Including Ovulation Rate Research Articles

Evaluation of effectiveness of Letrozole in treatment of infertility in women with polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disease, characterized by hyperandrogenism, oligomenorrhea, and polycystic ovaries. PCOS is one of the most causes that affect the women of childbearing age, and often leads to infertility. Various managements were proposed for infertile women with PCOS. However, the optimal management option has not been addressed satisfied. Although multiple treatments including weight reduction, clomiphene citrate, metformin, gonadotropins, and ovary cauterization have been reported to treat such condition, the efficacy still has insufficient evidence to support. Objectives: Purpose of this study was to evaluate the effectiveness of Letrozole in treatment of infertility in women with polycystic ovary syndrome. Materials & method: This study was carried out to assess the effectiveness of letrozole and on pregnancy outcomes including the ovulation induction, pregnancy rate, and endometrial thickness in infertile women with polycystic ovarian syndrome (PCOS). Total 106 infertile PCOS patients were recruited and allocated in two groups, Group-L (received letrozole at 2.5 mg twice daily on the 3rd–5th days of menstrual cycle for 5 consecutive days), Group-G 75 U/d−1 gonadotropin through intramuscular injection for 5 days starting from the third day of menstrual cycle). All patient in both arm completed treatment and follow-up. Patients in both groups were treated up to 5 treatment cycles. During follow up, transvaginalultrasonogram (TVS) was performed to see the details of the follicles and the endometrium. Data was processed and analysed with the help of computer program SPSS and Microsoft excel. Quantitative data expressed as mean and standard deviation and qualitative data as frequency and percentage. Comparison was done by tabulation and graphical presentation in the form of tables, pie chart, graphs, bar diagrams, histogram & charts etc. Result: Mean age of the patient was 26.3 ± 5.7 years in group-L and 25.9 ± 6.1 years in group-G. There were no statistical significant differences between the 2 groups regarding age, body weight, height, body mass index (BMI). Present study results showed that patients who received letrozole exert better outcomes in primary endpoint, including ovulation rate (86.7% in group-L & 62.2% in group-G, P =0.004), endometrial thickness (9.3 ± 1.1 mm in group-L & 8.5 ± 1.1 mm in group-G, P = 0.003) and pregnancy rate (64.1% in group-L & 30.1% in group-G, P =0.005). Abortion rate (till the end of 12th week) and multiple pregnancy rate were higher in group-G, but result were non-significant in between groups. Live birth rate in the letrozole group was higher 29(54.7%) than group-G 14(26.4%), the difference was statistically significant (P < .05). Conclusion: Patients who took Letrozole had significantly higher endometrial thickness than other group. Due to the higher pregnancy rate and lower incidence of abortion or multiple pregnancy, letrozole can be an effective for the treatment of anovulatory subfertility of the PCOS patients. Central Medical College Journal Vol 7 No 1 January 2023 Page: 13-19

MON-029 Polycystic Ovary Syndrome (PCOS) in Adolescent Girls:Toward a Simple On-Treatment Predictor of Post-Treatment Ovulation Rate

