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Estradiol-induced follicular atresia in rhesus monkeys is not prevented by exogenous gonadotropins.

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American Journal of Primatology 23:247-255 (1991)
BRIEF REPORTS
Estradiol-I nduced FolIicuIar At resia in Rhesus Monkeys
Is Not Prevented by Exogenous Gonadotropins
REINHOLD J. HUTZ,' DONALD. J. DIERSCHKE? AND RICHARD C. WOLF2
'Department of Biological Sciences, Uniuersity of Wisconsin, Milwaukee; and 2Wisconsin
Regional Primate Research Center, Madison, Wisconsin
Estradiol-17P (E,) induces atresia of the dominant preovulatory follicle
(DF) when administered on day 6 of the menstrual cycle. The present
study was designed to determine whether the atretogenic effect of E2 could
be averted by the administration of exogenous gonadotropins, in an attempt to determine whether E,-induced atresia in primates is due to a
direct action at the ovarian level or is mediated via pituitary secretion.
After identification of the DF during laparoscopy, cyclic monkeys received
Silastic capsules containing E, placed S.C.for 24 hours, plus one of the
following treatments: phosphate-buffered saline, or 25 I.U. of either human urinary menopausal gonadotropin (hMG), FSH-rich hMG, human
urinary FSH (uFSH), or human pituitary FSH (pFSH) injected i.m. twice
daily for 2 days. The control treatment resulted in atresia of the DF and
extended follicular phases (26.3 5.9 days, x % S.D.), but in normal luteal
phases following ovulation of a substitute DF. Similar results occurred in
all animals receiving FSH-rich hMG or pFSH, and in 11 of 16 animals
receiving hMG or uFSH (P > 0.05). Since all possible routes and regimens
of gonadotropin administration were not attempted, a central action of E,
cannot be ruled out. However, we believe that the experimental observations support our contention that the atretogenic action of E, is exerted in
part a t the ovary.
*
Key words: Mucuca muluttu, steroids, follicle-stimulating hormone, preovulatory follicle
INTRODUCTION
We have demonstrated previously that estradiol-17P (E,), administered S.C.in
Silastic capsules for 24 hours on day 6 of the menstrual cycle, induced atresia of the
dominant preovulatory follicle (DF) [Dierschke et al., 19851; this allowed for the
ovulation of a substitute follicle and for a marked extension of the follicular phase.
During treatment, circulating amounts of follicle-stimulating hormone (FSH) de-
Received for publication August 9, 1990; revision accepted October 18, 1990.
Address reprint requests to Dr. Donald J. Dierschke, Wisconsin Regional Primate Research Center, 1223
Capitol Ct., Madison, WI 53715-1299.
0 1991 Wiley-Liss, Inc.
248 I Hutz et al.
clined transiently, and showed a rebound after removal of the capsules; the
amounts of luteinizing hormone (LH) did not change consistently [Dierschke et al.,
19851. Local intrafollicular effects of E,, administered s.c., were confirmed by
studying contents of the DF obtained by aspiration on day 10 of the cycle. Viability
and steroidogenic capability of granulosa cells were reduced distinctly; the binding
of FSH t o granulosa cells was not altered, but FSH added in culture had limited
capability to reverse the effect of estrogen [Hutz et al., 19861. E,, administered
locally by injection into the stroma of the ovary containing the DF, also induced
atresia in the majority of animals; this treatment induced brief increases in circulating amounts of estrogen at six hours after injection in some animals, but did
not alter circulating amounts of FSH or LH [Hutz et al., 19881. In related studies
with hamsters and monkeys, direct exposure of granulosa cells to E, in long-term
culture resulted in their reduced steroidogenic capability [Hutz et al., 1987a,
1987b, 19891. Although much of the data available to date tends to support our
hypothesis that estrogen may induce atresia of the DF by an action at the ovarian
level, we cannot rule out the possibility that altered secretion of gonadotropins by
the pituitary is also a factor [Zeleznik et al., 19853. The present study was done to
test this possibility by using gonadotropin preparations having a variety of potencies as replacement therapy, in conjunction with estrogen treatment.
