scholarly journals Short photoperiod-induced ovarian regression is mediated by apoptosis in Siberian hamsters (Phodopus sungorus)

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 771-782 ◽  
Author(s):  
C S Moffatt-Blue ◽  
J J Sury ◽  
Kelly A Young
Keyword(s):  
Caspase 3 ◽  
Ovarian Function ◽  
Corpora Lutea ◽  
Control Data ◽  
Antral Follicles ◽  
Siberian Hamsters ◽  
Estradiol Secretion ◽  
Induced Changes ◽  
Active Caspase

Siberian hamster reproduction is mediated by photoperiod-induced changes in gonadal activity. However, little is known about how photoperiod induces cellular changes in ovarian function. We hypothesized that exposing female hamsters to short (inhibitory) as opposed to long (control) photoperiods would induce an apoptosis-mediated disruption of ovarian function. Ovaries and plasma from hamsters exposed to either long (LD, 16 h light:8 h darkness) or short (SD, 8 h light:16 h darkness) days were collected during diestrus II after 3, 6, 9 and 12 weeks and processed for histology or RIA respectively. Apoptosis was assessed byin situTUNEL and active caspase-3 protein immunolabeling. No significant differences were observed among LD hamsters for any parameter; therefore, these control data were pooled. SD exposure induced a decline in preantral follicles (P< 0.05), early antral/antral follicles (P< 0.01) and corpora lutea (P< 0.01) by week 12 as compared with LD. Terminal atretic follicles appeared by SD week 9; by week 12, these had become the predominant ovarian structures. Estradiol concentrations decreased by weeks 9 and 12 SD when compared with both LD and week-3 SD hamsters (P< 0.05); however, no changes were observed for progesterone. TUNEL-positive follicles in SD ovaries increased at week 3 and subsequently declined by week 12 as compared with LD ovaries (P< 0.01). Active capsase-3 protein immunostaining peaked at SD week 3 as compared with all other groups (P< 0.01). TUNEL and capsase-3 immunolabeling were localized to granulosa cells of late-preantral and early-antral/antral follicles. These data indicate that SD exposure rapidly induces follicular apoptosis in Siberian hamsters, which ultimately disrupts both estradiol secretion and folliculogenesis, resulting in the seasonal loss of ovarian function.

scholarly journals Inhibition of matrix metalloproteinases in Siberian hamsters impedes photostimulated recrudescence of ovaries

Reproduction ◽  
2010 ◽  
Vol 140 (6) ◽  
pp. 875-883 ◽  
Author(s):  
Julie Whited ◽  
Asha Shahed ◽  
Carling F McMichael ◽  
Kelly A Young
Keyword(s):  
Matrix Metalloproteinases ◽  
Ovarian Function ◽  
Corpora Lutea ◽  
Gelatinase Activity ◽  
Antral Follicles ◽  
Mmp Inhibitor ◽  
Siberian Hamsters ◽  
First Time ◽  
Long Photoperiod

Exposure of Siberian hamsters to short photoperiod for 14 weeks induces ovarian regression. Subsequent transfer to long photoperiod restores ovarian function, and 2 weeks of photostimulation increases plasma estradiol (E2), antral follicles, and corpora lutea (CL). Because tissue remodeling involved with photostimulated ovarian recrudescence is associated with differential expression of matrix metalloproteinases (MMPs), we hypothesized that inhibiting MMP activity using a broad-spectrumin vivoMMP inhibitor, GM6001, would curtail recrudescence. One group of hamsters was placed in long days (LD; 16 h light:8 h darkness) for 16 weeks. Another group was placed in inhibitory short days (SD; 8 h light:16 h darkness) for 14 weeks. A third group was placed in SD for 14 weeks and transferred to LD for 2 weeks to stimulate recrudescence. During weeks 14–16, animals were either not treated or treated daily with i.p. injections of GM6001 (20 mg/kg) or vehicle (DMSO). GM6001 reduced gelatinase activity and decreased immunohistochemical staining for MMP1, MMP2, and MMP3 compared with vehicle. No differences between controls, vehicle, or GM6001 treatment were observed among LD animals, despite a trend toward reduction in CL and E2with GM6001. Although SD reduced ovarian function, photostimulation of transferred controls increased uterine mass, plasma E2, appearance of antral follicles, and CL. With GM6001 treatment, photostimulation failed to increase uterine mass, plasma E2, antral follicles, or CL. These data show, for the first time, thatin vivoGM6001 administration inhibits MMP activity in hamster ovaries during photostimulation, and indicate that this inhibition may impede photostimulated recrudescence of ovaries. This study suggests an intriguing link between MMP activity and return to ovarian function during photostimulated recrudescence.

