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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 7 2233-2238
Copyright © 1997 by The Endocrine Society

Experimental Studies

Tonic Support of Luteinizing Hormone Secretion by Adrenal Progesterone in the Ovariectomized Monkey Replaced with Midfollicular Phase Levels of Estradiol1

Ennian Xiao, Linna Xia-Zhang, David Shanen and Michel Ferin

Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Michel Ferin, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although it is known that progesterone facilitates the estradiol-induced gonadotropin surge at midcycle, its effect on LH secretion at other times of the follicular phase remains to be investigated. In this study, we investigate the role of progesterone on tonic LH secretion in the ovariectomized primate replaced with estradiol at levels representative of the follicular phase. The experiments were performed in nine ovariectomized rhesus monkeys, either unreplaced with estradiol or after a 5-day estradiol therapy to mimic early follicular (10–36 pg/mL; low dose) and midfollicular (medium dose; 40–75 pg/mL) concentrations. We used two antiprogesterone compounds, RU-486 (5 mg) and ORG-31806 (1 mg), to antagonize endogenous progesterone activity and studied their acute effects on LH secretion in each group. LH concentrations were measured at 15-min intervals for a 3-h baseline period and during a 5-h period after antagonist administration. LH concentrations remained unchanged after either antiprogesterone compound or diluent (ethanol) administration in the estrogen-unreplaced monkeys or after low dose estradiol replacement. However, both antiprogesterone compounds significantly decreased LH secretion in monkeys pretreated with the medium dose of estradiol; by 5 h, the mean (±SE) areas under the LH curve were 54.8 ± 4.1% and 64.0 ± 4.2% after RU-486 and ORG-31806, respectively (P < 0.05 vs. unreplaced and low dose estrogen-replaced groups). To exclude the possibility that the LH response reflects an agonist action of the progesterone antagonist, LH responses to progesterone infusions (at three doses to reproduce preovulatory, luteal, and pharmacological levels) were also examined in monkeys pretreated with midfollicular levels of estradiol. In none of these was there a decrease in LH; rather, progesterone infusions resulted in an increase in LH secretion in all three groups (to 115–194% of baseline in seven of eight monkeys). Finally, we determined that at the dose used in our protocol, neither of the two progesterone antagonists was able to prevent dexamethasone-induced cortisol suppression, thus excluding the possibility that results after progesterone antagonist administration may reflect a putative antiglucocorticoid activity of these compounds. When the doses of the antiprogesterone compounds were increased 6 times, only RU-486 counteracted the effect of dexamethasone on cortisol.

In summary, our data indicate support by progesterone of tonic LH secretion in the nonhuman primate under estrogenic conditions similar to the midfollicular phase of the menstrual cycle. Significantly, because the experiments were performed in ovariectomized monkeys, and endogenous progesterone was most probably of adrenal origin, the data also demonstrate a role of the hypothalamo-pituitary-adrenal axis in support of gonadotropin secretion.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
STUDIES IN various species have demonstrated a role for progesterone in the control of LH secretion. Several reports, for instance, support a facilitative effect of progesterone on the spontaneous or estradiol-induced LH surge (1, 2, 3). RU-486, a progesterone antagonist (4), has indeed been shown to delay or block the LH surge when administered at the end of the follicular phase in humans (5) and monkeys (6). Other studies in which RU-486 was administered earlier in the follicular phase suggest that in addition to influencing the estradiol- related LH surge, progesterone may modulate tonic LH secretion during the follicular phase. Indeed, when administered during the midfollicular phase, RU-486 produces a delay in folliculogenesis and a decrease in estradiol secretion (7), both of which are presumably related to a decline in tonic gonadotropin secretion (8).

Although the ovary is not thought to secrete substantial amounts of progesterone during the follicular phase, recent data using sensitive assay methods have clearly demonstrated small, but detectable, amounts of circulating progesterone in women during that period of the cycle (9). The source of the steroid at that time was presumed to be the adrenal gland (9). Thus, the possibility exists that progesterone of adrenal origin may play a role in support of the tonic secretion of gonadotropin. To study this phenomenon in the absence of ovarian input, we used the ovariectomized (OVX) monkey as a model and studied the effects of two different progesterone antagonists, RU486 (4) and ORG-31806 (10), on pulsatile LH secretion in the presence of estradiol replacement that reproduces estrogen amounts observed during the early or midfollicular phase. To exclude the possibility that the results could be due to a putative progesterone agonist activity of the progesterone antagonist in the presence of estradiol, as has been speculated previously (6), we also report on the effects of progesterone infusions on LH secretion in the same animals. An additional experiment was performed to demonstrate that at the dose used in our protocols, the two progesterone antagonists do not exert any overt antiglucocorticoid action.


