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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1656
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 641-645
Copyright © 2006 by The Endocrine Society

Evidence That Termination of the Estradiol-Induced Luteinizing Hormone Surge in Women Is Regulated by Ovarian Factors

K. Dafopoulos, I. Mademtzis, P. Vanakara, A. Kallitsaris, G. Stamatiou, C. Kotsovassilis and I. E. Messinis

Departments of Obstetrics and Gynecology (K.D., I.M., P.V., A.K., I.E.M.) and Anesthesiology (G.S.), University of Thessalia, 41222 Larissa, Greece; and Clinical Chemistry Laboratory (C.K.), General Hospital of Athens "G. Gennimatas," 11527 Athens, Greece

Address all correspondence and requests for reprints to: Professor I. E. Messinis, Department of Obstetrics and Gynecology, University of Thessalia, 22 Papakiriazi Street, 41222 Larissa, Greece. E-mail: messinis{at}med.uth.gr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: The endogenous LH surge is the result of the estrogen-positive feedback effect. However, the factors that are responsible for the termination of LH surge are not known.

Objective: The objective of the study was to investigate the mechanism that terminates the LH surge in women.

Subjects and Methods: Eight normally cycling women (aged 42–48 yr) were investigated in two cycles, i.e. cycle 1 (control) and cycle 2. In cycle 2 total abdominal hysterectomy plus bilateral salpingooophorectomy was performed on d 3. In both cycles, estradiol was administered transdermally at the dose of 100 µg on d 3 and 150 µg on d 4 and 5. Blood samples were obtained every 12 h from d 3 to 5 and every 6 h thereafter until d 9.

Results: In both cycles, after suppression of gonadotropins, the women displayed an endogenous LH surge. The time intervals between the commencement of estradiol treatment and the LH surge onset (73.5 ± 1.5 vs. 76.5 ± 2.5 h) and peak LH values (11.4 ± 1.9 vs. 12.4 ± 3.1 IU/liter) were comparable in the two cycles (mean ± SEM). After peaking, LH values decreased gradually in cycle 1, whereas in cycle 2 they remained stable and were higher than the corresponding values in cycle 1 (P < 0.05). Before the LH surge onset, estradiol values showed in both cycles a preovulatory pattern of changes, but starting 24 h after the onset of the LH surge, they were lower in cycle 2 (P < 0.05). Progesterone levels were similar in both cycles until the day of the LH surge onset, but in cycle 2 they declined thereafter and were lower than in cycle 1 (P < 0.05).

Conclusions: It is suggested that ovarian factors rather than exhaustion of pituitary reserves are important for termination of the endogenous LH surge during the normal menstrual cycle.


   Introduction
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 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT HAS BEEN established that estradiol (E2) is the main component of the positive feedback mechanism that induces the occurrence of the endogenous LH surge at midcycle. Several studies have reproduced the triggering effect of E2 on LH secretion in experiments performed either during the follicular phase of the menstrual cycle or in postmenopausal women (1, 2, 3, 4, 5, 6). Progesterone alone is unable to express a positive feedback effect unless its administration is preceded by estrogen treatment (7, 8). In such cases, progesterone advances the onset and enhances the amplitude of the E2-induced LH surge (4, 6). It is likely that progesterone sensitizes the pituitary to GnRH because administration of the antiprogestagen mifepristone to normal women during the follicular phase of the cycle results in a reduction in the pituitary response to GnRH (9).

It is evident from these data that both the onset and amplitude of the midcycle LH surge are dependent on the ovarian steroids, although a gonadotropin surge-attenuating factor (GnSAF) may also play a role (10). However, the mechanism that is responsible for the termination of the E2-induced LH surge is not known. Exhaustion of the pituitary reserves is a possibility, but this has not been investigated. Another possibility is that the increasing progesterone values after the onset of the LH surge at midcycle may contribute to the surge termination, according to experiments in women including the exogenous administration of gonadal steroids (6). Nevertheless, the role of endogenous steroids has not been studied.

