{"slug":"estradiol-fsh","name":"Estradiol and FSH (women)","aliases":["E2","Follicle-stimulating hormone","Menopause hormone panel"],"kind":"biomarker","system":"chronobiology","unit":"pg/mL (estradiol) and mIU/mL (FSH)","unitNote":"Many laboratories outside the United States report estradiol in pmol/L; multiply pg/mL by about 3.67 for pmol/L. FSH in mIU/mL is numerically the same as IU/L.","answer":"A single estradiol or FSH rarely answers the question. In 1,215 women of the SWAN cohort followed through a natural final menstrual period, FSH began rising about six years before it and estradiol did not start falling until about two years before, with both settling about two years after; the STRAW+10 consensus stages the transition by cycle pattern and bleeding, with an FSH above 25 IU/L on a random draw only characteristic of the late transition, and the Endocrine Society's 2015 guideline diagnoses menopause by 12 months without a period and states that hormone measurements do not further inform the diagnosis. Guidelines do not use levels to decide or dose hormone therapy, standard immunoassays cannot read the postmenopausal values below about 20 pg/mL where the bone and vessel effects live, and no optimal estradiol for a woman after menopause who is not on therapy has been defined.","summary":"Estradiol is the ovary's main estrogen and FSH is the pituitary's signal asking for it. Across a cycle, estradiol runs from under about 30 pg/mL in the early follicular days to several hundred at the mid-cycle peak, and across the transition FSH climbs toward about 50 to 100 mIU/mL while estradiol settles below about 20. Laboratories print phase- and stage-specific ranges. The literature is firm that the pattern over years and the symptoms stage a woman, that one draw does not, that an undetectable estradiol in older women keeps company with fracture, and that the hormone-therapy trials carry benefits and risks that depend on age and years since menopause.","whatItIs":[{"text":"Estradiol is made by the ovarian follicle under the pituitary's follicle-stimulating hormone, and the two are wired in a loop: estradiol and the follicle's inhibins hold FSH down, and as the follicle supply thins the brake lifts and FSH rises. In 150 Australian women measured annually for six years through a natural menopause, log FSH and log estradiol were strongly inversely correlated (r = -0.73), inhibin A and B were undetectable in most women by the final period, and the authors concluded that falling estradiol and inhibins drive the rising FSH. In the ovary the aromatase gene (CYP19) that makes estradiol is itself switched on by FSH; after menopause the same gene runs in fat, bone, vessel wall and brain under different promoters, so that circulating estradiol in a postmenopausal woman is, in one endocrinologist's phrase, reactive rather than proactive: it reflects estrogen made and used locally rather than directing it.","cites":["burger1999","simpson2003"],"grade":"B"},{"text":"Across a cycle the two numbers move in opposite directions and over a wide range. When 30 healthy premenopausal women gave blood daily and estradiol was measured by a mass-spectrometry method traceable to the CDC reference, the interval ran from about 8 to 210 pg/mL in the early follicular phase (days -15 to -6 before the LH peak), about 28 to 475 in the late follicular phase, about 75 to 780 on the day of the LH peak, about 41 to 529 in the mid-luteal phase, and under about 7 in 33 postmenopausal women; 64 men ran about 3 to 37. FSH is read on days 2 to 5 of the cycle for the same reason. In 76 Australian women sampled three times a week through one cycle, FSH, LH and estradiol in ovulatory cycles all rose with advancing STRAW stage, luteal progesterone fell, and 9 of 23 cycles in the late transition were anovulatory against 2 of 21 in mid-reproductive age; anti-Müllerian hormone fell 10- to 15-fold across the stages.","cites":["verdonk2019","hale2007"],"grade":"C"},{"text":"Across the transition the clock runs on a schedule set by the final menstrual period, not by age. SWAN enrolled 3,302 menstruating women aged 42 to 52 at seven sites in 1996 and drew annual serum; in the 1,215 with a documented natural final menstrual period by 2006, FSH began rising 6.10 years before it, accelerated 2.05 years before, slowed 0.20 years before and reached a stable level 2.00 years after, independent of age