Impaired Folliculogenesis and Ovulation in Older Reproductive Aged Women

Abstract

The objective of this study was to test the hypothesis that older reproductive aged women ovulate at a smaller follicle diameter and are more likely to produce multiple follicles during their menstrual cycle compared with midreproductive aged women. We performed a comparative study of 16 midreproductive aged women (MRA; 22-34 yr old) and 34 older reproductive aged women (ORA; >45 yr old). Women underwent serial transvaginal ultrasounds to follow follicular growth over 1 menstrual cycle. A subset of women (nine MRA and 19 ORA) had daily blood sampling. Scans were initiated within 1 wk of menses and were performed at least 3 times/wk until evidence of follicular collapse was observed. If there was no evidence of follicle growth beyond 10 mm by 20 d, observations (ultrasounds and blood sampling) were ended. Follicle growth was organized backward from maximum presumed preovulatory diameter. Hormones were standardized to d 0, the day when progesterone levels exceeded 2 ng/ml. Group comparisons were performed using ANOVA with Mann-Whitney post hoc testing and Kruskal-Wallis testing for integrated hormones. The main outcome measures were peak follicle diameter, follicle growth patterns, and circulating LH, F OLLICLE GROWTH PATTERNS in the menstrual cycles of reproductive aged women have been characterized using ultrasonographic evaluation. Several small studies, with up to 25 women, documented similar findings (1-3). Follicles in spontaneous cycles of midreproductive aged (MRA) women grow at a rate of between 2-6 mm daily, and ovulation has been reported to occur at a mean follicle diameter of 16 -27 mm. The latter estimates were from a study that used transabdominal scanning, which may have resulted in larger estimates of follicle size (2). Nonetheless, follicle dynamics have been noted to be consistent in populations of normally cycling women. Some recent studies have described the ovarian morphology and patterns of follicle growth associated with reproductive aging. Ovarian volume has been reported to decrease with age in a population of 13,963 women undergoing ovarian cancer screening (4). The inclusion of women in the age group between 30 -50 yr who were already naturally menopausal may have contributed disproportionately to these results, however, and the menopausal status of the younger women in this study is not provided. The number of antral follicles (i.e. Ͼ2 mm) in the ovaries has been reported to be significantly decreased in women over an age range of 22-42 yr old (5). These differences in follicle counts were independent of the stage of the menstrual cycle. Another study of 162 women that was confined to the early follicular phase alone (6) reported a mean yearly decline of antral follicle counts of about 5%, which increased to almost 12% after the age of 37 yr. Taken together, these data suggest that follicles in various stages of growth constitute the bulk of ovarian volume and that declining numbers of observable follicles occur concomitant with reproductive aging.Others have observed the patterns of f...

Body Shape and Size and Insulin Resistance as Early Clinical Predictors of Hyperandrogenic Anovulation in Ethnic Minority Adolescent Girls

“…LH and FSH were measured in duplicate using a solid-phase, two-site fluoroimmunometric assay (DELFIA, Perkin Elmer; Gaithersburg, MD: sensitivity 0.05 U/L and 0.05 U/L, intra-assay coefficient of variation (CV) 2.9% and 3.2%, and inter-assay CV 5.5% and 8.7%, respectively). (17,18) Testosterone was measured in duplicate using time-resolved fluoroimmunoassay (DELFIA: sensitivity 0.3nmol/ L intra-assay CV was 22.8% at a mean of 0.2 nmol/L and 16.9% at a mean of 3.71 nmol/L and inter-assay CVs were 10.3% and 17.7% at the same levels). A second testosterone assay system was also used to confirm results (DSL, Webster, TX) and had similar parameters.…”

Urinary beta-luteinizing hormone and beta-follicle stimulating hormone immunoenzymometric assays for population research

“…Preservatives, such as glycerol, thymol, bovine serum albumin, boric acid, thimerosal, and sodium azide, or adjustment of specimen pH to neutral, are used to prevent subunit dissociation and ensure accurate measurement of intact LH and FSH (e.g., (7,9,10,(13)(14)(15)). However, preservatives have some limitations for population level research, including time and expense invested in the advance preparation of specimen collection tubes for home or field collections, potential assay interference, effects on other hormones to be measured in the same specimen, and the fact that dilution volume correction may be necessary for the final urinary result (3,13).…”

A taxa de gestação em mulheres submetidas a técnicas de reprodução assistida é menor a partir dos 30 anos

“…A partir desta idade, apesar de ciclos regulares e níveis de estradiol e progesterona séricos normais, estas mulheres apresentam alteração da foliculogênese caracterizada pela ovulação a partir de um folículo de menor diâme-tro do que as mais jovens, comprometendo o potencial oocitário de fertilização e implantação 19 . Acredita-se na existência de defeitos nos estágios tardios de desenvolvimento folicular antral possivelmente devidos a uma deficiência de fatores de crescimento como o IGF-I, IGF-II e LH 19 . Além disso, a ovulação em estágio precoce de desenvolvimento, com oócitos imaturos, compromete não apenas a qualidade oocitária como também reduz a probabilidade de fertilização, causando maior incidência de anomalias cromossômicas 19 .…”

“…Acredita-se na existência de defeitos nos estágios tardios de desenvolvimento folicular antral possivelmente devidos a uma deficiência de fatores de crescimento como o IGF-I, IGF-II e LH 19 . Além disso, a ovulação em estágio precoce de desenvolvimento, com oócitos imaturos, compromete não apenas a qualidade oocitária como também reduz a probabilidade de fertilização, causando maior incidência de anomalias cromossômicas 19 . A integridade do fuso também parece se alterar com o aumento da idade 4 , contribuindo para a gênese das aneuploidias que são fortemente associadas com o aumento das taxas de aborto nas mulheres com idade avançada 4 .…”

“…A idade, portanto, compromete predominantemente a qualidade oocitária, e este fator supera o fator "quantidade oocitária", ou reserva ovariana, quando se consideram as taxas de implantação e gravidez 10,16 . Por isso, em procedimentos de reprodução assistida, a idade é considerada o melhor indicador da taxa de gravidez 10 na qualidade oocitária ocorram até os 35 anos de idade 19 . A primeira modificação endócrina ocorre por volta dos 35 anos que corresponderia à elevação dos níveis de FSH na fase folicular do ciclo devido à redução da produção de inibina B pelas cé-lulas da granulosa, que, por sua vez, é ocasionada pela redução no pool oocitário 2,19 .…”