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Endocrinology Vol. 139, No. 8 3480-3484
Copyright © 1998 by The Endocrine Society

ARTICLES

Luteal Dysfunction in Ewes Induced to Ovulate Early in the Follicular Phase1

William J. Murdoch and Edward A. Van Kirk

Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071

Address all correspondence and requests for reprints to: Dr. W. J. Murdoch, Department of Animal Science, P.O. Box 3684, University of Wyoming, Laramie, Wyoming 82071. E-mail: wmurdoch{at}uwyo.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The purpose of this investigation was to determine whether the timing of ovulation induction during the follicular phase is a determinant of consequent luteal function. Ewes were treated on day 14 of the estrous cycle with PGF2{alpha} to synchronize luteal regression and 12 or 36 h later with an ovulatory dose of GnRH. Luteal phase serum progesterone concentrations of normal magnitude were characteristic of animals elicited to ovulate by GnRH injection 36 h after PGF2{alpha} treatment. Follicles stimulated at 12 h of the induced follicular phase formed subfunctional corpora lutea that were deficient in large steroidogenic cells. Endometrial gland development was attenuated in ewes exhibiting luteal insufficiency. The pathophysiology of the luteal defect was associated with a retrospective lack of granulosal cells in preovulatory follicles not adequately primed by estradiol. Preovulatory LH surges were not affected by the time of GnRH treatment. Corpus luteum rescue indicative of maternal recognition of pregnancy occurred in inseminated ewes that were injected with GnRH 36 h after PGF2{alpha}. Gonadotropic stimulation 12 h after PGF2{alpha} typically resulted in gestational failure; a marginal improvement in the pregnancy rate was attained by progesterone supplementation. We suggest that premature induction of ovulation compromises the estrogen-mediated succession of granulosal cell proliferative events that necessitate the formation of a fully competent corpus luteum.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ABILITY to stimulate ovulation with hormones has been used extensively to regulate mammalian fertility (1, 2, 3). Unfortunately, ovulatory therapy can result in the formation of dysfunctional corpora lutea (4). Inadequate luteal function (progesterone deficiency) is a presumptive causal factor in pregnancy failure (5); progesterone stimulates the development of secretory endometrial glands that sustain the preimplantation embryo (6). The etiological basis of luteal endocrinopathy relative to ovulation induction is uncertain.

Small and large steroidogenic cells of the corpus luteum are derived from the theca interna and membrana granulosa of the ovulatory follicle, respectively (7). An experimental paradigm in the sheep is described in which stimulation of ovulation with GnRH early in the follicular phase is a prelude of granulosal lutein insufficiency.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal procedures were performed with the approval of the University of Wyoming animal care and use committee. Tissue excisions were made at death (by iv Beuthanasia, Schering-Plough Animal Health, Kenilworth, NJ). Reagents were purchased from Sigma Chemical Co. (St. Louis, MO) unless indicated otherwise.

Ovulation induction
Mature western-range ewes were observed twice daily for estrous behavior in the presence of vasectomized rams. Day 0 was considered the first day of estrus. Ewes were treated on day 14 of the estrous cycle with a luteolytic dose of PGF2{alpha} (5 mg dinoprost tromethamine, im; Upjohn, Kalamazoo, MI) followed by an agonistic analog of GnRH (5 µg des-Gly10-Ala6 ethylamide, im) 12 or 36 h later (natural gonadotropin surges commence at about 40 h). Ovulation occurs approximately 24 h after the administration of GnRH (8).

Exp 1
Six ewes were included in each GnRH treatment group. Jugular blood samples were collected by venipuncture daily from days 2–12 after GnRH injections (or after the onset of estrus during unmanipulated cycles; n = 6) and were analyzed for concentrations of progesterone in serum by RIA (9). Ovaries and uteri were removed on day 12. Corpora lutea were dissected and weighed. A small portion of luteal tissue was frozen and assayed for progesterone concentration (10). The remaining segments of luteal tissues and two samples of endometrium isolated from each uterine horn were immersed in Histochoice (Amresco, Solon, OH) fixative for 48 h, washed in PBS, dehydrated in a graded series of ethanol, cleared in xylene, and infiltrated with paraffin. Embedded specimens were sectioned at 5-µm thickness, transferred onto microscope slides, rehydrated, stained in hematoxylin and eosin, dehydrated, and coverslipped with Permount. Light microscopic (Olympus BH-2) computer-assisted image analyses (Optimas, Bothell, WA) were performed on eight random areas from each corpus luteum (percentage of large cells; magnification, x400) and four areas from each intercaruncular endometrial specimen (percentage of secretory glands; magnification, x200).