at the final period, race or smoking, while mean estradiol did not change until 2.03 years before, fell fastest at the final period and stabilized 2.17 years after. Median FSH rose from 19.25 at baseline to 99.30 mIU/mL at the ninth visit and median estradiol fell from 55.08 to 18.40 pg/mL. The paths were not uniform: trajectory clustering in the same cohort found four estradiol patterns (slow decline 26.9 percent, flat 28.6, rise then slow decline 13.1, rise then steep decline 31.5) and three FSH patterns (low 10.6 percent, medium 48.7, high 41.7), with obesity raising the odds of a flat estradiol and low FSH path in every ethnic group.","cites":["randolph2011","tepper2012"],"grade":"B"}],"origins":[{"text":"The shelf's testosterone entry carries the argument that the estrogen receptor is the ancestral steroid receptor, so this entry begins with the stranger fact: the human ovary stops decades before the woman does. The mechanism is depletion. Counting non-growing follicles by modern stereology in 122 normal ovaries from birth to age 51, the decline was best described by a power function in which follicles disappear faster with increasing age, with no sudden change in rate, a model that matched observed ages at menopause and left a considerable share of the variation between women unexplained by age. In most species the reproductive system ages at the pace of the rest of the body and females reproduce until death; a post-reproductive lifespan of any length is rare. A comparative analysis of published ovarian data from 16 toothed whale species found a significant post-reproductive lifespan in three (short-finned pilot whales, belugas and narwhals), which with killer whales doubled the number of nonhuman mammals known to show one in the wild, and its phylogenetic reconstruction suggested the trait evolved several times independently. In two killer whale populations with multigenerational records, post-reproductive mothers raised the survival of their offspring, particularly their older sons.","cites":["hansen2008","ellis2018","foster2012"],"grade":"C"},{"text":"Why humans would evolve such a thing is a hypothesis with evidence and critics. The grandmother hypothesis, set out in 1998, proposes that long postmenopausal lifespans, which distinguish humans from all other primates, evolved with mother-child food sharing: an aging female who provisioned her daughters' weaned children raised those daughters' fertility, which strengthened selection against senescence; combined with Charnov's assembly rules for mammalian life histories, the authors argue it also accounts for our late maturity, small size at weaning and high fertility. A 2011 simulation study pushed back: across a wide range of conditions the inclusive-fitness benefits of grandmothering were too small to change the evolution of longevity, largely because selection is weak on women near or past the end of reproduction, although grandmothers could favor a shorter reproductive period when their help shortened the weaning age of their grandchildren. The authors concluded that grandmothering is unlikely to explain human-like longevity but that allocare could have shaped a later first birth and a shorter female reproductive span. Whether menopause is an adaptation, a by-product of a lifespan that outran the follicle supply, or some of each remains argued.","cites":["hawkes1998","kachel2011"],"grade":"C"},{"text":"In the network, estradiol does far more than reproduction, and FSH is the pituitary's running estimate of what is left in the ovary. The Endocrine Society's measurement statement lists estradiol's effects on skin, blood vessels, bone, muscle, coagulation, liver cells, fat, kidney, gut, brain, lung and pancreas; after menopause the hormone is made in the mesenchymal cells of fat, in osteoblasts and chondrocytes, in vascular endothelium and aortic smooth muscle and at many sites in the brain, acting where it is made. The perimenopausal symptoms themselves are largely neurological: thermoregulation, sleep, circadian rhythm and sensory processing are estrogen-regulated systems, and a 2015 review describes the brain's estrogen-receptor network uncoupling from its energy metabolism during the transition. FSH, for its part, reads the follicle pool indirectly through inhibin and estradiol feedback, which is why anti-Müllerian hormone, made by the growing follicles themselves, predicts