There is no approved treatment for adolescent girls with PCOS. The vast majority of these patients are guided into a trajectory that starts with oral contraceptive (OC) treatment, leads into oligo-anovulatory subfertility, then into the use of assisted reproductive techniques, and ultimately into pregnancies with a double-to-triple risk for complications (such as gestational diabetes, preeclampsia and preterm birth) potentially with lifelong sequelae in the offspring.Evidence is converging into the insight that adolescent PCOS is frequently driven by hepato-visceral fat excess (“central obesity”) ensuing from a mismatch between (rather restrictive) prenatal and (rather abundant) postnatal nutrition, on a background of genetic susceptibility (Trends Endocrinol Metab 2018;29:815). This insight has prompted the exploration of an alternative PCOS treatment that aims at reducing the central-fat excess (without causing weight loss in non-obese girls) in order to normalize the entire phenotype, including ovulation rate.So far, this alternative approach has been tested in two randomized controlled pilot studies that were performed in non-obese girls with PCOS and with no need for contraception (total N=62; age 16 yr; BMI 24 Kg/m2; treatment for 1 year; ovulation assessment during the post-treatment year). In these studies, the effects of an OC were compared to those of SPIOMET, which is a low-dose combination of spironolactone (= a mixed anti-androgen and -mineralocorticoid, also activating brown adipose tissue; Diab Ob Metab 2019;21:509), pioglitazone and metformin (= two insulin sensitizers acting through different mechanisms).Pooled results of the pilot studies confirm the first report (J Adolesc Health 2017;61:446) that SPIOMET has more normalizing effects than OC; there were approximately 3-fold more ovulations post-SPIOMET than post-OC; normovulation occurred only post-SPIOMET; anovulation was >10-fold more frequent post-OC.Pooled results also disclosed two new features of adolescent PCOS: low concentrations of circulating CXCL14 (= a brown adipokine, signaling activity in brown adipose tissue; Cell Metab 2018;28:750) and miR-451a (= an inhibitor of THRSP-mediated hepatic lipogenesis; Mol Cell Endocrinol 2018;474:260), both of which remain abnormally low on OC, but normalize on SPIOMET treatment. The on-treatment Z-scores of fasting insulin and miR-451a explained together approximately 50% of the variation in post-treatment ovulation rates. This simple duo, if validated in larger and more diverse PCOS populations, may become a first on-treatment predictor of post-treatment ovulation rate.

A review on prolificacy genes in sheep.

Ovulation rate and litter size are important reproduction traits in sheep and are of high economic value. Reproduction traits typically have low to medium heritabilities and do not exhibit a noticeable response to phenotypic selection. Therefore, inclusion of genetic information of the genes associated with reproductive ability could efficiently enhance the selection response. The most important major genes affecting prolificacy and their genetic diversities in different sheep breeds were reviewed. Different causative mutations with major effects on reproductive traits including ovulation rate and litter size have been found in various sheep breeds around the world. A general overview of the studies on main prolificacy genes showed that some alleles may express different phenotypic effects in different breeds, and thus, further studies on epistatic effects are necessary for more understanding of genetic control of reproductivity in sheep. Regarding the polygenic control of fertility traits, application of new high-throughput technologies to find new variants is essential for future studies. Moreover, genomewide association studies and genomic best linear unbiased predictions of breeding values are likely to be effective tools for genetic improvement of sheep reproductive performance traits.

A genome-wide linkage analysis for reproductive traits in F2 Large White × Meishan cross gilts.

Female reproductive performance traits in pigs have low heritabilities thus limiting improvement through traditional selective breeding programmes. However, there is substantial genetic variation found between pig breeds with the Chinese Meishan being one of the most prolific pig breeds known. In this study, three cohorts of Large White × Meishan F2 cross-bred pigs were analysed to identify quantitative trait loci (QTL) with effects on reproductive traits, including ovulation rate, teat number, litter size, total born alive and prenatal survival. A total of 307 individuals were genotyped for 174 genetic markers across the genome. The genome-wide analysis of the trait-recorded F2 gilts in their first parity/litter revealed one QTL for teat number significant at the genome level and a total of 12 QTL, which are significant at the chromosome-wide level, for: litter size (three QTL), total born alive (two QTL), ovulation rate (four QTL), prenatal survival (one QTL) and teat number (two QTL). Further support for eight of these QTL is provided by results from other studies. Four of these 12 QTL were mapped for the first time in this study: on SSC15 for ovulation rate and on SSC18 for teat number, ovulation rate and litter size.

Selection for ovulation rate in rabbits: Genetic parameters, direct response, and correlated response on litter size1

