5 Changes in Uterine and Ovarian Perfusion with the Onset of Menopause There has been a growing trend in recent decades for women to postpone childbearing until 30 to 40 years of age. Many of these women are faced with infertility problems, however. The fact that natural fertility is very low at 45 years of age and older presents a challenge to the various specialties that are involved in the treatment of infertility. These include ultrasonography, especially transvaginal color Doppler and pulsed Doppler imaging. This innovative technique provides a unique, noninvasive method of evaluating the normal and the abnormal female pelvis. The perimenopausal years, which begin at 40 years of age, represent the transition between the reproductive period and the postmenopausal period. The decline in the fertility of couples with advancing age has been amply documented. It is believed that the age-related decline in pregnancy rates is caused by functional inadequacy of the ovaries and of the endometrium. Two major problems are the reduced ability of the zygote to implant and the aging of the oocytes. Numerous studies have addressed the question of which factor poses the greater problem. Some authors attribute the decline in fertility with aging to a decline in uterine receptivity. Ezra and Schenker12 described an increased abortion rate of genetically normal embryos in the population of older women, which may be attributable to uterine dysfunction. Highly sensitive tests for human chorionic gonadotropin (hCG) indicate that up to 30% of pregnancies are lost between implantation and the 6th week of gestation45. The frequency of both euploid and aneuploid abortions increases with maternal age. Experience with the oocytes of younger women who were donors for older women shows that aging oocytes, rather than endometrial factors, are the principal cause of decreased fertility. Some specialists believe that the significantly higher pregnancy rate with donor oocytes is attributable to their better quality. Navotetal.31 studied 35 infertile women over age 40 who had failed at attempts to conceive with their own oocytes. Oocytes were donated by 29 younger women (mean age 33.4 ± 0.7 years) undergoing in-vitro fertilization (IVF). The rate of implantation per embryo transferred was higher with donated oocytes (14.7%) than with self-oocytes (3.3%) in the women over 40 years of age (p < 0.01). To further study the effect of aging on reproductive outcome, pregnancy results were compared between the young donors and older recipients. The clinical pregnancy and delivery rates for the donors (33% and 23%) and recipients (40% and 30%) were not significantly different. These data suggest that the age-related decline in female fertility is related to oocyte quality and is correctible by oocyte donation. Drews et al.11 found that similar pregnancy and livebirth rates were achieved when donor oocytes from the same women were given to one woman over age 40 and another under age 40. In a second report39, uterine receptivity as determined by clinical pregnancy rates was similar for oocyte recipients over age 40 and young IVF surrogates when both groups received oocytes from young donors. The pregnancy rate declined when surrogates received oocytes from women over 40 years of age. In another study, Navot et al.32 evaluated 38 ovum donors throughout 102 oocyte donations. They documented 51 cycles in younger recipients (35.8 ± 3.1 years) and 51 cycles in older recipients (44.0 ± 3.1 years). They found that the capacity to conceive and to carry a pregnancy to term when oocyte quality is controlled appears to be independent of uterine aging in the fifth decade of life. Borini et al.3 attempted to determine the potential of the aging uterus in terms of implantation, pregnancy, abortion, and obstetric complications in postmenopausal women over age 50 who received donated oocytes. They found that women from 50 to 62 years of age can become pregnant with donated oocytes when they receive adequate hormone replacement therapy. It is also important, however, to consider the effect of pregnancy on preexisting maternal diseases and the rising risks of preeclampsia, hypertension, and diabetes mellitus. Patients 40 years of age or older who wish to undergo IVF therapy with their own oocytes should be thoroughly counseled by their doctor. The following risks should be mentioned42: When these risks are known, an additional test of ovarian capacity can help to identify the women for whom IVF, other forms of assisted reproduction, or surgical intervention are the most appropriate forms of treatment. Follicle-stimulating hormone (FSH). Toner et al.43 report that when age, infertility etiology, and semen quality are taken into account, FSH is the best predictive parameter of ovarian function. The combination of age and basal FSH in treated patients increases the accuracy of the prognosis and can provide an index for the functional ovarian reserve (“ovarian age”). Women over age 40 with a favorable hormonal profile respond well to assisted reproduction, whereas women of any age with a basal FSH level > 20 IU/l respond poorly to ovarian stimulation. Moreover, it is rare to find FSH levels above 25 IU/l in an existing pregnancy. Pregnancy is most likely to occur when the FSH level is between 10 