the final period better. The binding protein sits in the middle: in 6,291 postmenopausal women from 13 studies, obese women had estradiol 47 percent higher, calculated free estradiol 89 percent higher and SHBG 46 percent lower than thin women, so that the two numbers on this page are read beside SHBG, and the shelf links to that entry rather than repeating it.","cites":["rosner2013","simpson2003","brinton2015","finkelstein2020","ehbccg2011"],"grade":"C"}],"labRange":{"typical":"Phase-specific for cycling women: estradiol from about 20 to 30 pg/mL in the early follicular days to several hundred at the mid-cycle peak on most laboratory reports, and under about 30 after menopause (under about 7 by mass spectrometry); FSH about 3 to 10 mIU/mL in the early follicular phase and above about 25 to 30 after menopause; every laboratory prints its own intervals and they differ by assay","claims":[{"text":"The best reference intervals are method-specific and stage-specific, and most printed ones are neither. In the daily-sampled mass-spectrometry series of 30 premenopausal women, early follicular estradiol ran about 8 to 210 pg/mL and the LH-peak day about 75 to 780, with postmenopausal women under about 7; an immunoassay prints different, usually higher, low-end figures, which is why the Endocrine Society's statement asks for a universal estradiol standard, reference ranges that are age- and sex-specific, and ranges specific to the stage of puberty, the stage of the cycle and the stage of menopause, none of which exist in harmonized form.","cites":["verdonk2019","rosner2013"],"grade":"B"},{"text":"After menopause the laboratory figures depend on the assay and the years since the final period. In SWAN, measured on an automated immunoassay with a detection limit of 1 pg/mL, adjusted mean estradiol was 30.01 pg/mL at the final period, 18.35 at two years after and 19.12 at eight years, while FSH was 66.50 at the final period, 91.58 at two years and 98.21 at eight, on an assay the authors note reads FSH somewhat higher than many clinical laboratories; in 629 Michigan women with 5,757 annual FSH values over 14 years, FSH averaged 34 mIU/mL across the two years before and one year after the final period and 54 at the plateau that began one year after it. In the 13-study pooled analysis, estradiol in the first year after menopause averaged 64.4 pmol/L (about 17.5 pg/mL); the Endocrine Society statement cites values of about 4.9 pg/mL within five years of the last period and about 1.3 beyond it when measured carefully, and notes that elderly women and men are often under 5.","cites":["randolph2011","sowers2008","ehbccg2011","rosner2013"],"grade":"B"},{"text":"The only consensus line on the FSH scale is a staging aid, not a diagnosis. STRAW+10 names an FSH greater than 25 IU/L in a random blood draw as characteristic of the late transition, adds that the figure approximates more than 40 IU/L in the older urine-based gonadotropin standards, and tells researchers to evaluate the appropriate value for the assay they use; it treats all biomarkers as supportive criteria because of the lack of assay standardization, says they should not be read as required for diagnosis, and considers menstrual cycle criteria to remain the most important criteria.","cites":["harlow2012"],"grade":"A"}]},"evidence":{"headline":"The pattern tells the time; the number does not. STRAW+10 stages reproductive aging by cycle length and bleeding, with FSH above 25 IU/L only characteristic of the late transition; in 1,215 SWAN women FSH rose from about six years before the final period and estradiol fell from about two years before, both settling two years after; the Endocrine Society diagnoses menopause by 12 months without a period and says hormone measurements do not further inform it; NAMS 2022 says serum hormone testing to guide hormone therapy is rarely needed and salivary testing is unreliable; in women over 65 an undetectable estradiol under 5 pg/mL carried a relative risk of 2.5 for hip and vertebral fracture; and the 27,347-woman WHI trials found a complex pattern of benefits and risks, no change in mortality over 18 years, and no case for treatment as chronic disease prevention.","scale":{"min":0,"max":100,"ticks":[0,25,50,75,100]},"bands":[{"label":"Common laboratory early follicular-phase reference range for cycling women (cycle days 2 to 5), about 3 to 10 mIU/mL; laboratories