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

Nine adult female rhesus monkeys (Macaca mulatta), weighing 5–7 kg, were used in these experiments. The animals had been OVX at least 12 months before these studies. They were kept in individual cages in light (lights on, 0730–1930 h)- and temperature-controlled rooms and were fed once a day with Purina monkey chow (Ralston Purina, St. Louis, MO) and fresh fruit or vegetables. They had free access to water at all times. The experimental protocols were approved by the institutional animal care and use committee of Columbia University.

Experimental design

Exp 1. The effects of two antiprogesterone compounds, RU-486 (mifepristone, provided by Roussel-UCLAF, Romainville, France) and ORG-31806 (provided by NV Organon, Oss, The Netherlands), on LH secretion were investigated. Each compound was tested in OVX monkeys in the absence of estradiol replacement and after a 5-day estradiol therapy at two concentrations. For estradiol replacement, one SILASTIC capsule (SILASTIC brand tubing, Dow Corning, Midland, MI; id, 3.3 mm; od, 4.6 mm; length, 1 or 3 cm) was inserted sc under ketamine tranquilization. Each capsule had been filled with 17ß-estradiol (Steraloids, Wilton, NH) and preincubated for at least 24 h before implantation. RU-486 (5 mg) and ORG-31806 (1 mg) were dissolved in 0.5 mL ethanol and administered once im after the 3-h baseline control period. Control monkeys (nonreplaced and medium estrogen replacement) received an ethanol injection only. On the evening before the experiment, the monkeys were briefly tranquilized (15–30 min) with ketamine hydrochloride (5–7 mg/kg; Ketaset, Aveco Co., Fort Dodge, IA), and a catheter was inserted into the femoral vein for blood collection. They were then seated in a primate chair, to which they had previously been habituated. The experiment was initiated the next morning (0730–0800 h) and lasted 8 h. Blood samples (1.2 mL) were obtained at 15-min intervals for a 3-h baseline control period and a 5-h experimental period, and an equivalent amount of physiological saline was infused after each sample. The SILASTIC capsules were removed at the end of the experiment, and animals were returned to their home cage.

Exp 2. To exclude the possibility that the results of Exp 1 could be related to a putative progesterone agonist effect of the two antiprogesterone compounds, we also studied the effects of progesterone infusions on LH secretion in OVX monkeys pretreated with the higher dose of estradiol. A protocol similar to that employed in Exp 1 was used, except that a progesterone infusion replaced that of the progesterone antagonist. Three doses of progesterone were infused iv to produce serum levels of 0.85 \ 0.05 ng/mL (group 1; n = 3), 4.1 \ 0.29 (group 2; n = 3), and 18.3 \ 0.23 (group 3; n = 2). The progesterone (ICN Biochemical, Cleveland, OH) stock solution was prepared, as described previously (11), and diluted with normal saline containing 10% monkey plasma. Infusion of progesterone was initiated after a 3-h baseline control period and continued for the 5-h experimental period.

Exp 3. To evaluate whether the results of Exp 1 reflect a putative antiglucocorticoid activity of either of the two antiprogesterone compounds, an additional experiment was performed. Dexamethasone (0.4 mg, im; Lyphomed, Deerfield, IL) alone or together with two doses (equal to that in Exp 1 and 6 times that dose) of RU-486 or ORG-31806 was administered at 1900 h to free moving caged monkeys. Blood samples were obtained by venous puncture at 0800, 0900, and 1000 h on the next day, and the cortisol response to dexamethasone was measured.

Assays and statistical analysis

After centrifugation, sera were stored at -20 C until assay. LH was measured using a homologous RIA method (12). Estradiol, progesterone, and cortisol were also measured by RIA (Coat-A-Count, Diagnostic Products, Los Angeles, CA). Before the progesterone RIA, samples were extracted with petroleum ether (Aldrich Chemical Co., Milwaukee, WI); the extraction recovery rate was 94.2 \ 2.1%. Intraassay coefficients of variation were 6.6% (LH), 2.9% (cortisol), 3.0% (estradiol), and 4.8% (progesterone); interassay coefficients of variation were 13.3% (LH), 6.1% (cortisol), 11.0% (estradiol), and 9.1% (progesterone).