METHODS
Experimental Animals and Treatments
Thirty adult female rhesus monkeys (Macaca rnulatta), exhibiting normal
menstrual cycles of 24-32 days in length and estimated luteal phases of > 10 days
preceding treatment, were used. The animals weighed 4-8 kg and were 6-20 years
of age. Animal care and housing, blood sampling, and surgeries were as previously
described [Hutz et al., 19851.The DF was identified during laparoscopy on day 5 or
6 of the cycle. To induce atresia of the DF, 4-9 animals per group were treated with
4 Silastic capsules containing E, placed S.C.for 24 hours from the morning of day
6 (capsule preparation was as described previously [Dierschke et al., 19851). Other
treatments superimposed on the above were: phosphate-buffered saline (PBS, control); human urinary menopausal gonadotropin (hMG, Pergonal; FSH:LH = 1:l;
Serono, Randolph, MA), FSH-rich hMG (Neo-pergonal; FSH:LH = 3:l; Searle
Laboratories, Montrouge, France); human urinary FSH (uFSH; > 99% FSH activity; Metrodin, Serono, Randolph, MA); and human pituitary FSH (pFSH). PBS or
gonadotropin was administered i.m. in doses of 25 I.U. twice daily for 2 days (total
dosage, 100 I.U.), starting when the estrogen implants were installed. Blood samples were obtained daily, or more frequently (at 0800, 1500, and 2100 h) during
treatment days. Additional observations by laparoscopy were done at about day 15
of the cycle to evaluate ovulation or atresia of the original DF and were also done
later if necessary to evaluate ovulation of a substitute follicle [Dierschke et al.,
19851.
In a preliminary experiment, animals were treated with the atretogenic regimen of estrogen described above, and either hMG or uFSH was administered as
replacement therapy at a lower dosage (7.5 I.U.) but for a longer period (twice daily
for 4 days; total dosage, 60 I.U.). Normal ovulations of the original DF occurred in
0 of 5 controls, 2 of 7 treated with hMG, and 3 of 9 treated with uFSH. On the basis
of these preliminary observations, we selected the higher dosage for the present
study and concentrated the replacement therapy during the interval when endogenous FSH tended to be suppressed by estrogen treatment.
Gonadotropin and Estrogen on Monkey Follicles / 249
TABLE I. Effect of Exogenous Gonadotropins on Ovulation and Cycle Length in
Rhesus Monkeys Treated With Estradiol-17P
No. of animals
in which atresia
occurred/total'
Cycle length/length of luteal phase, days'
Saline vehicle
515
40.3 i 4.6 (4)"
23 (1)
114.0 k 1.4 (4)"
/anovulatory (1)
hMG
5/7
23 (2)
25.3 i 2.9 (3)'
51.0 t 15.6
113.0 t 2.8 (2)"
lanovulatory (3)
114.0 i 4.2 (2)"
FSH-rich hMG
515
43.7
uFSH
6/9
4.6 (3)"
33 (1)
24.7 t 2.1 (3)'
21.5 t 6.4 (2)bc
36 (3)
114.0 2 2.0 (3)"
lanovulatory (2)
/17.0 t 2.0 (3)"
/anovulatory ( 2 )
/15.0 -+ 1.4 (2Ia
pFSH
414
33.0 i 4.1 (4Ib
/13.3 i 1.9 (4)"
?
'There were no significant differences among treatment groups by the Fisher exact-probabilitytest (P > 0.05).
2Valuesare x 2 1 S.D. Numbers in parentheses denote observations.Cycle lengths of approximately 24 days and
ail luteal phases are in the normal range. Some animals were deleted because of incomplete cycle information.
FSH-richhMG and uFSH-treatedmonkeys in which ovulation occurred were further divided into 2 groups based
upon statistically different cycle lengths.
a,b%uperscriptswithin a column that do not contain a common letter indicate significant differences ( P < 0.05).