print their own","low":3,"high":10,"tone":"lab","source":"Typical US laboratories; Harlow 2012 (days 2 to 5)"},{"label":"Reproductive years and early transition: below the STRAW+10 late-transition line; the SWAN median at age 42 to 52 was 19.25 on an assay that reads higher than many clinical laboratories; a single value here says little without the cycle day","low":0,"high":25,"tone":"neutral","source":"Harlow 2012; Randolph 2011"},{"label":"Above 25 IU/L on a random draw is characteristic of the late transition in STRAW+10; the Michigan cohort averaged 34 mIU/mL across the two years before and one year after the final period, with estradiol in SWAN about 30 pg/mL at the final period","low":25,"high":40,"tone":"evidence","source":"Harlow 2012; Sowers 2008; Randolph 2011"},{"label":"Postmenopausal plateau: about 54 mIU/mL one year after the final period in Michigan, 67 at the final period and 92 to 98 at two to eight years in SWAN (73 at eight years in obese women); estradiol settles below about 20 pg/mL, often below 5","low":40,"high":100,"tone":"neutral","source":"Sowers 2008; Randolph 2011; Rosner 2013"},{"label":"Above 25 before age 40 with four or more months of missed periods meets the 2024 guideline criterion for premature ovarian insufficiency and belongs with a physician; on a combined pill the number is not interpretable (62.5 percent of menopausal women still read under 30 on the pill-free day 7)","low":25,"high":100,"tone":"caution","source":"Panay 2024; Creinin 1996"}],"claims":[{"text":"The staging system that the cohorts and guidelines use rests on bleeding, not blood. STRAW+10, drafted by scientists from five countries after reviewing the midlife cohorts, marks the early transition by a persistent difference of 7 days or more in the length of consecutive cycles, the late transition by an episode of amenorrhea of 60 days or longer (estimated to last one to three years, with FSH sometimes elevated into the menopausal range), and the final menstrual period only in retrospect, Stage +1a marking the end of the 12 months of amenorrhea required to define it; FSH keeps rising and estradiol keeps falling until about two years after the final period, and the whole early postmenopause lasts about five to eight years. The criteria are to be applied regardless of age, demographic, body size or lifestyle. The authors note that women with PCOS cannot be staged by menstrual criteria because their irregular cycles are not ovarian aging, that women after hysterectomy or endometrial ablation can be classified only as pre- or postmenopausal, and that in them a single FSH and estradiol may be ambiguous or misleading and at least one repeat is often required.","cites":["harlow2012"],"grade":"A"},{"text":"The guidelines keep the numbers out of the diagnosis and out of the dosing. The Endocrine Society's 2015 guideline suggests diagnosing menopause on the clinical criteria of the menstrual cycle (recommendation 1.1), states that in a woman with an intact uterus menopause is a clinical diagnosis based on cessation of menses for at least 12 months and that sex steroids, gonadotropins, inhibin B or anti-Müllerian hormone measurements do not further inform the diagnosis, allows repeated FSH and estradiol only after hysterectomy or with an unclear history (where elevated FSH and estradiol under 20 pg/mL on several occasions support but do not confirm it), says the measurements will not influence management unless a woman is seeking fertility, notes that clinicians usually do not measure estradiol to monitor therapy, and recommends against custom-compounded hormones, with scientific evidence lacking to justify salivary measurements. NAMS 2022 says the same in fewer words: salivary and urine hormone testing to determine dosing are unreliable and not recommended, serum hormone testing is rarely needed, and dosing by hormone testing is considered unreliable because of differences in pharmacokinetics and absorption, diurnal variation and within-person variability.","cites":["stuenkel2015","nams2022"],"grade":"A"},{"text":"The cohorts explain why. In 150 Melbourne women followed annually for six years through a natural menopause, FSH was on average 3 percent higher for each year of age and 2 percent lower for each kg/m2 of body mass index, estradiol about 9 percent lower per year of age, and the authors concluded that there is no single reliable hormonal