Estrogen Levels Increase with Age

Also see:
Fat Tissue and Aging – Increased Estrogen
Estrogen Related to Loss of Fat Free Mass with Aging

Quotes by Ray Peat, PhD:
“Estrogen increases with aging, and the characteristic changes of aging—including menopause, glucose intolerance/insulin resistance, autoimmunity and inflammatory dysregulation, respiratory decline, susceptibility to cancer, connective tissue hardening and slowed cellular responses—are produced by prolonged exposure to estrogen.”

“Many things in our environment are increasing the incidence of certain kinds of liver disease. The liver processes things that are ingested or that enter the blood stream after being inhaled or absorbed through the skin, so in a toxic environment it is susceptible to injury. If deprived of good nutrition or adequate thyroid hormone it is especially sensitive to toxins. The body’s own estrogen is a burden on the liver, causing women’s livers to be on average slower than men’s in processing environmental chemicals.

Almost any kind of toxin causes the liver to be less efficient at excreting other substances, including hormones. In malnutrition, sickness, and in aging, there is a tendency for higher levels of estrogen to remain circulating in the blood.”

“Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example, the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create the “hormone replacement” business.

If aging involves the same processes that are created by estrogen, then our knowledge of how to protect ourselves against estrogen can be used to protect ourselves against aging.”

“It turns out that the meaning of “excess estrogen” has to be interpreted in relation to the balance of estrogen (and the multitude of factors which mimic estrogen’s effects) with all of the antiestrogen factors. I have concentrated on thyroid, progesterone, and red light as the most important factors that protect against estrogen, and these all turn out to be protective against stress, shock, ionizing radiation, free radicals, lipid peroxidation, thymic atrophy, osteoporosis, arthritis, scleroderma, apoptotic cell death, and other problems that are involved in tissue degeneration or aging.”

J Gerontol. 1978 Mar;33(2):191-6.
Circulating plasma levels of pregnenolone, progesterone, estrogen, luteinizing hormone, and follicle stimulating hormone in young and aged C57BL/6 mice during various stages of pregnancy.
Parkening TA, Lau IF, Saksena SK, Chang MC.
Young (3-5 mo of age) and senescent (12-15 mo of age) multiparous C57BL/6 mice were mated with young males (3-6 mo of age) and the numbers of preimplantation embryos and implantation sites determined on days 1 (day of plug), 4, 9, and 16 of pregnancy. The numbers of viable embryos were significantly lower (p less than 0.02 to p less than 0.001) in senescent females compared with young females on all days except day 1 of pregnancy. Plasma samples tested by radioimmunoassay indicated circulating estradiol-17B was significantly lower (P less than 0.05) on day 1 and higher (p less than 0.05) on day 4 in older female, whereas FSH was higher on days 4, 9, and 16 (p less than 0.02 to p less than 0.001) in senescent females when compared with samples from young females. Levels of pregnenolone, progesterone, estrone, and LH were not significantly different at any stage of pregnancy in the two age groups. From the hormonal data it did not appear that degenerating corpora lutea were responsible for the declining litter size in this strain of aged mouse.

Probl Endokrinol (Mosk). 1981 Mar-Apr;27(2):48-52.
[Blood estradiol level and G2-chalone content in the vaginal mucosa in rats of different ages].
[Article in Russian]
Anisimov VN, Okulov VB.
17 beta-Estradiol level was higher in the blood serum of rats aged 14 to 16 months with regular estral cycles during all the phases as compared to that in 3- to 4-month-old female rats. The latter ones had a higher vaginal mucosa G2-chalone concentration. The level of the vaginal mucosa G2-chalone decreased in young rats 12 hours after subcutaneous benzoate-estradiol injection (1 micrograms/100 g body weight) to ovariectomized animals but increased in 14- to 16-month-old female rats. One year following ovariectomy the vaginal mucosa G2-chalone level was lower than in young and aged female rats 2 weeks after surgery. Possible role of age-associated disturbances of the regulatory cell proliferation stimulant (estrogen) and its inhibitor (chalone) interactions in neoplastic target tissue transformation is discussed.