Hourly areas under the LH curve during the 5-h experimental period were calculated and expressed as a percentage of the 3-h baseline control period. The posttreatment percent change in different treatment groups was then analyzed by the Kruskal-Wallis ranking test, followed by Tukey’s test. Student’s t test was used to compare control morning baseline cortisol concentrations with those obtained after dexamethasone alone or in combination with RU-486 or ORG-31806.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Exp 1

LH remained unchanged after the administration of either progesterone antagonist (RU-486 or ORG-31806) to OVX monkeys in the absence of estrogen replacement or after the lower 5-day estradiol replacement therapy (1-cm SILASTIC capsule; early follicular phase levels; Fig. 1Go, left and center panels). In contrast, both antagonists acutely decreased LH secretion after the medium estradiol replacement therapy (3-cm SILASTIC capsule; midfollicular phase levels; Fig. 1Go, right panels). By 5 h after administration of the progesterone antagonist, the mean area under the LH curve was 54.8 \ 4.1% (\SE) of the 3-h baseline period and 64.0 \ 4.2% after RU-486 and ORG-31806, respectively (P < 0.05 vs. ethanol, unreplaced or low estrogen groups). Table 1Go summarizes mean estradiol concentrations in all groups and overall LH concentrations before and after progesterone antagonist administration. Figure 2Go illustrates the effects of the progesterone antagonists in two monkeys. Progesterone concentrations did not significantly differ between groups. Overall, the mean morning baseline concentration was 88 \ 9.7 (\SE) pg/mL, whereas the posttreatment afternoon concentration was 67 \ 7.3 pg/mL.



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  		Figure 1. LH responses to ethanol (top panels), RU-486 (5 mg; middle panels), and ORG-31806 (1 mg; lower panels). Diluent or progesterone antagonist were administered to steroid-unreplaced OVX monkeys (left panels) or after 5-day therapy with estradiol (E) to mimic early follicular phase levels (low E; range, 10–36 pg/mL) or midfollicular phase levels (medium E; range, 40–75 pg/mL). The LH response is illustrated as the hourly area under the LH curve (mean ± SE), expressed as a percentage of the value during the 3-h baseline control period. Both progesterone antagonists acutely decreased tonic LH secretion in the presence of midfollicular phase levels of estradiol, but not with lower estradiol replacement or in the absence of estrogen (a, P < 0.05 vs. no E and low E; b, P < 0.05 vs. ethanol).

 

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  		Table 1. Estradiol (E) concentrations and overall baseline (3-h) and response (5-h) of LH in the control ethanol and progesterone antagonist groups

 


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  		Figure 2. LH responses to RU-486 (5 mg; left panels) or ORG-31806 (1 mg; right panels) in two OVX monkeys without (upper panels) or with a 5-day estradiol pretreatment that reproduced early follicular phase (middle panels) or midfollicular phase (lower panels) estradiol concentrations. The horizontal linerepresents mean LH baseline values. Note the acute LH decrease after treatment with either progesterone antagonist in the animals with midfollicular phase estradiol concentrations.

 
Exp 2

In none of the three groups receiving different amounts of progesterone did we observe a decrease in LH secretion within the 5-h experimental period (mean estradiol concentration in all three groups, 58.7 \ 3.6 pg/mL). Instead of a LH decrease, we observed an increase in LH in all eight monkeys, independent of the progesterone dose. This LH increase ranged from 115–194% of baseline by 5 h in seven animals. One monkey showed a larger increase of 430%. Figure 3Go illustrates the mean hourly LH changes over baseline during the 5-h progesterone infusion in seven of eight animals.



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  		Figure 3. Mean (±SE) LH response (illustrated as the hourly area under the LH curve, expressed as a percentage of the 3-h baseline control value) to 5-h iv progesterone infusions in seven estrogen-replaced (E; 58.7 ± 3.6 pg/mL) monkeys. As an increase in LH occurred in all animals independent of the progesterone dose, results were pooled. The eighth animal was excluded because, although it also showed a LH increase, this increase (430%) was well outside the range of response in the other seven animals. In none of the animals was there a LH decrease such as that observed with the progesterone antagonist, thus excluding the possibility that the inhibition of LH observed in Figs. 1Go and 2Go is related to an agonist effect of the progesterone antagonists.

