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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 4047-4053
Copyright © 1998 by The Endocrine Society

Original Studies

On the Mechanism of the Positive Feedback Action of Estradiol on Luteinizing Hormone Secretion in the Rhesus Monkey1

Tamás Ördög2, Jason R. Goldsmith3, Ming-Dao Chen4, Martin A. Connaughton5, Julane Hotchkiss and Ernst Knobil

Laboratory for Neuroendocrinology and Department of Integrative Biology and Pharmacology, The University of Texas-Houston Medical School, Houston, Texas 77225

Address all correspondence and requests for reprints to: Dr. Ernst Knobil, Laboratory for Neuroendocrinology, The University of Texas- Houston Medical School, P.O. Box 20708, Houston, Texas 77225. E-mail: eknobil{at}girch1.med.uth.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In women and rhesus monkeys, both the negative and positive feedback actions of estradiol (E2) on gonadotropin secretion (inhibition followed by a surge) can be exerted directly at the level of the pituitary gland. We have tested the hypothesis that the positive feedback action of E2 represents but an "escape" from its negative feedback inhibition of gonadotropin secretion consequent to a desensitization of the gonadotropes occasioned by sustained exposure to elevated concentrations of the steroid. We have attempted to replicate such a desensitization by blocking the negative feedback action of E2 by the administration of a potent estrogen receptor antagonist devoid of any agonistic properties (ZM 182,780) to rhesus monkeys in the midfollicular phase of the menstrual cycle (n = 14). The estrogen antagonist, administered at a dose that in separate experiments completely blocked both the negative and the positive feedback effect of exogenous E2 on pituitary LH secretion, failed to produce a surge-like increase in serum LH concentrations. The present results do not support the hypothesis that the LH surge is the consequence of the removal of the negative feedback action of E2. Evidence is presented that ZM 182,780, in contrast to its inhibition of E2-induced LH surges, cannot block the inhibition of hypothalamic GnRH pulse generator activity by E2.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN THE RHESUS monkey, as in the human female, the preovulatory gonadotropin surge is initiated by rising levels of plasma 17ß-estradiol (E2) at the end of the follicular phase of the cycle (see Ref. 1 for review). This action of E2, the so-called positive feedback effect of the steroid, can easily be demonstrated experimentally early in the menstrual cycle of rhesus monkeys by the administration of E2 benzoate in a manner to mimic the time course of E2 late in the follicular phase. These induced LH surges are indistinguishable from those observed to occur spontaneously in normal menstrual cycles (2).

That the site of action of E2 in this regard is at the level of the pituitary gland was demonstrated in ovariectomized rhesus monkeys using an experimental preparation that involves the placement of lesions in the mediobasal hypothalamus that abolish endogenous GnRH production, as evidenced by a cessation of gonadotropin secretion (3). LH and FSH secretion were then reestablished by the pulsatile administration of GnRH of unvarying frequency and amplitude. E2 administration to such animals first inhibited gonadotropin secretion (the negative feedback action of the steroid) and then initiated gonadotropin surges indistinguishable from those seen in nonlesioned animals (3). Similar findings have been reported in women deprived of endogenous GnRH secretion undergoing replacement therapy with exogenous GnRH (4, 5).

The mechanisms underlying this so-called biphasic effect of E2 on gonadotropin secretion have defied compelling explanation. It has been suggested that the only action of E2 is its negative feedback action, and that its positive feedback effect represents an escape from its negative feedback inhibition consequent to a desensitization of the gonadotropes in response to the sustained action of the steroid (1, 6). This idea is supported by the observations of Gorski and collaborators (7) that the stimulatory effect of E2 on uterine glucose oxidation, and DNA and protein synthesis is abolished on repeated exposure to the estrogen. The peculiar temporal component of the positive feedback action of E2 on pituitary gonadotropin secretion, namely that elevated concentrations of the steroid must be maintained for 36 h or longer for the stimulatory action of E2 to become manifest (8), has been provocative in this regard.