and 20 IU/l. E2. Another parameter that is useful in the prediction of “ovarian age” is the basal E2, with values higher than 50 pg/ml indicating a poor ovarian reserve. For this reason, it is best to consider age, FSH, luteinizing hormone (LH), and E2 for the optimum prediction of ovarian response. Provocative tests of ovarian function are probably superior to static tests, but they are difficult to perform and are not widely practiced. Age. Fitzgerald et al.13 studied the effect of age on follicular growth and endometrial thickness. Ultrasound examinations were done to confirm ovulation and to measure follicular and endometrial growth. Ovulation occurred later in older women, with an increase in the mean follicular phase length from 13.9 days (20–25 age group) to 15.9 days (37–45 age group; p < 0.05). The mean maximum follicular diameter before ovulation was significantly smaller in older women: 16.7 mm (37–45 years), 21.3 mm (32–36 years), and 19.6 mm (21–25 years). The maximum endometrial thickness during the luteal phase was greatest in older women: 15.9 mm (37–45 years), 12.1 mm (21–25 years; p < 0.001). While the levels of ovarian steroids showed no differences, the serum gonadotropin levels during menstruation were higher in older women. These data point to significant age-related differences in the pituitary–ovarian axis and endometrial thickness that influence the management of older women in medically assisted reproduction programs. Meldrum29 emphasizes in his review that decreased implantation with aging is associated with a high incidence of delayed or absent secretory transformation of the endometrium. In patients who were treated with physiological amounts of progesterone replacement, a marked regression of implantation was found with increasing age. Treatment with high doses of progesterone significantly improved the implantation rates. Thus, oocytes donated by young women and an elevated progesterone level can correct the age-related deficits in older women. Rhythmic changes in uterine blood flow during the menstrual cycle are sometimes related to the ratio of progesterone and estrogen in the blood15,22,47. The higher the ratio of estrogen to progesterone, the greater the blood flow in the uterine vascular bed10,16,24. Progesterone antagonizes the vasodilator effect of estrogen on the uterus6,39, the magnitude of this inhibition depending upon the ratio of the two steroids6. The periarterial sympathetic vasoconstrictor nerves of the uterus are recognized as important factors in the regulation of uterine blood flow. Exposure to progesterone increases the vasoconstrictor effect of these nerves, while exposure to estrogen decreases it18,19. The results of Ford et al.17 indicate that ovarian steroids affect the function of uterine periarterial sympathetic nerves by altering the number of alpha-adrenergic receptors. This may contribute to the marked changes in uterine blood flow observed during the estrous cycle of pigs. To determine whether ovarian hormones at physiological levels affect uterine vascular resistance, De Ziegler et al.9 studied young women with loss of ovarian function who received physiological amounts of exogenous estradiol and progesterone. Their results show that in the absence of endogenous estrogen production by the ovaries, the uterine arteries have a high vascular resistance as indicated by low systolic Doppler flow and high PI (pulsatility index) values. Goswamy and Steptoe21 theorize that persistent diastolic flow during the early follicular phase is a more common phenomenon in multiparous women than in nulliparae. They observed a profound alteration of the Doppler flow pattern reflecting a marked decline of vascular resistance following the transdermal administration of estradiol (0.1–0.4 mg/day). This observation is consistent with the hypothesis that the periovulatory decline in vascular resistance is mediated by estradiol34. Since estrogen receptors have been identified in the wall of the uterine arteries, it is reasonable to suppose that estradiol has a direct effect on uterine Doppler flow. It is postulated that the effect of estrogen on uterine arterial vascular resistance is directly related to the plasma level of biologically active estrogen and that a direct dose–response relationship exists37. Other possible mechanisms include the modulation of the production and/or secretion of various vasoactive substances such as prostaglandins40, CGRP (calcitonin gene-related peptide29), and ERF (endothelial relaxing factor30) by estradiol. There is no question that transvaginal Doppler flow studies of the uterine arteries are a valuable tool for assessing the biological efficacy of various estrogen treatments. This is particularly important in evaluating the effects of postmenopausal hormone replacement therapy in women with increased hepatic estrogen metabolism resulting in lower plasma estradiol levels.
Decline of Fertility in the Perimenopausal Period
Uterine Receptivity
Oocyte Quality
A 30–50% reduction in pregnancy potential
A rising risk of chromosome abnormalities
Abortion and stillbirth
Ovarian Function
Effects of Estradiol and Progesterone on Vascular Resistance
Sympathetic Innervation of the Uterus
Estrogen Effect
Progesterone Effect
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