marker of menopausal status for an individual woman. In 629 Michigan women with 5,757 FSH values over 14 years, four stages were visible only in the rate of change: a modest rise until seven years before the final period, a major acceleration from seven to two years before, an acute rise from two years before to one year after (mean FSH 34 mIU/mL), and a plateau from one year after (mean 54), and the authors offer that timing information, together with FSH level and cycle characteristics, as the way to judge a woman's stage. In SWAN, estradiol and FSH trajectories were not uniform across women, and body mass index and ethnicity changed the shape of both.","cites":["burger1999","sowers2008","tepper2012"],"grade":"B"},{"text":"What giving estrogen does was tested in the Women's Health Initiative: 27,347 postmenopausal women aged 50 to 79 at 40 US centers, randomized to conjugated equine estrogens with medroxyprogesterone acetate (8,506) or placebo (8,102) for a median 5.6 years if they had a uterus, or to estrogen alone (5,310) or placebo (5,429) for a median 7.2 years after hysterectomy, with 13 years of cumulative follow-up. During the combined-therapy intervention, coronary heart disease ran at a hazard ratio of 1.18 (196 versus 159 cases) and invasive breast cancer 1.24 (206 versus 155), with more stroke, pulmonary embolism, dementia in women aged 65 and over, gallbladder disease and urinary incontinence, and fewer hip fractures, less diabetes and fewer vasomotor symptoms; most risks and benefits dissipated after stopping, though breast cancer stayed elevated through cumulative follow-up (hazard ratio 1.28). With estrogen alone the picture was more balanced (coronary disease 0.94, breast cancer 0.79), and women aged 50 to 59 had more favorable results for mortality, heart attack and the global index. Neither regimen changed all-cause mortality. Absolute excess adverse events ran from 12 per 10,000 women a year at ages 50 to 59 to 38 at 70 to 79 on combined therapy, and from 19 fewer at 50 to 59 to 51 excess at 70 to 79 on estrogen alone. The authors concluded that the findings do not support the therapy for chronic disease prevention, although it is appropriate for symptom management in some women. With follow-up extended to 18 years and 7,489 deaths, all-cause mortality was 27.1 percent on hormone therapy and 27.6 percent on placebo (hazard ratio 0.99), with no difference in cardiovascular (1.00) or cancer mortality (1.03); the ratio of hazard ratios for women aged 50 to 59 against 70 to 79 was 0.61 during the intervention and 0.87 over the 18 years.","cites":["manson2013","manson2017"],"grade":"A"},{"text":"The guidelines read those trials through age and time since menopause, and this page reports their reading without endorsing a treatment. NAMS 2022 states that hormone therapy remains the most effective treatment for vasomotor symptoms and the genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture; that its risks differ by type, dose, duration, route, timing of initiation and whether a progestogen is used; that for women younger than 60 or within 10 years of menopause onset without contraindications the benefit-risk ratio is favorable for bothersome vasomotor symptoms and prevention of bone loss; and that for women starting more than 10 years from menopause onset or older than 60 the ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism and dementia. Its own absolute figures from the WHI: nine additional breast cancers per 10,000 person-years on combined therapy; six fewer hip fractures per 10,000 women a year on either regimen across all ages, but no reduction in hip fracture in the 50 to 59 subset; a stroke risk of about 5 per 10,000 person-years for combined therapy in younger women; and a doubling of all-cause dementia (23 cases per 10,000 women) when combined therapy was started after 65. The Endocrine Society's 2015 guideline concludes that benefits may exceed risks for the majority of symptomatic women under 60 or within 10 years of menopause, that current evidence does not justify use to prevent coronary disease, breast cancer or dementia, and, for women with primary ovarian insufficiency or early menopause, suggests therapy until the age of anticipated natural menopause (recommendation 3.4d). Whether any of this applies to a given woman is a decision made with her physician.","cites":["nams2022","stuenkel2015"],"grade":"A"},{"text":"At