 
Exp 3

Administration of dexamethasone at 1900 h inhibited cortisol secretion. At 1000 h the next morning, for instance, the mean ( \ SE) cortisol concentration was 4.3 \ 0.6 µg/dL after dexamethasone treatment vs. 21.3 \ 2.4 in controls (P < 0.05; Fig. 4Go). This inhibitory effect of dexamethasone was still present when it was coadministered with RU-486 at the 5-mg dose (4.6 \ 1.1 µg/dL) or with ORG-31806 at the 1-mg (5.9 \ 1.2) or 6-mg (5.3 \ 1.5) dose. At the dose of 30 mg, RU-486 counteracted this inhibitory effect; at 1000 h, the cortisol concentration was 22.7 \ 7.3 (P = NS vs. control).



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  		Figure 4. Mean (±SE) cortisol concentrations after dexamethasone (DEX; 0.4 mg administered at 1900 h on the evening of the previous day) alone or in combination with the progesterone antagonist RU-486 (RU; 5 or 30 mg/animal administered at the same time as DEX; left panel) or ORG-31806 (ORG; 1 or 6 mg administered at the same time as DEX; right panel). Closed circles represent control morning cortisol concentrations in untreated OVX monkeys. As expected, DEX inhibits cortisol secretion; this inhibition is unaffected by RU (5 mg) or ORG (1 or 6 mg). However, RU at the dose of 30 mg significantly prevents this effect. *, P < 0.05 vs. controls.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our data show a significant decrease in tonic pulsatile LH secretion after the administration of either of two progesterone antagonists to OVX monkeys pretreated with estradiol for 5 days to mimic estrogen concentrations typical of the midfollicular phase of the cycle. The observed decrease in LH concentrations after RU-486 or ORG-31806 treatment is rapid and observed by 3 h after injection of the progesterone antagonist. This inhibitory effect is not present when either antagonist is given to steroid-unreplaced animals or with lower estradiol concentrations representative of the early follicular phase.

Several studies in the human and the nonhuman primate have investigated the effects of RU-486 on the menstrual cycle, although most of these have focused on the time of the cycle when progesterone production is maximal, i.e. the luteal phase (13, 14, 15, 16) or the late follicular phase (5, 6, 17). In the first of two studies in which RU-486 was administered during the midfollicular phase after the emergence of the dominant follicle, investigators reported a decline in serum estradiol concentrations accompanied by a decrease in the size of the dominant follicle and a delay in the onset of the gonadotropin surge (7). Although no significant effects of RU-486 on LH or FSH were observed, this probably reflected the paucity of blood sampling early in the experiment. Indeed, a second study in the human clearly demonstrated that, as in our estradiol-pretreated OVX monkeys, administration of RU-486 in the midlate follicular phase produces a substantial reduction in plasma LH (8). Significantly, as in our experiment, the reduction was dependent upon the initial plasma estradiol concentration. The arrest in the growth of the dominant follicle and the decreased estradiol secretion observed in the first study (7) may then have reflected the dependence of the follicle on gonadotropin support at this stage of development. This conclusion is supported by the demonstration that a short term blockade of pulsatile LH secretion by a GnRH antagonist during the follicular phase results in a transient arrest in the ongoing process of follicular maturation and, hence, a decrease in estradiol secretion (18). Chronic RU-486 administration during the follicular phase also effectively suppresses folliculogenesis (19). In accord with the above data, our study in the nonhuman primate indicates a role for progesterone in the maintenance of tonic pulsatile LH secretion during the normal follicular phase.

The mechanism by which progesterone may act to modify tonic LH concentrations remains to be investigated. Because of the short term observation period, we could not ascertain whether the decrease in LH concentrations relates to a change in LH pulse frequency or pulse amplitude. Animal studies have demonstrated a stimulatory effect of progesterone on hypothalamic GnRH release (20, 21) and GnRH messenger ribonucleic acid levels (22), suggesting a possible hypothalamic site of action. However, a pituitary site cannot be discounted. What most studies have clearly indicated is that estrogen is an obligatory requirement for progesterone-stimulated GnRH release (20, 21, 22, 23). This is also clear from our data and from reports in the human (8), in that the effectiveness of RU-486 to decrease tonic LH release depends upon the presence of estradiol concentrations above a critical level. Indeed, there was no change in LH after RU-486 treatment in the steroid-unreplaced OVX animal or in the presence of early follicular phase-like concentrations. Although there are some reports that hypothalamic areas of spayed monkeys or hamsters still contain some progesterone receptor-positive cells (24, 25), in most species hypothalamic progesterone receptor activity is lacking in OVX animals, but increases dramatically after estradiol treatment (24, 26, 27, 28). Thus, it may be speculated that the absence of an effect by the antiprogesterone in individuals lacking the critical estradiol concentrations may reflect suboptimal activity of the progesterone receptor. Unfortunately, there is no report in the literature quantifying hypothalamic or pituitary progesterone receptor activity throughout the menstrual cycle. Alternatively, it is also possible that critical levels of estradiol are required to induce the formation of intermediary substances necessary for progesterone’s action on GnRH and/or LH release.