If the desensitization hypothesis were correct, the opening of the negative feedback loop of E2 late in the follicular phase of the menstrual cycle should elicit a premature gonadotropin surge. To this end, we used a steroidal E2 receptor antagonist, ZM 182,7806 (ZM), that has been reported to be a potent antiestrogen in a variety of experimental systems, including monkeys (9, 10), without any detectable estrogenic activity (11, 12).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

Nineteen regularly cycling and three ovariectomized adult rhesus monkeys (Macaca mulatta; weight, 5.8–8.9 kg) were studied. The animals were housed singly in rooms with controlled temperature and illumination (lights on, 0700–1900 h) and were fed once daily with Purina monkey chow (Ralston Purina, St. Louis, MO) or High Protein Monkey Diet (PMI Feeds, Inc., St. Louis, MO) supplemented with fresh fruit three times weekly. Water was available ad libitum. The ovariectomized monkeys were fitted with bilateral recording electrode arrays, each consisting of nine Nichrome wires (California Fine Wire Co., Grover City, CA), 50 µm in diameter, chronically implanted in the mediobasal hypothalamus as described previously (13) and with chronic indwelling cardiac catheters connected to sc-implanted access ports (13). The animals were maintained and all experiments were performed in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all protocols were approved by the animal welfare and use committee of The University of Texas-Houston Health Science Center.

Experimental design

The estrogen receptor antagonist ZM (11) was dissolved in absolute ethanol and diluted with peanut oil (Sigma Chemical Co., St. Louis, MO). Doses ranging from 1–10 mg/kg were injected into the gluteal musculature in a volume of 1 mL containing 10% ethanol between 0800–0900 h on day 5 (n = 6) or 6 (n = 1) or between 1600–1800 h on day 7 (n = 6) of the menstrual cycle. In one monkey, the estrogen antagonist was administered at a dose of 0.1 mg/kg in propylene glycol vehicle (Fisher Scientific International, Inc., Houston, TX) twice a day for 3 days beginning on day 5 of the menstrual cycle. In four additional experiments, the antiestrogen was given 4 or 2 days after the sc implantation of SILASTIC brand capsules (Dow Corning Corp., Midland, MI) containing crystalline E2 (Sigma) (see Ref. 14 for details) on day 1 or 3 of the cycle. Blood samples were taken by femoral venipuncture, a procedure to which the animals had been thoroughly habituated, twice a day (between 0800–0900 and 1600–1700 h) for 10–18 days for the measurement of LH and E2 in the serum.

Control experiments

The estrogenicity of the antiestrogen was tested in four control experiments in three ovariectomized animals. The monkeys were restrained in primate chairs. Central venous blood was withdrawn from the cardiac catheters every 10 min for the measurement of serum LH concentrations, and hypothalamic multiunit electrical activity (MUA) associated with GnRH pulse generator activity was recorded as described previously (13). After a control period, ZM in peanut oil was given im at a dose of 5 or 10 mg/kg. MUA recording and blood sampling were continued for approximately 4 h and were repeated the next day.

The efficacy of the antiestrogen was assessed by attempts to block the positive and negative feedback actions of E2 on LH secretion. In ovary-intact animals, LH surges were induced by the sc administration of 7 µg/kg E2 benzoate (Sigma) in peanut oil (2) twice a day for 2.5 days beginning on the morning of day 4 of the menstrual cycle in the absence (n = 4) or the presence of 10 mg/kg of the estrogen antagonist in peanut oil, given im 12 h before the first E2 benzoate injection (n = 3). Blood samples were taken twice a day as described above.