Exp 2
The dominant preovulatory follicle was isolated from ovaries 20 h after GnRH injections (n = 6). Follicles were hemisected, and diameters of antral cavities were estimated. Tissues were prepared for light microscopic morphometric examination; the numbers of theca interna and granulosal cells associated with the basement membrane along a 200-µm length were counted within eight random cross-sections of follicular wall.

Exp 3
Jugular serum samples to be assayed for concentrations of 17ß-estradiol (11) were obtained at 6-h intervals beginning at PGF2{alpha} administration and continuing until 12 h after GnRH injections (n = 6).

Exp 4
Jugular serum samples to be assayed for concentrations of LH (12) were collected at 1-h intervals for 8 h after GnRH injections (n = 6).

Exp 5
Preovulatory follicles were dissected 12 h after PGF2{alpha}, hemisected, and incubated in 1 ml medium 199 containing 10% FCS with or without 0.25 µg 17ß-estradiol (n = 8) for 24 h at 37 C; the selected dose of 17ß-estradiol was within the range of pregonadotropin surge follicular fluid concentrations (13). Thecal and granulosal cells were quantitated as described for Exp 2.

Exp 6
Ovaries were examined for ovulation points, and ipsilateral intrauterine inseminations (2.5 x 107 M1105–302 motile sperm cells; ExCell Breeders International, Bismarck, ND) were performed via laparoscopy (iv sodium thiopental anesthesia) 28 h after administrations of GnRH (n = 5). Jugular serum samples for progesterone analysis were obtained on days 10–20 after GnRH treatment.

Exp 7
Inseminated ewes that were induced to ovulate prematurely were supplemented (day 4 after GnRH) with progesterone (Eazi-Breed CIDR intravaginal device; InterAg, Hamilton, NZ) or were not treated (n = 6). Jugular serum samples for progesterone analysis were collected on days 5, 8, 11, and 14. On day 14, uteri were removed, and the numbers of corpora lutea were noted. Each uterine horn was cut open lengthwise and inspected for filamentous embryonic tissues (elongated blastocysts).

Statistics
Hormonal patterns were contrasted using a split-plot ANOVA procedure (14). Subsample morphometric data were averaged for each animal. Two-group mean comparisons were made using Student’s t test. Treatment differences were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Exp 1
Circulatory progesterone concentrations were depressed after exogenous gonadotropic stimulation at 12 h compared with those 36 h after the initiation of luteolysis. Progesterone concentrations in serum of animals treated with GnRH 36 h after PGF2{alpha} were similar to those during control estrous cycles (Fig. 1Go).



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  		Figure 1. Luteal phase serum concentrations of progesterone in untreated control ewes and in ewes treated with GnRH 12 or 36 h after PGF2{alpha}. The mean ± SE are plotted. Serum progesterone levels were lower (P < 0.01) in animals induced to ovulate early in the follicular phase.

 
Rates of ovulation, based on numbers of corpora lutea on day 12, were not different between GnRH treatment groups (Fig. 2Go). Corpora lutea formed from ovulations stimulated at 12 h were smaller and contained less progesterone than tissues generated from follicles stimulated at 36 h of the follicular phase (Fig. 2Go). Luteal and endometrial tissues of ewes induced to ovulate early were deficient in large steroidogenic cells (Figs. 2Go and 3Go) and glands (Figs. 2Go and 4Go), respectively.



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  		Figure 2. Effects of timing of ovulation on functional parameters (day 12) of luteal and endometrial tissues (*, P < 0.05; **, P < 0.01).

 


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  		Figure 3. Representative light photomicrographs (x200) of day 12 corpora lutea of ewes injected with GnRH 12 h (upper panel) or 36 h (lower panel) after PGF2{alpha}. Note the relative lack of large cells (arrows) in the premature ovulation group.

 


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  		Figure 4. Representative photomicrographs (x100) of intercaruncular endometrial tissues of ewes injected with GnRH 12 h (upper panel) or 36 h (lower panel) after PGF2{alpha}. Note the relative lack of glandular (G) development in the premature ovulation group. L, Uterine lumen.

 
Exp 2
The diameters of the dominant follicle collected 32 or 56 h after the administration of PGF2{alpha} were not significantly different. Likewise, there were no temporal differences in numbers of theca interna cells contiguous with the follicular basement membrane (Fig. 5Go). There was a deficit of granulosal cells within follicles of the early ovulation induction group (Figs. 5Go and 6Go).