The aim of this work was to evaluate the response to 10 generations of selection for ovulation rate. Selection was based on the phenotypic value of ovulation rate, estimated at d 12 of the second gestation by laparoscopy. Selection pressure was approximately 30%. Line size was approximately 20 males and 80 females per generation. Traits recorded were ovulation rate at the second gestation, estimated by laparoscopy as the number of corpora lutea in both ovaries; ovulation rate at the last gestation, estimated postmortem; ovulation rate, analyzed as a single trait including ovulation rate at the second gestation and ovulation rate at the last gestation; right and left ovulation rates; ovulatory difference, estimated as the difference between the right and left ovulation rates; litter size, estimated as the total number of kits born and the number of kits born alive, both recorded at each parity. Totals of 1,477 and 3,031 records from 900 females were used to analyze ovulation rate and litter size, respectively, whereas 1,471 records were used to analyze ovulatory difference, right ovulation rate, and left ovulation rate. Data were analyzed using Bayesian methodology. Heritabilities of ovulation rate, litter size, number of kits born alive, right ovulation rate, left ovulation rate, and ovulatory difference were 0.16, 0.09, 0.08, 0.09, 0.04 and 0.03, respectively. Phenotypic correlations of ovulation rate with litter size, number of kits born alive, and ovulatory difference were 0.09, 0.01, and 0.14, respectively. Genetic correlations of ovulation rate with litter size and with number of kits born alive were estimated with low accuracy, and there was not much evidence for the sign of the correlation. The genetic correlation between ovulation rate and ovulatory difference was positive (P = 0.91). In 10 generations of selection, ovulation rate increased in 1.32 oocytes, with most of the response taking place in the right ovary (1.06 oocytes), but there was no correlated response on litter size (-0.15 kits). In summary, the direct response to selection for ovulation rate was relevant, but it did not modify litter size because of an increase in prenatal mortality.

Adaptive evolution of mammalian aromatases: lessons from Suiformes.

Estrogen synthesis evolved in chordates to control reproduction. The terminal enzyme in the cascade directly responsible for estrogen synthesis is aromatase cytochrome P450 (P450arom) encoded by the CYP19 gene. Mammals typically have a single CYP19 gene but pigs, peccaries and other Suiformes have two or more resulting from duplication in a common ancestor. Duplication of CYP genes in the steroid synthetic cascade has occurred for only one other enzyme, also terminal, 11beta-hydroxylase P450 (P450c11). P450arom and P450c11 share common substrates and even physiological functions as possible remnants from a common P450 progenitor, perhaps an ancestral P450arom, which is supported by phylogenetic analysis. Conserved tissue-specific expression patterns of P450arom paralogs in placenta and gonads of pigs and peccaries suggest how functional adaptation may have proceeded divergently and influenced adopted reproductive strategies including ovulation rate and litter size. Data suggest that the porcine placental paralog evolved catalytically to protect female conceptuses from testosterone produced by male siblings; the gonadal paralog to synthesize a novel, nonaromatizable testosterone metabolite (1OH-testosterone) that may increase ovulation rate. This would represent a coevolution facilitating litter bearing as pigs diverged from peccaries. Evidence of convergence between the peccary CYP19 genes and lower tissue expression may therefore represent initiation of loss of the functional paralogs. Studies on the Suiforme aromatases provide insights into the evolution of the steroidogenic cascade and metabolic pathways in general, how it translates into physiological adaptations (altered reproductive strategies for instance), and how duplicated genes become stabilized or disappear from genomes.

Meat and Livestock Association Plenary Lecture 2005. Oocyte signalling molecules and their effects on reproduction in ruminants

Sheep (Ovis aries) are a highly diverse species, with more than 900 different breeds that vary significantly in their physiological characteristics, including ovulation rate and fecundity. From examination of inherited patterns of ovulation rate, several breeds have been identified with point mutations in two growth factor genes that are expressed in oocytes. Currently, five different point mutations have been identified in the BMP15 (GDF9b) gene and one in GDF9. Animals heterozygous for the GDF9 and/or the BMP15 mutations have higher ovulation rates than their wild-type counterparts. In contrast, those homozygous for any of the aforementioned BMP15 or GDF9 mutations are sterile owing to arrested follicular development. In bovine and ovine ovaries, GDF9 was expressed exclusively in oocytes throughout follicular growth from the primordial stage of development, whereas in sheep BMP15 was expressed exclusively in oocytes from the primary stage: no data for the ontogeny of BMP15 expression are currently available for cattle. In vitro, ovine growth differentiation factor 9 (oGDF9) has no effect on (3)H-thymidine incorporation by either bovine or ovine granulosa cells, whereas ovine bone morphogenetic protein 15 (oBMP15) has modest (1.2- to 1.6-fold; P < 0.05) stimulatory effects. Ovine GDF9 or oBMP15 alone inhibited progesterone production by bovine granulosa cells, whereas in ovine cells only oGDF9 was inhibitory. The effects of oGDF9 and oBMP15 together were often cooperative and not always the same as those observed for each factor alone. Active immunisation of ewes with BMP15 and/or GDF9 peptides affected ovarian follicular development and ovulation rate. Depending on the GDF9 and/or BMP15 vaccine formulation, ovulation rate was either increased or suppressed. A primary and single booster immunisation of ewes with a BMP15 peptide in a water-based adjuvant has led to 19-40% increases in lambs born per ewe lambing. Collectively, the evidence suggests that oocyte signalling molecules have profound effects on reproduction in mammals, including rodents, humans and ruminants. Moreover, in vivo manipulation of these oocyte signalling molecules provides new opportunities for the management of the fertility of ruminants.