IN-VITRO STEROIDOGENESIS OF NEWLY FORMED CORPORA LUTEA AND THE NON-LUTEAL OVARY IN THE RAT, RABBIT, HAMSTER AND GUINEA-PIG

1980 ◽  
Vol 84 (1) ◽  
pp. 101-108 ◽  
Author(s):  
P. F. TERRANOVA ◽  
S. K. SAIDAPUR ◽  
G. S. GREENWALD
Keyword(s):  
Guinea Pig ◽  
Corpus Luteum ◽  
Ovarian Function ◽  
Serum Testosterone ◽  
The Other ◽  
Corpora Lutea ◽  
Serum Progesterone ◽  
Antral Follicles ◽  
Baseline Levels

The steroidogenic abilities of the newly formed corpus luteum (8–10 h after ovulation) and the non-luteal ovary were compared in the guinea-pig, hamster, rabbit and rat using an invitro incubation technique. Histologically, newly formed rat corpora lutea (CL) were highly luteinized whereas the CL of the rabbit and guinea-pig were only partially luteinized. The CL of the hamster showed the least amount of luteinization. Serum progesterone was highest in the rat (18 ± 3 (s.e.m.) ng/ml). In the hamster, it was about 8 ng/ml, whereas in the rabbit and guinea-pig it was about 1 ng/ml. Serum androstenedione ranged between 0·5 and 1 ng/ml. Serum testosterone was lowest in the hamster (60 pg/ml) and highest in the rabbit (470 pg/ml), whereas in the rat and guinea-pig, testosterone levels were similar (about 240 pg/ml). Serum oestrogens were at baseline levels in all species. The CL of the rat exhibited considerably greater steroidogenic ability than the CL of the other species, producing 70 ± 6 ng progesterone/mg per h, 215 ± 14 pg androstenedione/mg per h, 49 ± 3 pg testosterone/mg per h, 3 pg oestrone/mg per h and 1 pg oestradiol/mg per h. Rabbit CL produced only progesterone (7 ± 2 ng/mg per h). Newly formed hamster CL produced none of the above steroids. In general, the ability of the CL to produce progesterone in vitro correlated with the degree of luteinization found by histological observation. Guinea-pig CL were embedded deeply in the ovary and could not be obtained without damage. Consequently, a portion of the ovary containing a corpus luteum was incubated. There was no difference in the steroid production by this portion of the ovary compared with the non-luteal ovary. The non-luteal ovary of the rat produced the highest amount of progesterone (10 ± 2 ng/mg per h). The guinea-pig non-luteal ovary produced about 5 ± 2 ng progesterone/mg per h, whereas the non-luteal ovary of the rabbit did not produce any. On the other hand, the hamster non-luteal ovary lost progesterone. Non-luteal ovaries from all species produced androgens. The non-luteal ovary of the guinea-pig contained especially large numbers of atretic antral follicles. The guinea-pig non-luteal ovary produced extremely large amounts of androstenedione (1110 ± 210 pg/mg per h) and testosterone (606 ± 154 pg/mg per h) compared with the amounts produced by the non-luteal ovary of the rat, hamster and rabbit. In the non-luteal ovary, interstitium and atretic antral follicles are the probable source of androgens. Oestrogen production by the non-luteal ovary was at baseline levels in the four species studied correlating with the absence of healthy antral follicles. The results indicate the extreme species differences that exist in ovarian function in the early postovulatory period.

Localization of ovine follistatin and α and βA inhibin mRNA in the sheep ovary during the oestrous cycle

1994 ◽  
Vol 12 (2) ◽  
pp. 181-193 ◽  
Author(s):  
D J Tisdall ◽  
N Hudson ◽  
P Smith ◽  
K P McNatty
Keyword(s):  
Gene Expression ◽  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Indirect Evidence ◽  
Oestrous Cycle ◽  
Corpora Lutea ◽  
Α Subunit ◽  
Ovarian Follicle Development ◽  
Antral Follicles