The present study was undertaken to investigate the role of the ovary in the termination of the E2-induced LH surge to gain further insight into the mechanisms that control gonadotropin secretion in women.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study included eight healthy women with normal menstrual cycles and no clinical evidence of climacteric transition, aged 42–48 yr. Characteristics of the women are shown in Table 1Go. The women were recruited from those undergoing total abdominal hysterectomy plus bilateral salpingooophorectomy for benign uterine lesions. All women volunteered for the study and gave written informed consent after careful explanation of the purpose of the study. Approval of the study was obtained from the local ethics committee. Ovulation was confirmed in all women by serum progesterone measurement and ultrasound scan of the ovaries before admission to the study. Each woman was investigated in two cycles, i.e. cycle 1 (control) and cycle 2 in which total abdominal hysterectomy plus bilateral salpingooophorectomy was performed under general anesthesia. The indication for the operation was benign lesions of the uterus, and the ovaries were normal as confirmed by histology. The operation was performed on cycle d 3 (0900 h). Between the two cycles, there was a month’s break. In both cycles, the women received E2 through skin patches at the dose of 100 µg on d 3 (0900 h) and 150 µg on d 4 and 5. In cycle 2, the first E2 patch was applied immediately after the operation. The purpose was to induce serum concentrations of E2 similar to those seen during the preovulatory period of the normal menstrual cycle. The dose of E2 was chosen on the basis of previously published data (11). Blood samples were obtained from all women in both cycles every 12 h from d 3 to 5 (0900 and 2100 h) and every 6 h (0900, 1500, 2100, and 0300 h) thereafter until d 9 (0900 h). FSH, LH, and E2 were measured in all blood samples. Progesterone was measured only in the daily morning samples. All blood samples were centrifuged at 1000 x g for 15 min, and the serum was stored at –20 C until assayed. Before the operation, all women were in good condition with hemoglobin levels greater than 12 g/dl. There were no complications during the operation, which in all cases lasted less than 90 min from the beginning to the end of the anesthesia. In all women, the estimated blood loss was less than 300 ml. The postoperative period was uneventful, and the women were in good condition when they were discharged home.


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  		TABLE 1. Characteristics of the women before the onset of the experiments on d 3 of cycle 1 (control)

 
Assays

Measurement of FSH, LH, and E2 in serum was performed using a chemiluminescent microparticle immunoassay (Architect FSH, Architect LH, and Architect estradiol, respectively; Abbott Laboratories, Abbott Park, IL). The results are expressed as international units per liter for FSH and LH and picograms per milliliter for E2. Progesterone was measured in serum using a microparticle enzyme immunoassay (AxSYM progesterone, Abbott Laboratories). The results are expressed as nanograms per milliliter. The lower limits of detection for FSH, LH, E2, and progesterone were 0.05 IU/liter, 0.07 IU/liter, 17.9 pg/ml, and 0.2 ng/ml, respectively. Inter- and intraassay coefficients of variation were 3.1 and 3.4%, 2.0 and 3.4%, 4.5 and 6.0%, and 6.0 and 6.7%, respectively.

Data analysis

Hormone values were normally distributed (one sample Kolmogoron-Smirnov test). Statistical analysis was performed by paired t test and repeated-measures one-way ANOVA followed by Bonferroni post hoc testing. All values are expressed as means ± SEM. An alpha level of 0.05 was used to determine statistical significance. The statistical software package used was SPSS (version 10.0; SPSS Inc., Chicago, IL).


   Results
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 Abstract
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 Subjects and Methods
 Results
Discussion
 References
 
Basal values of LH, FSH, and E2 before the onset of the experiments on cycle d 3 did not differ significantly between the two cycles (Fig. 1Go). As a result of E2 administration, serum E2 values increased significantly and similarly in both cycles, i.e. in cycle 1 from 84.8 ± 19.4 to 243.8 ± 23.4 pg/ml at 72 h (P < 0.001) and in cycle 2 from 71.1 ± 6.0 to 249.3 ± 33.8 pg/ml at 72 h (P < 0.001). The increase in E2 values led to a significant reduction in LH and FSH concentrations in both cycles. In particular, 66 h after commencement of E2 administration, serum LH and FSH values decreased in cycle 1 from 6.2 ± 0.9 to 2.6 ± 0.3 IU/liter (P < 0.001) and from 12.1 ± 2.4 to 5.0 ± 0.9 IU/liter, respectively (P < 0.05) and in cycle 2 from 7.3 ± 2.3 to 2.8 ± 0.7 IU/liter (P < 0.001) and from 14.3 ± 3.9 to 5.4 ± 1.6 IU/liter, respectively (P < 0.05). The percentage decrease of LH was similar to that of FSH at any time point in the two cycles (Fig. 2Go).