Inhibition of ovulation in the postpartum cow and the lactating sow

Increased genetic selection and capacity for milk production in dairy cows has been associated with a decline in fertility. Following parturition, nutritional requirements increase rapidly with milk production and the resulting negative energy balance (NEBAL) extends for 8–10 weeks of early lactation. NEBAL delays the timing of first ovulation through attenuation of LH pulse frequency and low levels of blood glucose, insulin and IGF-I that collectively limit oestrogen production by dominant follicles. NEBAL results in mobilization of adipose tissue and loss of body condition score (BCS), which is strongly associated with the length of the postpartum anovulatory period. Failure of ovulation of the first wave dominant follicle is associated with elevated nonesterified fatty acids and ketones in plasma and greater accumulation of triglycerides in the liver during the first 3 weeks of lactation. NEBAL is related to lower fertility in dairy cows both through inhibition of ovulation in early lactation and effects exerted later during the breeding period. Management strategies to minimize the inhibitory effects of NEBAL on first ovulation should begin during the prepartum transition period and include maintaining moderate BCS and energy intake through parturition. Modern sows have been improved genetically for higher productivity including ovulation rate, litter size and milk production. Peak milk yield is achieved within 10 days after farrowing with consequent massive mobilization of body fat and protein mass. Conservation of body protein mass (< 12% loss) during the first lactation minimizes the weaning to estrus interval by advancing ovarian follicular development toward ovulation. The lysine requirement in early lactation is extraordinary. Plasma insulin and IGF-I concentrations seem unrelated to the observed differences in ovarian follicular development. Overall, NEBAL inhibits ovulation in both high producing cows and sows, but there are species differences in response to protein losses and hormonal interactions.

260. Effects of diet-induced obesity on ovarian function and female fertility

Obesity and its related complications (metabolic syndrome, Type II diabetes and polycystic ovary syndrome) are increasingly associated with female infertility. Our research is focused on understanding how diet-induced obesity, which triggers insulin resistance and symptoms of chronic inflammation, directly impacts ovarian function and female fertility. Female mice were maintained on a “Western style” diet (22% fat, 0.15% cholesterol) or a matched control diet. Body weights were monitored weekly and after 16 weeks fasting insulin levels and glucose tolerance were assessed. Mice were then paired with males and tissues collected on day 1 on pregnancy. Blood samples were taken to determine levels of progesterone, metabolites (glucose, HDL/LDL) and inflammatory cytokines. Tissue weights (fat pads, liver, kidney, spleen, pancreas, ovary and uterus) were recorded and the reproductive tissues were fixed for analysis of histology and gene expression. Zygotes were isolated from the oviduct, cultured in vitro and scored for on-time development and differentially stained to assess blastocyst quality. Indices of ovarian function, including ovulation rate, steroid production and oocyte quality/blastocyst development will then be correlated with degrees of insulin resistance, dyslipidemia and inflammation. Five strains of mice were tested (CBA, Balb/c, C57, SV129 and Swiss) and showed significant differences in susceptibility to diet-induced obesity and insulin resistance. In CBA mice, the first group to be completed, the high fat diet significantly increased body weight, but did not result in overtly impaired glucose tolerance. The number of days to mating was slightly extended compared to mice on the control diet. Interestingly, the high fat diet did not affect ovulation rate but resulted in dramatically impaired blastocyst development. The results of this study will reveal how ovarian folliculogenesis, oocyte competence and ovulation are affected by obesity-induced metabolic changes, which are increasingly affecting women of reproductive age.