Radioimmunoassays
Serum concentrations of LH, FSH, estrogen (El, and progesterone (P) were
determined by methods described previously [Clark et al., 1978, 19791. Serial dilutions of the various FSH preparations exhibited linearity in the FSH assay over
the range 1:0 to 1:lOOO. PFSH cross-reacted 100% in our assay. The LH present in
hMG and FSH-rich hMG did not cross-react perceptibly in the LH assay.
Statistical analyses
Fisher's exact test [Zar, 19741 was used to compare ratios in Table I after
pooling similar data. Lengths of cycle and luteal phase were analyzed by completely randomized one-way analysis of variance (ANOVA) [Zar, 19741followed by
Student-Newman-Keuls (SNK) test (Table I). Amounts of circulating hormones
were quantitated by integrating and digitizing the areas under hormone curves
[Dierschke et al., 19851, and analyzed by one-way ANOVA and SNK (Table 11).
RESULTS
In rhesus monkeys, prevention of estrogen-induced atresia of the DF and concomitant extension of the follicular phase did not occur to a significant extent,
regardless of the superimposition of four different gonadotropin preparations possessing from 50 to 100% FSH activity (Table I). Examples of a control animal in
which atresia of the DF resulted and a uFSH-treated animal in which ovulation
occurred are shown in Figures 1 and 2. Atresia was induced in 25 of 30 animals,
including all animals receiving saline, FSH-rich hMG, and pFSH; ovulations occurred only in 2 of those receiving hMG and 3 receiving uFSH (Table I) (P > 0.05).
All luteal phases, whether derived from the original DF or from the substitute
follicle, were of normal duration (Table I).
Total circulating amounts of LH, as measured by digitized areas under hormone curves, were not consistently affected, regardless of whether cycles were
250 / Hutz et al.
TABLE 11. Effect of Exogenous Gonadotropins on Hormone Patterns in Rhesus
Monkeys Treated with Estradiol-l7P, Total Area Under Hormone Curves*
FSH
Estrogen
Proge s te rone
Saline vehicle
0.86 f 0.08 (4)'
0.81
LH
(atresia)
(anov.)
0.97 t 0.04 (4)"
1.03
0.74 ? 0.02 (4)"
0.64
0.60 2 0.09 (4)"'
0.31
hMG
0.34 2 0.10 (2Iab
0.32 ? 0.01 (2)"
0.57 t 0.25 (3)"''
(ovul.)
(atresia)
(anov.)
1.02 ? 0.11 (2)"
0.89 ? 0.02 (2p
1.20 t 0.30 (3)"
1.34 2 0.08 (2)''
0.81 0.09 (2Ib
0.56 2 0.03 (2Iab 0.89
0.73 ? 0.15 (3)" 0.34 t 0.09 (3)"
FSH-rich hMG
0.37 i 0.03 (3Yb
0.36 2 0.12 (2)"
(atresia)
(anov.)
0.95 ? 0.03 (3)"
0.91 t 0.04 (2)"
0.78 2 0.08 (3)"
0.57 t 0.01 (3Iab
0.57 ? 0.20 (2Iab 0.52 2 0.32 (2)ab
uFSH
0.71 t 0.12 (3)bc (ovul.)
0.44 ? 0.07 (3)"
(atresia)
(anov.)
0.26
1.28 t 0.16 (3)"
1.35 ? 0.24 (3)"
0.91
1.15 f 0.05 (3)''
0.90 f 0.09 (3)"'
0.80
0.77 2 0.20 (3Fb
0.71 t 0.19 (3Fb
0.06
hFSH
0.62 t 0.07 (3Iab'
0.25
1.18 t 0.14 (3)
1.59
0.85 2 0.03 (3)"
0.62
0.53 2 0.16 (3)"'
0.54
(atresia)
(anov.)
*
*Relative units ( 2 1 SEM) for integrated areas under curves using X-axis a s the base; normalized per day.
Numbers within parentheses denote observations. Values for LH and FSH, E, and P represent the entire cycle,
follicular phase, and luteal phase, respectively.
ovul. = ovulatory cycle.
atresia = cycle in which atresia of dominant follicle resulted.
anov. = anovulatory cycle.