Am J Obstet Gynecol. 1987 Aug;157(2):312-7.
Age-related changes in the female hormonal environment during reproductive life.
Musey VC, Collins DC, Musey PI, Martino-Saltzman D, Preedy JR.
Previous studies have indicated that serum levels of follicle-stimulating hormone rise with age during the female reproductive life, but the effect on other hormones is not clear. We studied the effects of age, independent of pregnancy, by comparing serum hormone levels in two groups of nulliparous, premenopausal women aged 18 to 23 and 29 to 40 years. We found that increased age during reproductive life is accompanied by a significant rise in both basal and stimulated serum follicle-stimulating hormone levels. This was accompanied by an increase in the serum level of estradiol-17 beta and the urine levels of estradiol-17 beta and 17 beta-estradiol-17-glucosiduronate. The serum level of estrone sulfate decreased with age. Serum and urine levels of other estrogens were unchanged. The basal and stimulated levels of luteinizing hormone were also unchanged. There was a significant decrease in basal and stimulated serum prolactin levels. Serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate decreased with age, but serum testosterone was unchanged. It is concluded that significant age-related changes in the female hormonal environment occur during the reproductive years.

J Clin Endocrinol Metab. 1995 Feb;80(2):608-13.
Diminished function of the somatotropic axis in older reproductive-aged women.
Wilshire GB, Loughlin JS, Brown JR, Adel TE, Santoro N.
Circulating GH and insulin-like growth factor-I (IGF-I) levels in adults generally fall with age. Studies in aging women have rarely controlled for menstrual cycle stage or status or body mass index. We hypothesized that GH and IGF-I levels in reproductive-aged women fall with age despite the stimulatory effects of endogenous estradiol (E2). Eight older reproductive-aged women (aged 42-46 yr) with regular menses, of normal weight, and in good health were compared to a group of eight young control subjects (aged 19-34 yr). Daytime frequent blood sampling was performed in the early follicular phase of the menstrual cycle to characterize pulsatile GH and LH concentrations. Pooled samples were also analyzed for IGF-I, E2, progesterone, and FSH levels. Older reproductive-aged women had lower 12-h integrated daytime GH concentrations (mean +/- SE, 171 +/- 35 vs. 427 +/- 130 micrograms min/L; P = 0.036) than younger controls and a strong trend for lower IGF-I levels (22.7 +/- 2.1 vs. 31.3 +/- 3.5 nmol/L; P = 0.055) than younger controls despite having higher circulating E2 on the day of sampling (368 +/- 51 vs. 167 +/- 20 pmol/L; P = 0.002). We conclude that older reproductive-aged women have lower daytime GH concentrations than younger controls despite having higher E2 levels on the day of sampling and overall normal gonadal hormone parameters.

J Clin Endocrinol Metab. 1996 Apr;81(4):1495-501.
Characterization of reproductive hormonal dynamics in the perimenopause.
Santoro N, Brown JR, Adel T, Skurnick JH.
Medical therapy for women in the perimenopausal period is controversial, in part due to varying degrees of ovarian hormone secretion characteristic of this time of life. To extend our understanding of the reproductive endocrine milieu of perimenopausal women, we studied 6 cycling women, aged 47 yr and older, for 6 months with daily collections of first morning voided urine. Five additional older reproductive aged (43-47 yr old) women were studied with daily urine and serum sampling for a single menstrual cycle; their urinary hormone data were combined with the former group for menstrual cycle comparisons. Urine was assayed for LH, FSH, estrone conjugates, and pregnanediol glucuronide and normalized for creatinine (Cr). Eleven midreproductive aged (19-38 yr old) normally cycling women, 5 women with well defined premature ovarian failure, and 5 women aged 54 yr and older who were at least 1 yr postmenopausal were used for comparison. Perimenopausal women had shorter follicular phases (11 +/- 2 days vs. 14 +/- 1 days; P = 0.031) and, hence, shorter menstrual cycles than midreproductive aged controls. FSH excretion in perimenopausal women was greater than that in younger women (range of means, 4-32 vs 3-7 IU/g Cr; P = 0.0005). LH secretion was overall greater than that in younger normal subjects (range of means, 1.4-6.8 vs. 1.1-4.2 IU/g Cr; P < 0.026). Overall mean estrone conjugate excretion was greater in the perimenopausal women compared to that in the younger women [76.9 ng/mg Cr (range, 13.1-135) vs. 40.7 ng/mg Cr (range, 22.8-60.3); P = 0.023] and was similarly elevated in both follicular and luteal phases. Luteal phase pregnanediol excretion was diminished in the perimenopausal women compared to that in younger normal subjects (range for integrated pregnanediol, 1.0-8.4 vs. 1.6-12.7 microg/mg Cr/luteal phase; P = 0.015). Compared to postmenopausal women, perimenopausal women had more overall estrone excretion (2.5-6.2 ng/mg Cr in postmenopausal women; P = 0.02) and lower mean FSH (range of means for postmenopause, 24-85 IU/g Cr; P = 0.017) and LH (range for postmenopause, 4.3-14.8 IU/g Cr; P = 0.041). Compared to women with premature menopause, perimenopausal women again had lower FSH (range of means for premature menopause, 36-82 IU/g Cr; P = 0.0022), lower LH (range of means for premature menopause, 5.5-23.8 IU/g Cr; P = 0.0092), borderline higher mean estrone conjugates (range of means for premature menopause, 4-44 ng/mg Cr; P = 0.064), and far longer periods of ovarian activity (one to two cycles in prematurely menopausal women vs. three to six cycles in perimenopausal women). We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.