Site of action of the antiestrogen

The site of action of the antiestrogen was tested in two experiments in ovariectomized animals. Hypothalamic MUA was recorded, and central venous blood was sampled every 10 min for the measurement of serum LH concentrations as described for the control experiments above. After a control period, E2 (Sigma) in physiological saline vehicle containing 10% absolute ethanol was administered at a dose of 500 ng/kg as a single injection (0.1 mL/kg) into a peripheral vein at the end of a MUA volley. Recording and blood sampling were continued for about 6 h. Beginning 1 h after the onset of the MUA volley immediately preceding the E2 injection, hourly GnRH challenges (Peninsula Laboratories, Inc., Belmont, CA; 0.1 µg in 0.1 mL physiological saline administered through the central venous catheter) were given. On the following day, ZM in peanut oil was given im at a dose of 5 or 10 mg/kg. On the third day, the protocol involving E2 and GnRH administration was repeated in an identical manner, with E2 administered 24 h after the antiestrogen injection.

Hormone assays

Blood samples were allowed to clot overnight at 4 C, and sera were separated and stored at -20 C until assay. LH was measured by the gerbil Leydig cell bioassay as described previously (15), using the NIH monkey LH reference preparation (NICHHD RP-1, WD-XV-20) as a standard. Purified monkey pituitary FSH is devoid of biological activity in this bioassay, which has a sensitivity of 3.1 pg LH/tube (1.0 ng/mL when 3 µL serum are assayed), with intra- and interassay coefficients of variation of 10.0% and 14.0%, respectively.

E2 levels in serum were measured using a double antibody RIA kit (Diagnostic Products Corp., Los Angeles, CA) modified for use in the rhesus monkey. The product literature reports significant cross-reactivity with estrone (12.5%) and 17ß-estradiol-3ß-D-glucuronide (6.0%), but insignificant cross-reactivity (<5%) with 40 additional steroids or steroid conjugates. A 0.1% cross-reactivity with ZM was also detected, resulting in E2 levels not exceeding 10 pg/mL. E2 standards (3–1400 pg/mL) were prepared in ovariectomized rhesus monkey serum, and 100-µL aliquots of the standards and experimental serum samples were assayed without extraction. Replicates of five pooled sera (with E2 concentrations ranging from 80–800 pg/mL) were included in each assay. In 20 assays, the intra- and interassay coefficients of variation for these five pools ranged from 1.3–2.0% and from 6.7–9.3%, respectively.

Statistical analyses

All statistical analyses were performed using the SigmaStat Statistical Analysis System, version 1.01 (Jandel Scientific, Sausalito, CA). The changes in LH and E2 secretion in response to E2 benzoate or ZM or to the antiestrogen followed by E2 benzoate administration during the first 6 posttreatment days were tested by one-way repeated measures ANOVA followed by multiple comparisons (Bonferroni’s t test; comparison of all groups vs. the mean pretreatment levels as controls). The influences of the dose of ZM and the mean E2 concentrations in serum before the antiestrogen treatments on the increase in LH levels (expressed as a percentage of the mean pretreatment levels) were analyzed by linear regression and Pearson product-moment correlation. P < 0.05 was used as the limit of statistical significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In four experiments performed in three ovariectomized rhesus monkeys, ZM, administered im at doses up to 10 mg/kg, did not suppress LH secretion or GnRH pulse generator activity for the duration of monitoring, which was performed between 0–4 and 20–25 h after the treatment (Fig. 1Go), whereas it effectively antagonized the negative feedback action of exogenous E2 at the level of the pituitary gland (see below). This together with our earlier finding that E2 benzoate (84 µg/kg) given sc in peanut oil vehicle arrests GnRH pulse generator activity and inhibits LH secretion within the same time period (16, 17) indicate that ZM is devoid of estrogenic activity on gonadotropin secretion.



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  		Figure 1. Absence of an effect of ZM on LH secretion (top) or GnRH pulse generator activity (MUA; bottom) in an ovariectomized rhesus monkey. ZM was administered im at a dose of 10 mg/kg at time zero (closed triangle). MUA recording and blood sampling were continued for approximately 4 h and were repeated on the next day.