",bscSuperscriptswithin a column that do not contain a common letter indicate significant differences (P< 0.05).
ovulatory or anovulatory, or whether or not atresia of the original DF resulted, and
regardless of the type of exogenous gonadotropin therapy used (Table 11). FSH
concentrations were likewise not significantly altered with uFSH administration
(Table 11). Total estrogen and progesterone were expectedly elevated in ovulatory
vs. anovulatory cycles (Table 11).
DISCUSSION
The present experiment indicated that the atretogenic action of estradiol-17P
on the DF of rhesus monkeys was an all-or-none event, as it was not forestalled to
any appreciable extent, regardless of the type or dosage of FSH preparation superimposed upon treatment. FSH-rich hMG and pFSH had no effect, while hMG
and uFSH prevented E,-induced atresia in a non-significant number of individual
animals. Other workers have demonstrated that in rhesus monkeys FSH-rich hMG
appeared to compensate partially for the induction of luteal phase defects and FSH
suppression by porcine follicular fluid [diZerega & Hodgen, 19811. Our results
differ substantially from those of Archer et al. in women, where hMG reversed the
atretogenic effect of oral administration of ethinyl estradiol [Archer et al., 19881;
the discrepancy between our studies may be attributed to a number of factors,
among them species differences, route, composition and metabolism of administered agents, and length of treatment.
Exogenous FSH preparations appeared, in some instances, to mask or mute
the "inhibition" and "rebound" phenomena characterizing endogenous FSH after
S.C. E, administration [Dierschke et al., 19851. Figure 2 shows that FSH concentrations in a monkey given Metrodin remained at a fairly steady state or were even
slightly elevated during treatment with respect to baseline concentrations that
existed prior to E, exposure. This elevation was evident across animals, but was
not correlated with increased incidence of ovulation. The effect was partly due to
the cross-reaction of these preparations in our FSH assay; the reduction in the
Gonadotropin and Estrogen on Monkey Follicles / 251
600
550
500
450
I
-5
c
400
350
300
250
Y
3
200
- 200
- 100
- 50
150
100
-
50
1 1 .
0
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487.3
300
250
200
150
100
50
0
0
2
4
6
tttt
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Day of Cycle
Fig. 1. Hormonal patterns in a rhesus monkey treated with four capsules of estradiol-17p (E,) for 24 hours on
day 6 of the menstrual cycle (descendingarrow) and with saline vehicle twice daily for 2 days (ascendingarrows).
In this animal, treatment with E, resulted in atresia of the original dominant follicle, and extension of the
follicular phase with ovulation of a substitute follicle. Treatment resulted in small, transient declines in LH and
FSH. After capsule removal, both LH and FSH “rebounded” to large peaks, but only transiently. This hormonal
pattern was also typical of monkeys treated with exogenous gonadotropins, but where atresia occurred nevertheless.
252 I Hutz et al.
450
I-
RhQ72
- 900
400
-
800
350
-
700
cn
- 600 5
-
3
500
- 400
- 300
-
-
cc)
\
3
Y
I
I
I
200
100
0
I
f
-&I
P
300
-
250
-
200
-
150
-
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
itit
Day of Cycle
Fig. 2. Hormonal patterns in a rhesus monkey treated with 4 capsules of estradiol-17p (E,) for 24 hours on day
6 of the menstrual cycle (descending arrow) and with 25 I.U. uFSH twice daily for 2 days (ascending arrows).
UFSH reversed the atretogenic effect of E, in this animal and allowed for timely ovulation of the original
dominant follicle. Treatment resulted i n timely surges of gonadotropins and attenuated any rebound of these
hormones following capsule removal.
typically exaggerated "rebound" response to E2 withdrawal may also have signaled
an involvement of FSH in E,-induced atresia. Interestingly, Figure 2 shows no
surge of FSH coincident with that of LH; a possible hypothesis is that the injected
FSH enhanced inhibin production, which in turn served to inhibit peripheral FSH
[Rivier et al., 19861.