the low end, the estradiol a standard assay cannot see is the one that matters for bone. In women aged 65 and older in the Study of Osteoporotic Fractures, those with undetectable serum estradiol (under 5 pg/mL, 18 pmol/L) had a relative risk of 2.5 for later hip fracture and 2.5 for vertebral fracture compared with women whose estradiol was detectable (133 hip and 138 vertebral cases against randomly chosen controls, women on estrogen excluded, adjusted for age and weight); an SHBG of 34.7 nmol/L or higher carried relative risks of 2.0 and 2.3, and the two together 6.9 and 7.9. In 274 women of the same cohort, those with estradiol of 10 to 25 pg/mL had 4.9, 9.6, 7.3 and 6.8 percent greater bone density at the hip, heel, radius and spine than those under 5, about 0.4 standard deviations after adjustment, and vertebral deformities were less common above 5 (odds ratio 0.4). These are associations in older women, measured with the sensitive assays of the time.","cites":["cummings1998","ettinger1998"],"grade":"B"},{"text":"For the heart the observational signal points the same way and is thinner. In 2,834 postmenopausal women of the Multi-Ethnic Study of Atherosclerosis (mean age 64.9) followed 12.1 years, with 283 cardiovascular, 171 coronary and 103 heart failure events, each standard deviation of log estradiol carried a hazard ratio of 0.94 for cardiovascular disease, 0.77 for coronary disease and 0.78 for heart failure, while a higher testosterone-to-estradiol ratio ran the other way (1.19, 1.45 and 1.31). The result is one cohort, the measurements sit in the range the Endocrine Society calls too low to measure routinely with accuracy, and the trials above, which raised estradiol directly, found no mortality benefit, so the association is reported here as an association.","cites":["zhao2018","rosner2013","manson2017"],"grade":"C"},{"text":"As a measure of what is left in the ovary, FSH has been overtaken. In 1,537 SWAN women who were pre- or early perimenopausal at a mean age of 47.5 and were followed to 12 months of amenorrhea, anti-Müllerian hormone (AMH), measured on an assay with a detection limit of 1.85 pg/mL, predicted whether the final period would arrive within 24 months significantly better than FSH; a woman with an AMH under 10 pg/mL had a 51 percent chance of her final period within 12 months at under 48 years of age and 79 percent at 51 and older, while one above 100 pg/mL had a 97 to 90 percent chance of not reaching it in that year. The limits are real: in an individual-data meta-analysis of 2,596 regularly cycling women (1,077 reached menopause), age alone predicted time to menopause with a C-statistic of 84 percent and adding AMH raised it only to 86, although for early menopause before 45 AMH lifted the figure from 52 to 80 percent; individual predictions of the age at menopause remained imprecise. AMH is a better reserve marker than FSH and still not a calendar.","cites":["finkelstein2020","depmann2018"],"grade":"B"},{"text":"Two patterns at the edges have their own criteria. Premature ovarian insufficiency, loss of ovarian function before 40, has a prevalence the 2024 international guideline now puts at 3.5 percent, higher than previously thought; that guideline requires only one elevated FSH above 25 IU/L for the diagnosis, with repeat FSH or AMH where there is diagnostic uncertainty, where the 2016 ESHRE guideline had asked for two values more than four weeks apart. In polycystic ovary syndrome the gonadotropin pattern is the reverse of ovarian aging: among 61 women with the syndrome defined by irregular cycles and excess androgen, sampled every 10 minutes for 8 to 12 hours, 75 percent had an elevated pooled LH and 94 percent an elevated LH-to-FSH ratio once recently ovulatory women were set aside, with LH falling as body fat rose. A high FSH in a woman under 40 and a high LH relative to FSH in a woman with irregular cycles are both reasons for a physician, not a page.","cites":["panay2024","taylor1997"],"grade":"B"}]},"levers":[{"name":"Body fat after menopause","effect":"raises estradiol, raises free estradiol more, lowers SHBG and blunts the FSH rise","claim":{"text":"After the ovary stops, fat is the main estrogen source, and the scale shows it. Across 6,291 postmenopausal women in 13 prospective studies, obese women (body mass index 30 or more) had estradiol 47 percent higher, calculated