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  		Figure 5. Preovulatory follicular characteristics 20 h after GnRH treatments 12 or 36 h following the administration of PGF2{alpha}. *, P < 0.05.

 


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  		Figure 6. Representative photomicrographs (x200) of follicular walls of 12-h (upper panel) and 36-h (lower panel) GnRH stimulation groups. Note the comparative deficiency of granulosal (G) cells in the premature ovulation group. T, Theca interna.

 
Exp 3
A salient rise in systemic 17ß-estradiol concentrations within the 12-h period after administration of PGF2{alpha} was abruptly curtailed by GnRH injection. Elevated circulatory levels of 17ß-estradiol were sustained for an additional 24-h period in ewes in which treatment with GnRH was delayed until 36 h after PGF2{alpha} administration (Fig. 7Go).



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  		Figure 7. Jugular serum concentrations of 17ß-estradiol during the preovulatory period of ewes treated with GnRH at 12 or 36 h during the follicular phase.

 
Exp 4
There were no significant differences in the magnitudes or durations of LH surges due to the timing of GnRH injections (Fig. 8Go).



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  		Figure 8. Jugular serum concentrations of LH after the injection of GnRH at 12 or 36 h during the follicular phase; patterns are not significantly different.

 
Exp 5
Exposure of explanted follicular walls to 17ß-estradiol caused a proliferative response among granulosal (but not theca interna) cells (Fig. 9Go); the numbers of cells were comparable to those observed in preovulatory follicles obtained 56 h after PGF2{alpha} treatment (Exp 2).



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  		Figure 9. In vitro effect of 17ß-estradiol on granulosal cell mitogenesis. *, P < 0.01.

 
Exp 6
An extension of luteal function indicative of pregnancy occurred in inseminated ewes given GnRH 36 h after PGF2{alpha}. Depressed serum profiles of progesterone and ensuant luteal regression were evident following GnRH stimulation 12 h after PGF2{alpha} (Fig. 10Go). Ovulation rates (presence of corpora hemorrhagica) were similar in 12- and 36-h GnRH treatment groups (2.3 ± 0.8 vs. 2.2 ± 0.8).



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  		Figure 10. Circulatory progesterone during the prospective period of pregnancy recognition in inseminated ewes that were treated with GnRH at 12 or 36 h during the follicular phase (P < 0.01).

 
Exp 7
Peripheral concentrations of serum progesterone were elevated by intravaginal supplementation (Fig. 11Go). One conceptus was identified among the six ewes not given progesterone. Four embryos were observed among three of six ewes treated with progesterone. A total of 13 corpora lutea were represented within each group.



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  		Figure 11. Effect of intravaginal (IV) progesterone delivery on jugular venous progesterone in ewes induced to ovulate prematurely (P < 0.01).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Luteal disorders that have been associated with infertility include the short lived corpus luteum and luteal phase insufficiency (5, 15, 16). A precocious luteolytic stimulus is the apparent cause of abbreviated luteal phases. The more common problem of luteal phase insufficiency is characterized by reduced progesterone output within a cycle of normal duration. A number of theories have been proposed to explain the basis of luteal phase insufficiency: a suboptimal preovulatory gonadotropin surge, defective follicular cell maturation, and/or diminutive luteotropic support.

The primary luteal defect observed in our study was related to an inherent lack of follicular development at the time of ovulation. We believe that inadequate priming of the preovulatory follicle by estradiol, precipitated by a premature surge release of gonadotropins (Ref. 13 and the present study), underscored the granulosal lutein abnormality. Granulosal cell proliferation is up-regulated in preovulatory follicles (17) by estradiol (Refs. 18, 19, 20 and the present study). Whether spontaneous luteal insufficiencies are commensurate with the innate timing of the preovulatory gonadotropin surge is unknown.

Given that estradiol enhances pituitary sensitivity to GnRH (21), it was somewhat surprising that the induced LH surge was not affected by an abbreviated follicular phase; perhaps this is related to the fact that a potent GnRH agonist was used and/or that a relatively short exposure to estradiol is sufficient to prime a full surge. That postovulatory luteotropin was rate limiting to progesterone output seems unlikely in that (predominate) small (LH-responsive) (7) cells were evidently carrying the functional load of the luteal gland (i.e. complete luteal collapse would otherwise have been expected). A lack of luteal responsiveness to LH due to insufficient follicular estradiol exposure (22), failure of large luteal cell differentiation (23), and/or depressed LH production during metestrus are potential causes of luteal malfunction (24).