020. Oocyte signalling molecules and their effects on reproduction in ruminants

Sheep (Ovis aries) are a highly diverse species with more than 900 different breeds that vary significantly in their physiological characteristics including ovulation rate and fecundity. From examination of inherited patterns of ovulation rate in sheep, several breeds have been identified with point mutations in two growth factor genes that are expressed in oocytes. Currently, five different point mutations have been identified in the BMP15 (GDF9b) gene and one in GDF9. Animals heterozygous for the GDF9 and/or the BMP15 mutations have higher ovulation rates (i.e. +0.6 to +5.0) than their wild-type contemporaries. In contrast, those homozygous for any of the aforementioned BMP15 or GDF9 mutations are sterile due to abnormal follicular development from the primary stage of growth. In bovine and ovine ovaries, GDF9 is expressed exclusively in oocytes throughout follicular growth from the primordial stage of development, whereas in sheep BMP15 is expressed exclusively in oocytes from the primary stage: no data for BMP15 are available for the cow. In vitro, ovine GDF9 (oGDF9) has no effect on 3H-thymidine incorporation by either bovine or ovine granulosa cells, whereas oBMP15 has modest (1.2 to 1.6-fold; P &lt; 0.05) stimulatory effects. GDF9 or BMP15 alone inhibited progesterone production by bovine granulosa cells, whereas with ovine cells only GDF9 was inhibitory. The effects of GDF9 and BMP15 together were often cooperative and not always the same as those observed for each factor alone. Active immunisation of ewes with BMP15 and/or GDF9 peptides affected ovarian follicular development and ovulation rate. Depending on the GDF9 and/or BMP15 vaccine formulation, ovulation rate was either increased or suppressed. For example, immunisation of ewes with a BMP15 peptide in a water based adjuvant has led to a 25% increase in lambs born per ewe lambing. Collectively the evidence suggests that oocyte signalling molecules have profound effects on reproduction in mammals including rodents, humans and ruminants. Moreover, that in vivo manipulation of these oocyte signalling molecules provides a new approach to managing the fertility of ruminants.

Endocrine and paracrine control of follicular development and ovulation rate in farm species

Productivity in farm species is controlled by many factors, including ovulation rate. In cattle, single ovulations occur most frequently and in sheep (and goats) the number of ova released can range from one to many depending upon the breed, whilst the pig is polyovular. The processes of recruitment and selection determine the number of ovulatory follicles in all these species with FSH and subsequently LH playing major roles. GnRH-agonist models in which endogenous gonadotrophin secretion is suppressed and exogenous LH and/or FSH are administered at specific concentrations in defined patterns, are useful in all three species for elucidating the precise roles of specific hormones in stimulating follicular development. Differences in the hypothalamic–pituitary–ovarian feedback response lead to the differences in the number of ovulatory follicles, as does the pool of antral follicles from which the ovulatory ones are selected. Precocious development of follicles is also associated with more ovulations, as is the case with the Booroola due to the single gene acting through bone morphogenetic proteins (BMPs). It is well established that ovulation rate can also be influenced by exogenous hormone administration and by environmental factors such as nutrition. It has become apparent that these nuritional effects are mediated by a direct action at the level of the ovary, involving insulin, insulin-like growth factors (IGF) I and II and their binding proteins among other factors. These factors can also affect the quality of the oocyte and consequently embryo development and survival. Recently, the regulation of follicular angiogenesis has been shown to be important for the development of ovulatory follicles, particularly vascular endothelial growth factor (VEGF) which is produced primarily by the granulosa cells within the ovary and can be stimulated by gonadotrophins. Administration of VEGF has been shown to stimulate pre-antral follicular growth and increase the number of pre-ovulatory follicles. In summary both extra- and intra-ovarian factors are involved in the control of ovulation rate. Manipulation of the angiogenic process may also provide new opportunities for regulating the quality and number of follicles that ovulate.

A simulation model including ovulation rate, potential embryonic viability, and uterine capacity to explain litter size in mice: II. Responses to alternative criteria of selection.

