animals; and V, ketoconazole-treated animals. Experimental cryptorchidism has been shown to result

in preferential

impairment

with relative preservation (Swerdloff et al., 1971). shown by us and others inhibit

T biosynthesis

Organ frozen

24

h

for the

the

last

recorded,

by

was administered i.m. injection

Sikka

et a!.,

organs

in

the

All

initiation

concentration were measured

NIADDK.

IntraRIAs 2.6

The

rat

(Bhasin

et

a!.,

created et al.,

by methods 1979), 2 wk

treatment.

of rat by

minima!

and were and

interassay as follows:

LH (rLH) reagents

detectable

LH radioimmunoassay RP-2 and for FSH

was

and rat supplied

concentration

(RIA) was 0.75 ng/m!

coefficients rLH ± 3.1

FSH by for

0.05 ng/ml of of rFSH RP-2.

of variation and 11.0%;

for the rFSH ±

12.0%.

T was described Serum

of GnRH-A

measured previously was

extracted

in

extracted (Fundenburgh with

10

and

variation

8.3%,

±

expressed

by

for

the

serum

T

respectively.

as mean

analysis

of

SEM.

±

variance

using

Data the

were BMDP

1985).

(Dixon,

RESULTS

Body between

treated decrease

serum

Measurements

Serum (rFSH) the rLH

was Kretser

are software

weights the GnRH of the

serum et volumes

by a!.,

RIA as 1983). of

ethyl

were not significantly agonistor saline-treated

of

Table tions.

prostate

1, closely In controls,

were low cryptorchid

and and

seminal

paralleled the cryptorchid,

groups, GnRH-A in serum T

Castrated suppression decline castrated

different animals

5 groups.

Serum T concentrations ketoconazole-treated,

in the castrated, animals. The

vesicles, serum and

shown

in

T concentraketoconazole-

treatment led to a significant and accessory organ weights.

animals had already achieved maximal of serum T and showed no further with GnRH-A treatment. In T-replaced animals, T implant prevented any further

decline in serum T after GnRH-A treatment. All the groups behaved true to expectation, thus establishing the validity of our experimental mode!. Examination of representative sections of testes from

ever,

Hormone

data

statistical

was

the

injection.

Cryptorchidism cryptorchidism described (de

of

RIA. and

Analysis

the

normal animals

Bilateral previously

3.9%

analyzed

weights

1986).

before

were

Statistical

the by

in corn oil at a 3 times a day for the

male

±

the end of were killed

treatment period. This dose of ketowas shown in previous experiments to effectively serum testosterone and weights of sex

assay

in any

4-wk

accessory

coefficients

divided into 2 of either saline D-leu6 desGly’#{176}

GnRH-A and

interassay

(3:2 v/v) prior to over 90%. Intra-

function function has been and directly

1982;

wk. At animals

hexane mixture were consistently

cell

Administration

Ketoconazole dose of 25 mg entire conazole inhibit

4

after

weights were at -20#{176} C.

Ketoconazole

et al.,

5 groups was daily injections GnRH agonist

GnRH-EA (GnRH-A) 4-wk treatment period, decapitation

of tubular

of Leydig Ketoconazole to selectively

(Pont

1985). Each of the subgroups to receive or 1 jig of a potent

AL.

acetate and Recoveries

Design

One divided

ET

control

animals

testicular also had the

by light

histology. normal

cryptorchid

microscopy

revealed

The ketoconazole-treated testicular histology.

testes

revealed

the germinal epithelium, hyalinization tubules, and Leydig cell hyperplasia. The serum LH response to GnRH-A

How-

degeneration of some

of of the

is shown

as

absolute values corresponding Intact animals

in Table 1 and as percentage of saline-treated controls in Figure 1. showed significant elevation of basal

LH concentrations Saline-treated

after castrated

significantly

elevated

compared castrated sensitivity

4 wk of GnRH-A treatment. animals, as expected, had basal

LH

to intact controls. GnRH-A animals again demonstrated to the suppressive effects

concentrations treatment of their exquisite of GnRH-A.

Cryptorchid animals with preferential impairment of tubular function also showed significant suppression of LH after GnRH-A treatment. However, ketoconazole-treated animals with inhibition of

TESTES TABLE

1. Effects

of GnRH-agonist

MODULATE

(GnRH-A)

treatment

Intact Groups

Prostate (gm)

weights

Serum T (nglml)

Serum

LH

aData that

are

seen

mean

‘GnRH-A *

FSH

0.026

0.023

0.392

0.320

0.363

0.201”

0.246

0.169’

±

±

±

±

±

±

±

±

0.026

0.001

0.002

0.047

0.035

0.03

0.042

0.040

0.019

0.25

0.25

0.8”

0.035

Since

3.9

1.1”

1.4

1.4

3.3

0.7”

1.5

±

±

±

±

±

±

±

0.7

0.1

0.4

0.1

0.5

0.1

0.1

0.1

0.50

0.68”

11.2

1.12”

1.20

0.49”

1.32

0.95”

0.64

0.80”

±

±

±

±

±

±

±

±

±

±

0.02

0.02

0.04

0.10

0.02

0.05

0.02

0.04

0.03

is different

in the

castrated

animals

SEM,

n=10

0.03

in each

because

group.

of absence saline

The

saline

=

in the

did

we treated

compared

not

have for

affect shown 3 days

to

oil vehicle-

thus indicating, effects on pituitary

et a!.,

that LH or

weights

in mean

significantly

and

prostate

different

serum

2). GnRH-A with 22.5-mm

weights

from

treatment T implants,

those of

T

that

in

serum

animals

LH

(Table

response

LH

above that 2). Thus, to normalize

GnRH-A

in

We recognize

Percent

of T

castrated

rats

cannot

that

the

be explained

LH

501000 C

castrated

response

50-

to

than in eugonadal response of the on

the

basis

of

or

similar

selective led to

the T(regard-

qualitatively

that

the

Leydig

similar

selectivity

cell

to

that

suppression an LH response to

of the

function

of of T to

that

of

impairment

induced

rLH

Response

to

by

GnRH-Agonist

these

Treatment

Saline

Data

Co

I -J

in hypogonadal in the LH

qualitatively

0

a.

demonstrate

was

0

0

data

that

rats. In contrast, by ketoconazole

GnRH-A that was intact male rats. tubular

response treatment

Treated

GnRH-A

DISCUSSION

These

from

T dose), was also qualitatively different rats. A preferential lesion of the tubular induced by cryptorchidism led to an

response

castrated synthesis

since the LH rats to GnRH-A

(Table

these castrated animals unlike intact controls, also

to

alone, castrated

not

2).

GnRH-A is different rats. The differences

T-replaced

the

were

of controls

failed to induce elevation of serum LH corresponding saline controls (Table replacement, regardless of dose, failed the

weight

animals.

less of the from intact compartment

of

1986).

castrated + 20-mm T implant groups were somewhat lower than in the intact controls, we inserted 22.5mm T implants in subsequent experiments. This dose of T resulted

T to prostate T-replaced

deficiency replaced

tubular function and demonstrated

ketoconazole used in the no differences in serum

controls, no direct

prostate

of serum

rhythms

p

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