The concepts that progesterone deficiency during early pregnancy predisposes to abortion and that hormonal replacement prevents embryonic loss are not novel. Notwithstanding, reported improvements in fertility as a result of treatments with supplemental progesterone have been mixed (5, 16, 25). Our findings indicate only a partial advantage of exogenous progesterone in reversing the detrimental effect of premature ovulation on pregnancy. Thus, it appears that luteal phase dysfunction is only a singular symptom of a multifaceted syndrome associated with inappropriate timing of an ovulatory stimulus. Ovulation of an ovum that is not properly aged at the time of conception could be of intrinsic significance. Indeed, preliminary studies indicate that preovulatory follicles of ewes treated with GnRH 12 h after PGF2{alpha} yielded oocytes of poor blastogenic capacity upon fertilization in vitro.

The potential to reproduce is a matter of timing. The results of this investigation demonstrate that formation of granulosa-deficient corpora lutea that compromise pregnancy outcome is an aftereffect of the induction of ovulation early in the follicular phase of ewes. Experiments are underway to examine the possible contributing role of oocyte maturational deficiencies in the pathogenesis of abortion due to premature ovulation. An understanding of temporal mechanisms that dictate folliculo-luteal transformation and oocyte quality is relevant to the design of ovulatory protocols that assure assisted reproductive success.


   Footnotes
 
1 This work was supported by a grant from the USDA (NRI 9702434). Back

Received January 28, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  4. Kubik CJ 1986 Luteal phase dysfunction following ovulation induction. Semin Reprod Endocrinol 4:293–299
  5. Fritz MA 1988 Inadequate luteal function and recurrent abortion: diagnosis and treatment of luteal phase deficiency. Semin Reprod Endocrinol 6:129–144
  6. Wathes DC 1992 Embryonic mortality and the uterine environment. J Endocrinol 134:321–325[Abstract/Free Full Text]
  7. Smith MF, McIntush EW, Smith GW 1994 Mechanisms associated with corpus luteum development. J Anim Sci 72:1857–1872[Abstract]
  8. Roberts AJ, Dunn TG, Murdoch WJ 1985 Induction of ovulation in proestrous ewes: identification of the ovulatory follicle and functional status of the corpus luteum. Domest Anim Endocrinol 2:207–210
  9. Eggleston DL, Wilken C, Van Kirk EA, Slaughter RG, Ji TH, Murdoch WJ 1990 Progesterone induces expression of endometrial messenger RNA encoding for cyclooxygenase. Prostaglandins 39:675–683[CrossRef][Medline]
  10. McPherson LA, Van Kirk EA, Murdoch WJ 1993 Localization of stress protein-70 in ovine corpora lutea during prostaglandin-induced luteolysis. Prostaglandins 46:433–440[CrossRef][Medline]
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  13. Murdoch WJ, Dunn TG 1982 Alterations in follicular steroid hormones during the preovulatory period in the ewe. Biol Reprod 27:300–307[Abstract]
  14. Gill JL, Hafs HD 1971 Analysis of repeated measurements of animals. J Anim Sci 33:331–336
  15. Garverick HA, Smith MF 1986 Mechanisms associated with subnormal luteal function. J Anim Sci [Suppl] 62:92–105
  16. Gibson M 1996 Treatment of human infertility: habitual abortion. The endocrine factor. In: Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive Endocrinology, Surgery, and Technology. Lippincott-Raven, Philadelphia, pp 2275–2285
  17. Gaytan F, Bellido C, Morales C, Aguilar E, Sanchez-Criado JE 1997 Proliferative activity of preovulatory follicles and newly formed corpora lutea in cycling rats from late prooestrus to early oestrus. J Anat 191:425–430
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  21. Karsch FJ, Bowen JM, Caraty A, Evans NP, Moenter SM 1997 Gonadotropin-releasing hormone requirements for ovulation. Biol Reprod 56:303–309[Abstract]
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  24. Peters KE, Bergfeld EG, Cupp AS, Kojima FN, Mariscal V, Sanchez T, Wehrman ME, Grotjan HE, Hamernik DL, Kittok RJ, Kinder JE 1994 Luteinizing hormone has a role in development of fully functional corpora lutea (CL) but is not required to maintain CL function in heifers. Biol Reprod 51:1248–1254[Abstract]
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