Gonadotropin and Estrogen on Monkey Follicles / 253
High-potency, “pure” FSH preparations may advance folliculogenesis [Schenken et al., 19841,and we observed cycle lengths with uFSH (24.7 2.1 [3],x S.D.
[nl) near the limit of that which we consider to be normal in untreated animals
(28.9 -1- 4.4 I2431 [Hutz et al., 19851. Administered in the early follicular phase,
prior to day 8 and establishment of follicle dominance, hMG caused a supernormal
number of follicles to develop in the cynomolgus macaque [diZerega & Hodgen,
19801. However, at the dosage and duration employed in the present study and in
other similar studies [Schenken and Hodgen, 19831, no hyperstimulation was observed with either hMG or uFSH.
The LH content or LH-like activity in some preparations has been shown in
other studies (e.g., using hCG) to exert anti-folliculogenic effects when administered in the mid to late luteal phase and delay the next LH surge [Goodman and
Hodgen, 19821. The presence of LH in our preparations may additionally have
altered the cycle by hastening DF atresia [Goodman & Hodgen, 19821, and the
biologic half-life of urinary gonadotropins like hMG, uFSH, and pregnant mare’s
serum gonadotropin is relatively long compared with that of pituitary preparations
[Chappel et al., 1983; Moor et al., 19851. Therefore, another important consideration in understanding the effects of some preparations is the biologic activity of
the preparations.
Differences in biologic activity can cause disparities between immuno- and
bioassayable concentrations of gonadotropins [Schenken et al., 19851. Several
workers have demonstrated that, based upon isoelectric points, multiple forms of
FSH exist in both pituitary and serum due to differences in sialic acid content
[Wide, 1982; Chappel et al., 19831. Increased sialic acid content of urinary gonadotropins enhanced biologic half-life and biologic activity in vivo, although receptorbinding activity was diminished [Chappel et al., 19831; this may account for the
few reversals of E,-induced effects by hMG and uFSH. Interestingly, as duration of
E, exposure increases, endogenous pituitary FSH forms appear with higher isoelectric points, augmented receptor binding, and reduced sialic acid incorporation
[Chappel et al., 1984; Harlin et al., 19861, thereby possessing a reduced biologic
half-life; this suggests one locus for a centrally mediated action of E, in the induction of atresia.
In conclusion, exogenous gonadotropins exert no significant effect in negating
the atretogenic action of E, on rhesus monkey DF. Since only two doses and two
durations of several gonadotropin preparations, and only one mode of administration were tested, the present study does not preclude central mediation of E2.
However, we believe that the present experiment, taken together with our evidence discussed in the introduction to this report, strongly implicates a role for the
atretogenic action of E2 directly at the ovarian level.
*
*
CONCLUSIONS
1. Administration of various gonadotropin preparations to cycling rhesus
monkeys did not reliably overcome the atretogenic effect of estradiol on the dominant follicle.
2. The present study, taken together with previous data, strongly implicates
the ovary as one site for estradiol’s effect, in addition to a possible central locus.
ACKNOWLEDGMENTS
We wish to thank Gail Krueger and Pat Meller for performing the hormone
assays; Drs. Gary Hodgen, Jones Institute, Norfolk, VA, and Salvatore Raiti, National Hormone and Pituitary Program, Baltimore, MD, for generously supplying
254 / Hutz et al.
the FSH-rich hMG and pFSH, respectively; Dr. J im Hutchison and Serono, Randolph, MA for the uFSH; and Alnita Allen and Dorothy Perry for the expert
preparation of this manuscript. This study was conducted in accordance with the
“Guide for the Care and Use of Laboratory Animals,” NIH Publication No. 85-23
and Public Law 89-544, “The Animal Welfare Act,” August 24, 1966, and its
amendments. Portions of this investigation were presented at the 68th Annual
Meeting of the Endocrine Society, Anaheim, CA, J u n e 25-27,1986. This research
was supported by NIH grants HD17370 and RR00167. This is publication 30-008
of the Wisconsin Regional Primate Research Center.
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