Of specific relevance is the fact that our experiments were performed in OVX estrogen-replaced animals, suggesting that the progesterone antagonist must block the effect of progesterone from a source other than the ovary, probably progesterone of adrenal origin. Thus, in this particular nonhuman primate model, the data may well suggest a role for adrenal progesterone in support of tonic LH secretion. What relevance this conclusion may have to events of the follicular phase is highlighted by observations in women that the source of small, but significant, amounts of progesterone during the follicular phase is likely to be the adrenal rather than the ovary (9). Indeed, in contrast to the luteal phase (29), during the follicular phase there is no relationship between LH and progesterone pulses, and dexamethasone totally suppresses serum progesterone as well as cortisol, suggesting that ACTH is the stimulus for pulsatile progesterone release. The data for progesterone antagonists in intact women together with our results in the OVX monkey may then indicate a putative role of the hypothalamic-pituitary-adrenal axis in support of the hypothalamic-pituitary-gonadal axis and of tonic gonadotropin secretion during a critical period of folliculogenesis. One important caveat remains, however, in that it cannot a priori be concluded that a 5-day estrogen replacement therapy in a long term OVX monkey entirely mimics the follicular phase.

Although both RU-486 and ORG-31806 have been used successfully in a variety of experiments to antagonize progesterone action (13, 14, 15, 16, 17), there are some reports that, for example, RU-486 may under specific estrogen conditions exert weak progestational effects on proliferative endometrium (6, 30, 31). Our data showing a lack of inhibitory effect on LH of progesterone infusions (at levels covering concentrations representative of the preovulatory period, the luteal phase, and the pharmacological range) exclude the possibility that the decrease in LH after the administration of either progesterone antagonist is the result of a putative agonist effect, at least within the 5-h experimental period.

Besides its antiprogesterone properties, RU-486 is known for its antiglucocorticoid action (32). For instance, it has been found to inhibit the negative feedback effect of dexamethasone (33) and at a dose of 3 mg/kg has been observed to increase cortisol secretion (13). However, we do not believe that the inhibitory effects of the antiprogesterone compounds on tonic LH secretion observed in this report are due to their antiglucocorticoid action. Indeed, at the dose used in our experiment (5 mg/monkey), RU-486 is unable to prevent dexamethasone-induced cortisol suppression. Further, a similar inhibition of tonic LH is obtained with ORG-31806, another progesterone antagonist, which at the dose used (about one fifth the dose of RU-486) is equally unable to prevent the inhibitory action of dexamethasone on the hypothalamic-pituitary-adrenal axis.

In conclusion, our data suggest a putative role of the hypothalamic-pituitary-adrenal axis, through its secretion of progesterone, in maintaining tonic LH secretion in the OVX monkey replaced with mid- to late follicular phase levels of estradiol. Whether a similar effect of the hypothalamic-pituitary-adrenal axis occurs during the follicular phase remains to be investigated.


   Acknowledgments
 
The authors thank Roussel-UCLAF (Romainville, France) for their generous gift of RU-486, and NV Organon (Oss, The Netherlands) for their generous gift of ORG-31806. They also thank Dr. A. F. Parlow (Harbor University-University of California-Los Angeles Medical Center) and the National Hormone and Pituitary Program, the NIDDK, the NICHHD, and the USDA for providing the reagents for the homologous monkey LH RIA.


   Footnotes
 
1 This work was supported by NIH Grants DK-39144 and HD-33003. Back

Received October 7, 1996.

Revised March 26, 1997.

Accepted March 28, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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M. Mizuno, M. Gearing, and E. Terasawa
The Role of Neuropeptide Y in the Progesterone-Induced Luteinizing Hormone-Releasing Hormone Surge in Vivo in Ovariectomized Female Rhesus Monkeys
Endocrinology, May 1, 2000; 141(5): 1772 - 1779.
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