ABSTRACT The sites of follistatin and α and βA inhibin gene expression were examined by in situ hybridization in sheep ovaries during the early and mid-luteal phases (days 3 and 10) of the oestrous cycle and a prostaglandin F2α (PGF2α)-induced follicular phase. Follistatin mRNA was detected in the granulosa cells of preantral, antral and early atretic follicles at all stages of the oestrous cycle, and in the corpora lutea at the early and mid-luteal stages of the cycle. However, only low levels of expression of follistatin were observed in the presumptive preovulatory follicle at 56 h after treatment with PGF2α. Both α and βA inhibin were shown to be expressed in ovaries at all stages of the oestrous cycle. In situ hybridization localized α subunit mRNA to the granulosa cells of most, but not all, healthy antral follicles, and to no other ovarian cell type. In contrast, expression of the βA subunit was confined to a few medium-to-large healthy antral follicles. In antral follicles expressing βA inhibin, mRNAs for α inhibin and follistatin were always detected, but the converse was not true. Unlike follistatin, no α and βA inhibin expression was seen in preantral follicles, developing corpora lutea, or follicles undergoing atresia. These results show that, in the adult sheep ovary, follistatin gene expression is a constitutive event in all growing follicles from the early preantral stage, and also provide indirect evidence of the involvement of follistatin, but not inhibin or activin, in the early stages of ovarian follicle development in sheep.

scholarly journals X-linked inhibitor of apoptosis protein and active caspase-3 expression patterns in antral follicles in the sheep ovary

Reproduction ◽  
2011 ◽  
Vol 142 (6) ◽  
pp. 855-867 ◽  
Author(s):  
Hollian R Phillipps ◽  
Ilona C Kokay ◽  
David R Grattan ◽  
Peter R Hurst
Keyword(s):  
Mrna Expression ◽  
Caspase 3 ◽  
Expression Patterns ◽  
Inhibitor Of Apoptosis ◽  
Mrna Levels ◽  
Follicular Atresia ◽  
Inhibitor Of Apoptosis Protein ◽  
Antral Follicles ◽  
Apoptosis Protein ◽  
Active Caspase

X-linked inhibitor of apoptosis protein (XIAP) interacts with caspases to inhibit their activity, thereby providing a potential mechanism for regulation of granulosa cell apoptosis occurring during follicular atresia. The aim of this study was to determine the presence and localization of XIAP mRNA and protein content in the sheep ovary and compare these expression patterns with active caspase-3 protein in the same antral follicles. Romney ewe estrous cycles (n=25) were synchronized with 2–3 Estrumate injections and ovarian tissue collected during the luteal and follicular phases of the cycle. The presence ofXIAPmRNA was confirmed by RT-PCR using laser capture microdissected ovarian cell samples.XIAPmRNA was subsequently localized byin situhybridization histochemistry and XIAP and active caspase-3 protein visualized by immunohistochemistry. In antral follicles extensive XIAP localization was evident in both granulosa and thecal cells. In contrast, mRNA expression was widespread in granulosa cells and only detected in thecal tissue from a small proportion of antral follicles. Active caspase-3 and XIAP comparative expression analysis showed positiveXIAPmRNA expression in all late luteal phase (day 14) follicles, despite varying levels of active caspase-3 protein. A proportion of follicular phase (days 15 and 16) follicles, however, showed an inverse expression relationship at the protein and mRNA levels in both granulosa and thecal tissue, as did XIAP protein in day 14 follicles. These results suggest high XIAP may prevent activation of caspase-3, thereby regulating follicular atresia in antral follicles and could potentially be utilized as a marker of follicular health.

scholarly journals Transcriptome analysis during photostimulated recrudescence reveals distinct patterns of gene regulation in Siberian hamster ovaries†

2019 ◽  
Vol 102 (3) ◽  
pp. 539-559
Author(s):  
Kathleen Leon ◽  
Jon D Hennebold ◽  
Suzanne S Fei ◽  
Kelly A Young
Keyword(s):  
Ovarian Function ◽  
Expression Patterns ◽  
Reproductive Function ◽  
Systematic Investigation ◽  
Ovarian Activity ◽  
Corpora Lutea ◽  
Gonadotropin Secretion ◽  
Siberian Hamsters ◽  
Ovary Function ◽  
Ovarian Cyclicity