Figure 1
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  		FIG. 1. Serum LH, FSH, and E2 concentrations (mean ± SEM) during the administration of E2 to normal women (n = 8) in a control cycle (cycle 1; {circ}) and a subsequent cycle (cycle 2; •) in which total abdominal hysterectomy plus bilateral salpingooophorectomy was performed (d 3). E2 was given via skin patches at the dose of 100 µg on d 3 and 150 µg on d 4 and 5. (Conversion factor for E2 is 3.67.)

 

Figure 2
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  		FIG. 2. Percentage decrease in LH ({circ}) and FSH (•) values (mean ± SEM) during the administration of E2 to normal women (n = 8) in a control cycle (cycle 1) and a subsequent cycle (cycle 2) in which total abdominal hysterectomy plus bilateral salpingooophorectomy was performed (d 3). E2 was given via skin patches at the dose of 100 µg on d 3 and 150 µg on d 4 and 5.

 
After the suppression of LH and FSH values, all women displayed an endogenous LH surge. The characteristics of the surge are shown in Fig. 3Go. The first LH value that exceeded 180% of the mean value of the previous four samples was taken to indicate that the surge had started, and the time of the previous sample was considered to be the time of the LH surge onset (12). The time interval from the application of the first E2 patch to the onset of the LH surge was in cycle 1 (73.5 ± 1.5 h) similar to that in cycle 2 (76.5 ± 2.5 h). The pattern of changes in E2 values before the onset of the LH surge was similar in the two cycles with no difference between them. The LH surge started on average 6 h after the peak value of E2. After the onset of the LH surge, E2 values declined in both cycles with no significant difference between them during the first 18 h. This pattern of changes in E2 concentrations before and during the LH surge is similar to that seen before and during the midcycle LH surge of spontaneous cycles in women (13). However, E2 values 24 h after the onset of the LH surge up to the end of the experiment were in cycle 2 significantly lower than in cycle 1 (Fig. 3Go).


Figure 3
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  		FIG. 3. Serum LH, FSH, and E2 values (mean ± SEM) before and during an LH surge induced by exogenous E2 in normal women (n = 8) in a control cycle (cycle 1; {circ}) and a subsequent cycle (cycle 2; •) in which total abdominal hysterectomy plus bilateral salpingooophorectomy was performed (d 3). E2 was given via skin patches at the dose of 100 µg on d 3 and 150 µg on d 4 and 5. The data were normalized to the time of onset of the LH surge (time 0). *, P < 0.05; **, P < 0.001. (Conversion factor for E2 is 3.67.)

 
LH values before the onset of the LH surge did not differ significantly between the two cycles at any point (Fig. 3Go). In both cycles, an ascending limb of LH values that reached a peak at 18 h in cycle 1 (11.4 ± 1.9 IU/liter, P < 0.05) and 12 h in cycle 2 (12.4 ± 3.1 IU/liter, P < 0.05) was seen. However, there was no significant difference in the time interval from the LH surge onset to the peak LH between the two cycles. Also, in both cycles LH values did not differ significantly between 12 and 18 h. Thereafter in cycle 1 LH values decreased gradually and significantly up to 72 h (4.7 ± 1.0 IU/liter) from the onset of the surge (P < 0.05). In contrast, in cycle 2 after the peak, LH values remained stable with no trend to decrease up to 72 h (11.0 ± 0.7 IU/liter) from the onset of the surge. During the surge, LH values were similar in the two cycles for the first 36 h and higher thereafter in cycle 2, compared with cycle 1 (Fig. 3Go). The difference was significant at 54, 60, and 72 h (P < 0.05). At 72 h after the onset of the surge, LH value in cycle 1 (4.7 ± 1.0 IU/liter) was similar to that at the time of the onset of the surge (4.1 ± 0.7 IU/liter).

After the initial suppression, FSH values showed surge-like changes in cycle 1, but the surge was less clear than that of LH. In particular, an ascending limb of FSH with a peak value at 24 h (11.3 ± 1.9 IU/liter, P < 0.05) was seen (Fig. 3Go). Thereafter FSH values remained stable until the end of the experiment. In contrast, in cycle 2, serum FSH values increased continuously from the onset of the surge up to the end of the experiment. FSH values were similar in the two cycles before the onset and during the first 30 h of the surge, but significantly higher, thereafter in cycle 2 than cycle 1 at all time points (Fig. 3Go).