 
A single dose of 10 mg/kg ZM in peanut oil, however, given im to ovary-intact monkeys 12 h before the first E2 benzoate injection completely prevented the LH surge induced by the E2 benzoate regimen (Fig. 2BGo; n = 3), indicating that this estrogen receptor antagonist is a potent inhibitor of the effects of E2 even at high (>600 pg/mL) concentrations of the steroid. In these experiments, the injection of ZM was followed by a fall in LH levels coincident with peak E2 concentrations. The nature of this inhibition is discussed below.



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  		Figure 2. Effects of ZM on pituitary LH secretion in ovary-intact rhesus monkeys. A, E2 benzoate (EB) control (n = 4): effect of EB administered on days 4–6 of the menstrual cycle (open triangles) on serum E2 (lower trace; mean ± SEM) and LH concentrations (upper trace; mean ± SEM). Time zero corresponds to the evening of day 3 of the menstrual cycle. Note the characteristic LH surges. B, ZM control (n = 3): blockade of EB-induced LH surges by a single injection of ZM given 12 h before EB administration on day 0 (= evening of day 3 of the menstrual cycle; closed triangle). Note the absence of the LH surge and the reduction in serum LH concentrations. C, Effect of ZM alone (n = 16) on serum LH concentrations (compare with A). *, Significant differences from mean pretreatment levels (see text for experimental and statistical details).

 
The estrogen antagonist alone (Fig. 2CGo) did not induce a LH surge comparable to that effected by E2. It did, however, produce a small, but significant, rise in serum LH levels (P < 0.001) along with a sustained increase (~4 days) in serum E2 concentrations (P < 0.001). On further analysis, a significant positive correlation between the magnitude of the LH peak and serum E2 concentrations during the pretreatment period was observed (r = 0.663; P < 0.01). Therefore, we examined whether the small, positive response to ZM could be amplified by increasing circulating E2 concentrations by the sc implantation of E2-containing silicone capsules. In two of these experiments, the elevation of estrogen levels to 103 ± 6 and 119 ± 5 pg/mL (mean ± SEM) for 2 days before the antiestrogen treatment did not result in a further increase in the amplitude of the LH response relative to that in the animals without exogenous E2, with the highest LH data points (48.4 and 42.8 ng/mL) remaining considerably below typical peak levels detected by bioassay during estrogen-induced or spontaneous LH surges (>100 ng/mL) (15). Therefore, these experiments were pooled with those not involving the implantation of E2-containing capsules to create Fig. 2CGo, and the linear regression and correlation analyses were recalculated (amplitude of LH response vs. pretreatment E2 concentrations: r = 0.725; P < 0.001; Fig. 3Go). No correlation between the amplitude of the LH response and the ZM dose was observed (r = 0.063; P = 0.816). The magnitude of the LH rise also appeared to be independent of the timing of ZM administration (day 5, 6, or 7 of the menstrual cycle; Fig. 3Go). In the remaining two animals given E2 implants, very similar increases in serum E2 levels (115 ± 4 and 100 ± 6 pg/mL; mean ± SEM) themselves elicited LH surges starting 2.5 and between 3.5–4 days after the implantation (Fig. 4Go). In these instances, unlike when given before the estrogen stimulus (Fig. 2BGo), the antiestrogen injections administered after the surge had been initiated were unable to prevent these induced LH surges (Fig. 4Go).



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  		Figure 3. Relationship between the LH response to ZM, expressed as a percentage of the mean pretreatment LH levels, and pretreatment mean E2 concentrations (A) or the dose of the estrogen antagonist (B) analyzed by linear regression. Thin lines represent 95% confidence limits. Data from all experiments were pooled (n = 16; see text for details). ZM was administered between 0800–0900 h on day 5 (circle) or day 6 (triangle down), between 1600–1800 h on day 7 (triangle up), or after E2 pretreatment (square). Six clustered data points in B (x = 10 mg/kg; y {approx}200%) were separated along the abscissa for clarity. Note the positive correlation between pretreatment E2 levels, and the response to the antiestrogen and the absence of an effect of the ZM dose.