Abstract In Siberian hamsters, exposure to short days (SDs, 8 h light:16 h dark) reduces reproductive function centrally by decreasing gonadotropin secretion, whereas subsequent transfer of photoinhibited hamsters to stimulatory long days (LDs, 16 L:8 D) promotes follicle stimulating hormone (FSH) release inducing ovarian recrudescence. Although differences between SD and LD ovaries have been investigated, a systematic investigation of the ovarian transcriptome across photoperiod groups to identify potentially novel factors that contribute to photostimulated restoration of ovarian function had not been conducted. Hamsters were assigned to one of four photoperiod groups: LD to maintain ovarian cyclicity, SD to induce ovarian regression, or post transfer (PT), where females housed in SD for 14-weeks were transferred to LD for 2-days or 1-week to reflect photostimulated ovaries prior to (PTd2) and following (PTw1) the return of systemic FSH. Ovarian RNA was extracted to create RNA-sequencing libraries and short-read sequencing Illumina assays that mapped and quantified the ovarian transcriptomes (n = 4/group). Ovarian and uterine masses, plasma FSH, and numbers of antral follicles and corpora lutea decreased in SD as compared to LD ovaries (P &lt; 0.05). When reads were aligned to the mouse genome, 18 548 genes were sufficiently quantified. Most of the differentially expressed genes noted between functional LD ovaries and regressed SD ovaries; however, five main expression patterns were identified across photoperiod groups. These results, generally corroborated by select protein immunostaining, provide a map of photoregulated ovary function and identify novel genes that may contribute to the photostimulated resumption of ovarian activity.

scholarly journals 220.TGFβ1 deficient mice exhibit impaired follicle growth and luteal maintenance

2004 ◽  
Vol 16 (9) ◽  
pp. 220
Author(s):  
R. L. Robker ◽  
W. V. Ingman ◽  
S. A. Robertson
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Follicular Development ◽  
Luteal Cell ◽  
Corpora Lutea ◽  
Normal Female ◽  
Female Reproduction ◽  
Antral Follicles

Transforming Growth Factor β1 (TGFβ1) is essential for normal female reproduction. Mice with a targeted deletion in the TGFβ1 gene (TGFβ1–/–) have severely impaired fertility with pregnancy occurring in <25% of mated females. TGFβ1 is implicated in several aspects of ovarian function, including potentiation of granulosa cell proliferation and suppression of luteal cell apoptosis. Our initial observations indicate that estrous cycling is disrupted in TGFβ1–/– mice and that ovulation rate is reduced. To further investigate how impaired ovarian function contributes to the infertility of TGFβ1–/– mice, ovaries were isolated from TGFβ1+/+ and TGFβ1–/– littermates at proestrus and fixed and sectioned for examination of follicle morphology and growth. BrdU labelling was performed to detect granulosa cell proliferation and blood samples were obtained for analysis of gonadotrophins and ovarian steroid hormones. Histological examination showed that ovaries from TGFβ1–/– mice were smaller than those of TGF–1+/+ mice, however large antral follicles were observed, indicating that TGFβ1 is not essential for granulosa cell proliferation. Compared to TGFβ1+/+ ovaries however, there were fewer antral follicles and only rare corpora lutea. Interestingly, in some cases there were large numbers of macrophages surrounding small follicles suggesting increased follicular atresia and/or altered macrophage activity in the TGFβ1–/– ovaries. Ovaries and serum were also isolated from females at d4 post-coital for assessment of corpora lutea morphology. TGFβ1–/– ovaries weighed less and had fewer corpora lutea than TGFβ1+/+ ovaries. TGFβ1–/– corpora lutea also contained increased numbers of apoptotic cells and infiltrating macrophages indicative of premature luteal regression. Circulating progesterone levels were reduced in TGFβ1–/– females, as was progesterone production per corpus luteum further indicating a functional defect in luteal maintenance. Cumulatively these observations show that TGFβ1 has essential roles in regulation of ovarian macrophage populations, in normal follicular development and in the generation, maintenance and steroidogenic function of corpora lutea.

435. Follicle differentiation and luteinisation in the mouse is associated with hypoxia inducible factor activity

2008 ◽  
Vol 20 (9) ◽  
pp. 115
Author(s):  
K. Tam ◽  
D. Russell ◽  
K. Kind ◽  
J. Thompson
Keyword(s):  
Granulosa Cells ◽  
Target Genes ◽  
Ovarian Function ◽  
Egfp Expression ◽  
Corpora Lutea ◽  
Limited Information ◽  
Antral Follicles ◽  
Follicle Differentiation