When the LH concentration area under the curve was calculated, a significant difference was observed between cycle 1 (15.6 ± 1.9 IU/liter per 18 h) and cycle 2 (24 ± 3.3 IU/liter per 18 h) from the time point of 54 h onward (P < 0.05) (Fig. 3Go). The FSH concentration area under the curve was significantly higher in cycle 2 (155.5 ± 23 IU/liter per 72 h) than cycle 1 (113.9 ± 17.5 IU/liter per 72 h) from the onset of the LH surge up to the end of the experimental period (P < 0.05) (Fig. 3Go).

Serum progesterone concentrations did not differ significantly in the two cycles before the onset of the LH surge (Fig. 4Go). However, progesterone values in cycle 2 showed a gradual decrease from the day of bilateral salpingooophorectomy (0.44 ± 0.04 ng/ml) up to the end of the experiment (0.28 ± 0.03 ng/ml) (P < 0.05) and were after the onset of the LH surge significantly lower than in cycle 1 (P < 0.05) (Fig. 4Go).


Figure 4
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  		FIG. 4. Serum progesterone values (mean ± SEM) before and during an LH surge induced by exogenous E2 in normal women (n = 8) in a control cycle (cycle 1; {circ}) and a subsequent cycle (cycle 2; •) in which total abdominal hysterectomy plus bilateral salpingooophorectomy was performed (d 3). E2 was given via skin patches at the dose of 100 µg on d 3 and 150 µg on d 4 and 5. The data were normalized to the time of onset of the LH surge (time 0). *, P < 0.05. (Conversion factor for progesterone is 3.18.)

 
All women in cycle 1 had withdrawal bleeding after the end of the experiment. Ovulation in that cycle was confirmed in all women by ultrasound 12–16 d after the end of the experiment and the women menstruated 12–14 d after ovulation.


   Discussion
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present results demonstrate that for the first 3 d after bilateral salpingooophorectomy in women, the pituitary functioned as if the ovaries were intact. In particular, the negative feedback effect of exogenous estrogen on basal LH and FSH secretion was clearly evident and of similar magnitude in both cycles, whereas the rise in gonadotropin concentrations expected after bilateral salpingooophorectomy (14) was inhibited. On the other hand, a positive feedback effect was induced by the rapidly rising E2 concentrations. It is interesting that neither the onset nor LH peak values of the induced LH surge were affected by bilateral salpingooophorectomy. In particular, these two characteristics of the surge were identical in the two cycles, suggesting that the factors that mediate the modulatory effect of the ovaries on the pituitary responsiveness to an appropriate estrogenic stimulus were still active during the immediate period after bilateral salpingooophorectomy. Previous research has indicated that a nonsteroidal substance, GnSAF, may play a role in the control of the amplitude of the LH surge (15, 16, 17). This factor is produced particularly by small growing follicles (18), i.e. in the early to midfollicular phase of the cycle (19), which in the present study corresponded to the immediate postoperative period. It is possible therefore that during that period bioactivity of GnSAF was still present in the circulation (20).

Although the E2-induced positive feedback effect during the control cycle resulted in a clear surge type of LH changes with an ascending and descending limb, in the cycle with bilateral salpingooophorectomy, the LH values during the surge after reaching a peak did not decline but remained stable. This difference in the configuration of the distal part of the LH surge between the two cycles indicates that the inability of LH values to return to the presurge level was related to the absence of the ovaries. This means that the termination of the LH surge is controlled by ovarian factors that in cycle 2 were eliminated from the circulation after bilateral salpingooophorectomy. Nonsteroidal and steroidal substances are possible candidates.

GnSAF is an attenuating factor, and therefore, an augmentation of the LH surge after the removal of the ovaries would be expected. The fact, however, that LH peak values were similar in the two cycles suggests also the presence of similar activity of GnSAF over the surge period. It is unlikely that a gradual elimination of GnSAF activity toward the end of the surge may be responsible for the maintenance of high LH levels after bilateral salpingooophorectomy because at midcycle the LH surge is clearly terminated despite an expected reduction in the activity of this factor during that period (10, 16, 18). On the other hand, even in cases with a markedly attenuated LH surge, such as in superovulated women, the surge is clearly characterized (12), suggesting thus that GnSAF is not the primary factor that terminates the LH surge. Other nonsteroidal ovarian factors, such as inhibins, are not considered potential candidates for the LH surge termination because these substances are inhibitors of only FSH and not LH secretion (21).