J Clin Endocrinol Metab. 2015 Sep;100(9):3539-47. doi: 10.1210/JC.2015-2191. Epub 2015 Jun 30.
Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women.Shaw ND, Srouji SS, Welt CK, Cox KH, Fox JH, Adams JA, Sluss PM, Hall JE.
Abstract
CONTEXT:
Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function.
OBJECTIVE:
The objective of the study was to determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women.
DESIGN:
The protocol included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle.
SUBJECTS:
Healthy, regularly cycling older (36-45 y; n = 13) and younger (22-34 y; n = 14) women participated in the study.
MAIN OUTCOME MEASURES:
Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression were determined.
RESULTS:
Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and antimullerian hormone levels. Late follicular phase serum E2 did not differ between the two groups. Follicular fluid E2 [older (O) = 960.0 [interquartile range (IQR) 765.0-1419.0]; younger (Y) = 994.5 [647.3-1426.5] ng/mL, P = 1.0], estrone (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/mL, P = 0.3), and the E2 to testosterone (T) ratio (O = 109.0 ± 41.9; Y = 83.0 ± 18.6, P = .50) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (P < .001), with no difference in FSH-R expression. CONCLUSIONS: Ovarian aromatase expression increases with age in regularly cycling women. Thus, up-regulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older premenopausal women.

Exp Gerontol. 2013 Nov;48(11):1243-54. doi: 10.1016/j.exger.2013.07.001. Epub 2013 Jul 11.
The influence of aging and estradiol to progesterone ratio on rat macrophage phenotypic profile and NO and TNF-α production.
Dimitrijević M1, Stanojević S, Kuštrimović N, Mitić K, Vujić V, Aleksić I, Radojević K, Leposavić G.
The phenotype and function of tissue macrophages substantially depend on the cellular milieu and biological effector molecules, such as steroid hormones, to which they are exposed. Furthermore, in female rats, aging is associated with the altered macrophage functioning and the increased estrogen level is followed by a decrease in that of progesterone. Therefore, the present study aimed to investigate the influence of estradiol/progesterone balance on rat macrophage function and phenotype throughout whole adult lifespan. We ovariectomized rats at the late prepubertal age or at the very end of reproductive lifespan, and examined the expression of ED2 (CD163, a marker of mature resident macrophages related to secretion of inflammatory mediators) on peritoneal macrophages and their ability to produce TNF-α and NO upon LPS-stimulation at different age points. In addition, to delineate direct and indirect effects of estrogen, we assessed the in vitro influence of different concentrations of 17β-estradiol on LPS-induced macrophage TNF-α and NO production. Results showed that: (a) the low frequency of ED2(high) cells amongst peritoneal macrophages of aged rats was accompanied with the reduced TNF-α, but not NO production; (b) estradiol level gradually increased following ovariectomy; (c) macrophage ED2 expression and TNF-α production were dependent on estradiol/progesterone balance and they changed in the same direction; (d) changes in estradiol/progesterone balance differentially affected macrophages TNF-α and NO production; and (e) estradiol exerted pro-inflammatory and anti-inflammatory effects on macrophages in vivo and in vitro, respectively. Overall, our study discloses that estradiol/progesterone balance contributes to the fine-tuning of rat macrophage secretory capacity, and adds to a better understanding of the ovarian steroid hormone role in the regulation of macrophage function, and its significance for the age-associated changes in innate immunity.