Direct selection for litter size was compared with selection for ovulation rate, ova success, or uterine capacity and for indexes of ovulation rate with ova success or uterine capacity. Selection was simulated for 10 generations in a mouse population based on a model integrating ovulation rate, potential embryonic viability, and uterine capacity. Two indexes including ovulation rate (OR) and ova success (OS) were I = .291 x OR + 2.19 x OS and I = .165 x OR + .736 x OS. Heritabilities for ovulation rate and ova success, assumed in the simulation and to derive the indexes, were .25 and .06, respectively. Both indexes resulted in the same response in litter size, 12.9% greater than response to direct selection for litter size. Two indexes including OR and uterine capacity (TUC = true total uterine capacity; UC = uterine capacity measured as number born for a female with right ovary excised) were I = .881 x OR + .223 x TUC and I = .876 x OR + .568 x UC. Heritabilities assumed for uterine capacity were .09 (TUC) and .065 (UC). The first index assumed true parameters for uterine capacity (TUC) and resulted in a response in litter size that was 23.9% greater than direct selection. The second index was calculated using parameters estimated under a unilateral-ovariectomy model and resulted in response that was 14.7% greater than direct selection. Selection for OR, TUC, UC, or OS resulted in responses that were 4.5, 48.5, 38.7, or 74.8%, respectively, less than that from direct selection for litter size.

Reproductive Performance of Chimeric Mice Produced from Genetic Lines that Differ in Litter Size

A population of chimeras was made by aggregating 8- and 16-cell embryos from two mouse strains: a randomly bred line (C) and a selected line characterized by large litters (JU), with litter sizes of 7.7 and 13.5, respectively. The two genotypes were developmentally "balanced", as judged by the high frequency (90%) of chimeras with an intermediate or high degree of coat-color chimerism, a chimeric sex ratio of 2.2:1 males:females, and a high percentage of chimeras (31% of males, 71% of females) with germ cells of both strains. Litter size characteristics, including ovulation rate, implantation rate, rates of pre- and postimplantation embryo survival and number born were studied in the female chimeras and compared with the performance of both parent lines and to the genetic cross of the two lines. Values for JU females exceeded those for C females for all parameters studied except postimplantation embryo survival, which was the same for both lines in second litters and was lower for JU's third litters. For most traits, means for genetic crossbreds and chimeras were similar, regardless of whether the means were at or above the midparent average. In contrast, for ovulation rate and body weight, genetic crossbreds and chimeras clearly differed, with chimeric females being similar to the JU line and genetic crossbred females exhibiting additive inheritance. Because of phenotypic differences between experimental chimeras and crossbreds produced from the same two lines, chimeras may provide a useful model for studying the physiologic basis for expression of genetic differences in quantitative traits.

Genetic improvement of mammalian fertility: A review of opportunities

The possibility of genetic improvement in the reproductive performance of domestic mammals is introduced. The paper is principally concerned with biological variation and change, but the need to consider economic factors when relating change to improvement is illustrated from time to time. Both male traits, such as semen quality, and female traits, such as litter size, are considered. There is considerable variation among existing populations and the importance of the choice of the most suitable of available populations whether pure or crossbred is emphasized. Variation in litter size is greatest among breeds of sheep (approx. 300%) and least among cattle (only 4%). The possibility that differences in performance may be specific to particular environments and the implications of such an interaction between genotype and environment for the choice of populations are discussed. Among cattle, variation in the incidence of calving difficulties may be marked; it may increase three-fold in cows mated to bulls of a large breed relative to cows mated to bulls of a small breed. Cross-breeding may improve reproductivity by 20%. Once the best population has been chosen, further improvement is dependent on selection within that population. Selection within populations has been rare due to low predicted rates of response. Low selection differentials have probably contributed more to slow responses than have low heritabilities, and recent marked changes achieved by group breeding schemes illustrate what can be done with intense selection. A principal reason for small selection differentials is the inability to measure all reproductive traits in both sexes; one sex has to be chosen at random. The common physiology of reproduction in males and females indicates common genetic control, and the possibility of indirect selection on, say, testis growth to alter ovarian activity is considered along with the use of other physiological selection criteria, including ovulation rate and hormone levels, to increase the rate of response to selection. Finally, the implementation of improvement schemes is discussed. The improvement of reproduction has to be balanced against improvement in other traits such as growth; as the benefits of selection for other traits decline, reproduction would receive greater emphasis. International collaboration to develop strains of extremely high merit for subsequent use by crossbreeding is advocated.