Because in the present study progesterone concentrations after the onset of the LH surge were significantly lower in the cycles with bilateral salpingooophorectomy than in the cycles with intact ovaries, it is probable that the inability of LH to return to the presurge level is related to the reduced progesterone levels. Previous research in women has suggested that progesterone may sensitize the pituitary gonadotrophs to GnRH, even at the low circulating concentrations during the follicular phase (9). It has also been shown that in ovariectomized and adrenalectomized rats treated with trilostane, estrogen-induced neuroprogesterone synthesis in hypothalamus is vital for the expression of the LH surge (22). On the other hand, after the exogenous administration of progesterone increasing values of this hormone facilitate the return of LH to the presurge level in a surge induced by exogenous estrogen (6). It is likely, therefore, that endogenous progesterone is important for the control of not only the onset (23) but also the amplitude of the midcycle LH surge partly via a contribution of rising progesterone values to the termination of the surge. Apart from progesterone, serum E2 values toward the end of the LH surge were also lower in the cycles with bilateral salpingooophorectomy than the cycles with intact ovaries. However, the extent to which this steroid might contribute to the declining pattern of LH values after the LH peak is unclear. Finally, it is rather unlikely that the termination of the endogenous LH surge in women is related to exhaustion of pituitary reserves because in the present study, LH secretion was uninterrupted at a high level after the removal of the ovaries.

The women included in this study were all in advanced reproductive age because for ethical reasons such experiments are not feasible in young individuals. Nevertheless, despite the compromised ovarian reserves, the results are valid because during cycle 1 the women were used as their own controls. Comparison of the present findings with those in postmenopausal women is difficult for the following reasons. The postmenopausal women are a different model with very high basal FSH and LH levels because the ovarian negative feedback mechanism is basically absent (24). Also, endocrinological studies in which exogenous estrogen and progesterone were administered to postmenopausal women did not have as an end point the termination of the LH surge (4, 5). Furthermore, these studies differ from the present study in that a strong negative feedback effect was reestablished with the maintenance of high E2 and progesterone concentrations during the whole experimental period (4, 5).

Besides pituitary, ovarian steroids affect hypothalamic GnRH secretion (25). In the present study, changes in frequency and amplitude of GnRH pulses as a result of alterations in steroids concentrations cannot be excluded; a pulsatility study may clarify this issue.

In conclusion, these results demonstrate for the first time that during the immediate period after bilateral salpingooophorectomy in the early follicular phase of the cycle, the pituitary in terms of onset and peak of the E2-induced LH surge behaves similarly to that in women with intact ovaries. After this period, ovarian factors eliminated from the circulation probably account for failure of peak LH values to return to basal level. It is suggested that termination of the endogenous LH surge is related to ovarian factors rather than exhaustion of pituitary reserves.


   Footnotes
 
The authors have no conflict of interest.

First Published Online December 6, 2006

Abbreviations: E2, Estradiol; GnSAF, gonadotropin surge-attenuating factor.

Received July 25, 2005.