 


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  		Figure 4. ZM does not block the LH surge when administered after its initiation. The two animals (A and B) were implanted with E2-containing SILASTIC brand capsules on day 1 of the menstrual cycle and injected with 10 mg/kg ZM 4 days later (= day 0). Note that the LH surge started 2.5 days (A) and 3.5–4 days (B) after the implantation. Also note that the scale of the y-axis (LH concentration) in B is different from those used in A and in Fig. 2Go.

 
As mentioned above, in the control experiments depicted in Fig. 2BGo, the injection of ZM was followed by a fall in LH levels coincident with peak E2 concentrations. This inhibition probably reflects a suppression of GnRH pulse generator activity by E2 as described during the immediate presurge phase of normal monkey menstrual cycles (15), an action of the steroid that may not be antagonized by the antiestrogen. That this is indeed the case was demonstrated by the experiments illustrated in Fig. 5Go. In this experiment, the GnRH pulse generator was arrested by E2 administration, an effect that could not be blocked by ZM administered 24 h earlier, whereas the inhibitory action of exogenous E2 on GnRH-induced gonadotropin secretion was fully abolished by the antiestrogen, as evidenced by the pulsatile secretion of LH in response to the pulsatile administration of exogenous GnRH.



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  		Figure 5. Experiments in a representative ovariectomized monkey demonstrating that ZM blocks the inhibitory action of E2 at the pituitary gland and not the inhibition by E2 of the GnRH pulse generator. On day 1 (A), E2 (closed triangle) was administered iv at a dose of 500 ng/kg. The hypophysiotropic drive, suppressed by E2, was replaced with exogenous GnRH, given once every hour through a permanent central venous catheter in the form of bolus injections (0.1 µg; open triangles). On day 2 (not shown), ZM (10 mg/kg) was administered as a single im injection. On day 3 (B), the protocol followed on the first day was repeated. Note that on day 3 (B), ZM blocked the inhibitory action of E2 on pulsatile LH secretion; LH pulses were fully evident in response to exogenous GnRH, without relieving the inhibition of the GnRH pulse generator by the steroid.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present results do not support the hypothesis that the positive feedback action of E2 that culminates in the LH surge is simply the consequence of removal of the negative feedback effect of this steroid. The administration of the potent estrogen receptor antagonist ZM during the follicular phase of the menstrual cycle only resulted in a relatively small, transient rise in LH and a consequent elevation in E2 secretion, effects consistent with the blockade of the negative feedback action of the steroid and not with the initiation of a massive gonadotropin discharge. The amplitude of this response, when expressed as a percentage of mean pretreatment levels, was clearly dependent on mean E2 concentrations in the serum during the preinjection period, a finding probably reflecting increasing gonadotropin stores in the pituitary gland with rising estrogen levels (18, 19), raising the possibility that full-blown LH surges could be induced if the gonadotropes had been exposed to higher steroid concentrations for more prolonged periods before opening the negative feedback loop. Our experiments with sc implanted E2-containing capsules, however, failed to demonstrate a further increase in the amplitude of the LH peak despite the fact that serum E2 was elevated to 100–120 pg/mL, levels that alone can elicit unambiguous LH surges on occasion.

Recently, Levran et al. (6) suggested that in women, the LH surge is temporally related to the decrease in E2 concentrations and is, therefore, the consequence of removal of the negative feedback of this steroid. In that study, however, the actual time of initiation of the surge could not be determined because only the peak LH secretion was significantly different from the mean of the preceding two samples. Treating the peak as the initiation of the surge together with the low resolution of the study (LH and E2 were measured in daily samples) resulted in the impression that the rise in gonadotropin secretion followed the decline in E2 levels. This possibility has, however, been excluded in both rhesus monkeys (8, 20) and women (21, 22) by using more frequent blood-sampling regimens.