Hypoxia inducible factors (HIF) are transcription factors that mediate the response to hypoxic stress. Under hypoxic conditions, HIF is stabilised, translocates to the nucleus, and binds to the Hypoxia Response Elements (HRE) upstream of numerous target genes involved in angiogenesis and glycolysis, including Vegf, Glut-1 and Ldha. Little is known about the role of HIFs in regulating ovarian function. In rat granulosa cells, FSH stimulates HIF 1α via the PI3K/Akt pathway, demonstrating a role for HIFs during follicular development. In contrast, there is limited information regarding the role of HIFs during corpus luteum formation. In this study we investigated whether HIFs play a role in follicle differentiation and luteinisation. Prepubertal C57Bl6 females were stimulated with eCG (5 IU) followed 46 h later by hCG (5 IU). Mice were sacrificed at 0, 4, 8, 12, 16 and 24 h post hCG and granulosa cells were collected for Western analysis of HIF-1a protein. To investigate HIF activation in the ovary, a transgenic reporter mouse line was developed by lenti-viral incorporation of an HRE (4)-SV40-eGFP construct. Ovaries were collected from mice plugged day 1, 4 and 8 for CL analysis in vivo.A time- dependent increase of HIF 1α protein levels in granulosa cells, maximal around time of ovulation, was observed. Ovaries from cycling HRE-eGFP transgenic mice exhibited no eGFP in primordial, primary or preantral follicles. Upon antrum formation, eGFP was evident in occasional sections in antral follicles but HIF signalling was restricted within the theca. In contrast, corpora lutea on pregnancy day 1, 4 and 8 readily expressed eGFP and eGFP expression increases as luteinisation progresses.These results demonstrate that in vivo HIFs may play a role in folliculogenesis, but this is restricted to theca cells of antral follicles before hCG stimulation. Following hCG, maximal HIF activity is associated with the time of ovulation. In addition, HIF activity is maintained during luteinisation.

scholarly journals Estrous cycle dependent changes in expression and distribution of Fas, Fas ligand, Bcl-2, Bax, and pro- and active caspase-3 in the rat ovary

2006 ◽  
Vol 188 (2) ◽  
pp. 179-192 ◽  
Author(s):  
Karin A Slot ◽  
Marsha Voorendt ◽  
Mieke de Boer-Brouwer ◽  
Harmke H van Vugt ◽  
Katja J Teerds
Keyword(s):  
Estrous Cycle ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Ovarian Tissue ◽  
Cell Types ◽  
Ovarian Surface Epithelium ◽  
Surface Epithelium ◽  
Corpora Lutea ◽  
Protein Levels ◽  
Active Caspase

In the present investigation, the localization of proteins involved in ovarian apoptosis were studied throughout the estrous cycle in the presence of fluctuating hormone levels. Fas, Fas ligand, Bcl-2, Bax and caspase-3 mRNA expression and proteins were detected in all ovarian tissue extracts, though the amount of protein varied with the phase of the estrous cycle. Fas, Bax and caspase-3 protein levels were highest at diestrus and decreased thereafter towards metestrus. In contrast, Fas ligand and Bcl-2 protein levels were lowest at diestrus and increased toward metestrus. Immunohistochemistry revealed that the staining of the anti-apoptotic protein Bcl-2 was more pronounced in healthy preantral follicles than in atretic follicles. In contrast, the pro-apoptotic proteins Fas, Fas ligand, Bax and active caspase-3 were more predominantly present in atretic follicles. In the ovarian surface epithelium (OSE), Fas, procaspase-3 and Bcl-2 immunostaining appeared independent of the phase of the estrous cycle. Fas ligand and Bax staining was detected particularly during proestrus in OSE cells surrounding the ovulatory follicles, while active caspase-3 was observed only in OSE cells at the postovulatory site during estrus. The proportion of luteal cells that stained positively for Fas, Bax and caspase-3 increased with the age of the corpus luteum, while Fas ligand and Bcl-2 immunostaining was strongest in newly formed corpora lutea and decreased thereafter. In conclusion, the components of the Fas signalling pathway were differentially expressed throughout the estrous cycle in a variety of ovarian cell types, which may correspond to hormone dependent survival mechanisms.