Accepted November 21, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Tsai CC, Yen SS 1971 Acute effects of intravenous infusion of 17-ß-estradiol on gonadotropin release in pre- and post-menopausal women. J Clin Endocrinol Metab 32:766–771[Abstract/Free Full Text]
  2. Yen SS, Tsai CC 1972 Acute gonadotropin release induced by exogenous estradiol during the mid-follicular phase of the menstrual cycle. J Clin Endocrinol Metab 34:298–305[Abstract/Free Full Text]
  3. Leyendecker G, Wardlaw S, Nocke W 1972 Experimental studies on the endocrine regulations during the periovulatory phase of the human menstrual cycle. The effects of exogenous 17-oestradiol and progesterone on the release of pituitary luteinizing and follicle stimulating hormones. Acta Endocrinol (Copenh) 71:160–178[Abstract/Free Full Text]
  4. Liu JH, Yen SS 1983 Induction of midcycle gonadotropin surge by ovarian steroids in women: a critical evaluation. J Clin Endocrinol Metab 57:797–802[Abstract/Free Full Text]
  5. Lutjen PJ, Findlay JK, Trounson AO, Leeton JF, Chan LK 1986 Effect on plasma gonadotropins of cyclic steroid replacement in women with premature ovarian failure. J Clin Endocrinol Metab 62:419–423[Abstract/Free Full Text]
  6. Messinis IE, Templeton AA 1990 Effects of supraphysiological concentrations of progesterone on the characteristics of the oestradiol-induced gonadotrophin surge in women. J Reprod Fertil 88:513–519[Abstract/Free Full Text]
  7. Chang RJ, Jaffe RB 1978 Progesterone effects on gonadotropin release in women pretreated with estradiol. J Clin Endocrinol Metab 47:119–125[Abstract/Free Full Text]
  8. March CM, Goebelsmann U, Nakamura RM, Mishell Jr DR 1979 Roles of estradiol and progesterone in eliciting the midcycle luteinizing hormone and follicle-stimulating hormone surges. J Clin Endocrinol Metab 49:507–513[Abstract/Free Full Text]
  9. Kazem R, Messinis LE, Fowler P, Groome NP, Knight PG, Templeton AA 1996 Effect of mifepristone (RU486) on the pituitary response to gonadotrophin releasing hormone in women. Hum Reprod 11:2585–2590[Abstract/Free Full Text]
  10. Messinis IE 2003 Modulatory effect of the ovary on LH secretion. Ann NY Acad Sci 997:35–41[CrossRef][Medline]
  11. Messinis IE, Papageorgiou I, Milingos S, Asprodini E, Kollios G, Seferiadis K 2001 Oestradiol plus progesterone treatment increases serum leptin concentrations in normal women. Hum Reprod 16:1827–1832[Abstract/Free Full Text]
  12. Messinis IE, Templeton A, Baird DT 1985 Endogenous luteinizing hormone surge during superovulation induction with sequential use of clomiphene citrate and pulsatile human menopausal gonadotropin. J Clin Endocrinol Metab 61:1076–1080[Abstract/Free Full Text]
  13. Messinis IE, Templeton AA 1988 The endocrine consequences of multiple folliculogenesis. J Reprod Fertil Suppl 36:27–37[Medline]
  14. Alexandris E, Milingos S, Kollios G, Seferiadis K, Lolis D, Messinis IE 1997 Changes in gonadotrophin response to gonadotrophin releasing hormone in normal women following bilateral ovariectomy. Clin Endocrinol (Oxf) 47:721–726[CrossRef][Medline]
  15. Messinis IE, Templeton AA 1989 Pituitary response to exogenous LHRH in superovulated women. J Reprod Fertil 87:633–639[Abstract/Free Full Text]
  16. Messinis IE, Templeton AA 1991 Attenuation of gonadotrophin release and reserve in superovulated women by gonadotrophin surge attenuating factor (GnSAF). Clin Endocrinol (Oxf) 34:259–263[Medline]
  17. Pappa A, Seferiadis K, Fotsis T, Shevchenko A, Marselos M, Tsolas O, Messinis IE 1999 Purification of a candidate gonadotrophin surge attenuating factor from human follicular fluid. Hum Reprod 14:1449–1456[Abstract/Free Full Text]
  18. Fowler PA, Sorsa T, Harris WJ, Knight PG, Mason HD 2001 Relationship between follicle size and gonadotrophin surge attenuating factor (GnSAF) bioactivity during spontaneous cycles in women. Hum Reprod 16:1353–1358[Abstract/Free Full Text]
  19. Dafopoulos K, Kotsovassilis CG, Milingos S, Kallitsaris A, Galazios G, Zintzaras E, Sotiros P, Messinis IE 2004 Changes in pituitary sensitivity to GnRH in estrogen-treated post-menopausal women: evidence that gonadotrophin surge attenuating factor plays a physiological role. Hum Reprod 19:1985–1992[Abstract/Free Full Text]
  20. Messinis IE, Milingos S, Kollios G, Seferiadis K, Papanikolaou N, Lolis D 1996 Changes in pituitary response to gonadotropin-releasing hormone following bilateral ovariectomy in women treated with follicle-stimulating hormone. Gynecol Endocrinol 10:383–390[Medline]
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