Interestingly, ZM was unable to prevent the full development of the LH surge when given after the initiation of the positive feedback action of E2 but about 12 h before the gonadotropin peak, although it exerted a complete blockade when injected 12 h before the start of surge-inducing treatments with E2 benzoate. That the absence of such an inhibition in the former was probably not due to insufficient drug levels resulting from its slow absorption from the oil-based vehicle is indicated by the fact that in other experiments, maximum LH responses to the antiestrogen were usually seen 12 h after its administration. Therefore, this finding extends our earlier conclusion that the continuing presence of the estrogen stimulus is required until the positive feedback is initiated (8) and also indicates that no further E2 action is necessary once the LH surge has started. The observation that the number of nuclear estrogen receptors in the pituitary gland of monkeys does not decrease at the time of the LH peak (23) suggests that the loss of estrogen dependency must be due to other mechanisms.

Our results in rhesus monkeys support the conclusion that ZM is a pharmacologically pure estrogen antagonist devoid of any residual estrogenic activity (11, 12, 24, 25, 26), even in the context of pituitary gonadotropin secretion (24). That ZM was able to antagonize the negative feedback action of endogenous E2 on pituitary gonadotropin secretion during the follicular phase was indicated by a small but significant rise in LH levels and a consequent elevation in serum E2 concentrations. Such an increase in E2 levels has also been described in premenopausal women in response to daily injections of 12 mg ZM (27). On the other hand, in intact rats, daily sc injections of the antagonist at doses that were able to reduce uterine weight to castrate levels did not appear to antagonize the inhibition of gonadotropin secretion by E2 (11), raising the possibility that ZM cannot block estrogen receptors in the hypothalamus (12), the primary site of E2 negative feedback in this species (28).

Our present data also indicate that ZM, a potent estrogen antagonist at the level of the pituitary gland, does not inhibit the action of the steroid on the GnRH pulse generator in the brain. While this could be explained by the failure of ZM to cross the blood-brain barrier (24, 29, 30), there is no evidence that such a mechanism pertains in the rhesus monkey. Moreover, it is also unknown whether the site of E2 action on the frequency of the GnRH pulse generator, a neuronal signal generator located in the mediobasal hypothalamus (31), is inside or outside the blood-brain barrier. Therefore, the possibility that E2 may not exert its effects on the GnRH pulse generator by way of its classical nuclear receptor, but, rather, via receptor sites on neural membranes (see Refs. 32, 33 for review) should also be considered. In any case, a ZM-resistant action of E2 via ERß, the recently discovered estrogen receptor protein (34), cannot be invoked because this antiestrogen has been reported to effectively inhibit E2 responses mediated by both ER{alpha} and ERß (35).


   Acknowledgments
 
The expert technical assistance of R. W. Thiagarajan, S. Tran, C. D. Williamson, and J. C. Woodhouse II is gratefully acknowledged. The authors are also very grateful to Dr. A. E. Wakeling of Zeneca Pharmaceuticals (Macclesfield, Cheshire, UK) for the generous gifts of ZM 182,780.


   Footnotes
 
1 This work was supported in part by NIH Grants HD-17438, HD-08610, and T32-HD-07324–07 and by the Ellwood Foundation. A preliminary report of this work was presented at the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, June 1997. Back

2 Current address: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Manville Building/351, Reno, Nevada 89557-0046. Back

3 Current address: Wyle Life Sciences, 1290 Hercules Drive, Suite 120, Houston, Texas 77058-2749. Back

4 Current address: Shanghai Institute of Endocrinology, Rui Jin Hospital, Shanghai No. 2 Medical University, 197 Rui Jin II Road, Shanghai 200025, Peoples Republic of China. Back

5 Current address: Department of Biology, Washington College, 300 Washington Avenue, Chestertown, Maryland 21620. Back

6 7{alpha}-[9-(4,4,5,5,5-Pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17ß-diol; alternative names: ICI 182,780, ZD9238, Faslodex. Back

Received June 2, 1998.

Revised July 23, 1998.

Accepted July 23, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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