335. X-LINKED INHIBITOR OF APOPTOSIS PROTEIN (XIAP) EXPRESSION PATTERNS IN THE SHEEP OVARY

2010 ◽  
Vol 22 (9) ◽  
pp. 135 ◽  
Author(s):  
H. R. Douglas ◽  
I. C. Kokay ◽  
D. R. Grattan ◽  
P. R. Hurst
Keyword(s):  
Inverse Relationship ◽  
Caspase 3 ◽  
Expression Patterns ◽  
Cysteine Proteases ◽  
Follicular Atresia ◽  
Study Objective ◽  
Antral Follicles ◽  
Xiap Expression ◽  
Apoptosis Protein ◽  
Active Caspase

At reproductive age, the ovary undergoes continual cyclicity of follicles due to multiple positive and negative signals that promote follicle growth and development, selection for ovulation, or atresia. The majority of follicles undergo atresia, a degenerative process involving granulosa cell apoptosis. This process is executed by caspases, which are cysteine proteases. Caspases are potently inhibited by XIAP providing a potential mechanism to control follicular atresia. The study objective was to test the hypothesis that XIAP will show elevated expression in healthy antral follicles compared to atretic antral follicles and will show an inverse relationship with active caspase-3 immunoreactivity in the same antral follicle during the sheep estrous cycle. Reproductively mature Romney ewes (n = 9) had estrous cycles synchronized with a prostaglandin F2α analogue, then tissue was collected on days 14, 15 and 16 of the subsequent natural cycle. Analysis involved determining the presence and localization of XIAP using in situ hybridization histochemistry and immunohistochemistry then comparing XIAP expression patterns with distribution of active caspase-3 protein. XIAP mRNA was not detected in primordial, primary and secondary follicles. In contrast, XIAP protein was present from the primary stage onwards. Antral follicles showed positive XIAP mRNA and protein expression in both granulosa and thecal cell layers and antral follicles on the same tissue section showed variable expression. All day 14 antral follicles were positive for XIAP mRNA expression irrespective of the level of active caspase-3 immunoreactivity, whereas an inverse relationship between active caspase-3 and XIAP was apparent in the majority of day 15 and 16 antral follicles. XIAP protein was widely expressed in active caspase-3 negative antral follicles and indicated a negative correlation with the onset of active caspase-3 expression in the majority of follicles. These results indicate that XIAP may regulate follicular atresia and act as an indicator of follicular health in the sheep ovary.

scholarly journals A rodent model of human dose-equivalent progestin-only implantable contraception

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Heather C. M. Allaway ◽  
Roger A. Pierson ◽  
Jesse Invik ◽  
Susan A. Bloomfield
Keyword(s):  
Repeated Measures ◽  
Ovarian Function ◽  
Virgin Female ◽  
Rodent Model ◽  
High Dose ◽  
Corpora Lutea ◽  
Average Dose ◽  
Estrus Cycle ◽  
Human Dose ◽  
Dose Dependent

Abstract Background Long-acting, reversible contraceptives (LARC; progestin only) are an increasingly common hormonal contraceptive choice in reproductive aged women looking to suppress ovarian function and menstrual cyclicity. The overall objective was to develop and validate a rodent model of implanted etonogestrel (ENG) LARC, at body size equivalent doses to the average dose received by women during each of the first 3 years of ENG subdermal rod LARC use. Methods Intact, virgin, female Sprague-Dawley rats (16-wk-old) were randomized to 1 of 4 groups (n = 8/group) of ENG LARC (high-0.30μg/d, medium-0.17μg/d, low-0.09μg/d, placebo-0.00μg/d) via a slow-release pellet implanted subcutaneously. Animals were monitored for 21 days before and 29 days following pellet implantation using vaginal smears, ultrasound biomicroscopy (UBM), saphenous blood draws, food consumption, and body weights. Data were analyzed by chi-square, non-parametric, univariate, and repeated measures 2-way ANOVA. Results Prior to pellet implantation there was no difference in time spent in estrus cycle phases among the treatment groups (p > 0.30). Following pellet implantation there was a dose-dependent impact on the time spent in diestrus and estrus (p < 0.05), with the high dose group spending more days in diestrus and fewer days in estrus. Prior to pellet insertion there was not an association between treatment group and estrus cycle classification (p = 0.57) but following pellet implantation there was a dose-dependent association with cycle classification (p < 0.02). Measurements from the UBM (ovarian volume, follicle count, corpora lutea count) indicate an alteration of ovarian function following pellet implantation. Conclusion Assessment of estrus cyclicity indicated a dose-response relationship in the shift to a larger number of acyclic rats and longer in duration spent in the diestrus phase. Therefore, each dose in this model mimics some of the changes observed in the ovaries of women using ENG LARC and provides an opportunity for investigating the impacts on non-reproductive tissues in the future.

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