free estradiol 89 percent higher and estrone 47 percent higher than thin women (under 22.5), with SHBG 46 percent lower; in the studies whose assays included a purification step, the estradiol difference was 82 percent. In SWAN, obesity attenuated the FSH rise and delayed its start to 5.45 years before the final period, and obese women ran lower FSH at every point (74 against 50 mIU/mL at the final period, 105 against 73 at eight years after) with higher estradiol after menopause (23 against 16 pg/mL at eight years). The adipose aromatase promoter answers to glucocorticoids and inflammatory cytokines, not to FSH, which is why body fat moves estradiol without the pituitary's say.","cites":["ehbccg2011","randolph2011","simpson2003"],"grade":"B"}},{"name":"Weight loss and exercise","effect":"weight loss lowers estradiol by about 16 to 20 percent over a year; exercise without fat loss does little","claim":{"text":"In a 12-month trial of 439 overweight or obese postmenopausal women aged 50 to 75 (mean body mass index 30.9), randomized to a reduced-calorie diet (118), aerobic exercise (117), both (117) or control (87), estradiol fell 16.2 percent with diet, 4.9 percent with exercise alone (not significant) and 20.3 percent with both, free estradiol fell 21.4 and 26.0 percent with diet and with both, estrone fell 9.6, 5.5 and 11.1 percent, and SHBG rose 22.4 and 25.8 percent; greater weight loss produced stronger effects. An earlier 12-month trial of 173 sedentary overweight postmenopausal women found estradiol down 7.7 percent at three months with 171 minutes a week of moderate exercise, no longer significant at 12 months, and significant only in women who lost 2 percent or more of body fat (13.7 percent lower estradiol). The lever is the fat, and exercise works on it when it moves the fat.","cites":["campbell2012","mctiernan2004"],"grade":"B"}},{"name":"Alcohol","effect":"raises estrone sulfate and DHEAS at one to two drinks a day; the estradiol effect is small and not shown in the feeding trial","claim":{"text":"In a controlled feeding study, 51 healthy postmenopausal women not on hormone therapy rotated in random order through three 8-week periods of 0, 15 and 30 g of alcohol a day with all food supplied and weight held constant; estrone sulfate rose 7.5 and 10.7 percent and DHEAS 5.1 and 7.5 percent, and estradiol and the other hormones did not change significantly. In the 13-study pooled cross-section, women drinking 20 g or more a day had higher levels of all the sex hormones than nondrinkers (DHEAS the largest, 25 percent) and SHBG 10 percent lower; the authors note that blood is usually drawn by day and alcohol drunk at night, and that estradiol's half-life of about three hours could hide an evening rise. The signal is modest, the mechanism is unknown, and the premenopausal cycle is not covered by either study.","cites":["dorgan2001","ehbccg2011"],"grade":"B"}},{"name":"Smoking","effect":"brings the final period about a year earlier; in postmenopausal women it raised, not lowered, the measured hormones","claim":{"text":"Across 46 studies in 24 countries the mean age at natural menopause was 48.8 years and smoking was associated with a reduction of about one year (weighted mean difference -0.91 years); education and occupation went with later menopause, and overweight and physical activity with modestly later menopause, less conclusively. The common statement that smoking lowers estrogen did not appear in the postmenopausal pooled data: women smoking 15 or more cigarettes a day had higher levels of all the sex hormones than never smokers, with the largest differences for androstenedione (18 percent), testosterone (20 percent) and free testosterone (19 percent) and no difference in SHBG. In SWAN, smoking shifted estradiol levels somewhat but not the pattern of change. Smoking's effect on the clock is better established than its effect on the number.","cites":["schoenaker2014","ehbccg2011","randolph2011"],"grade":"B"}},{"name":"Phytoestrogens","effect":"modestly fewer hot flashes in trials of mixed quality; no reliable effect on measured estradiol or FSH","claim":{"text":"Across 62 randomized trials with 6,653 women, phytoestrogens were associated with about 1.31 fewer hot flashes a day and a small improvement in vaginal dryness score (-0.31) but no significant change in night sweats; dietary and supplemental soy isoflavones gave about 0.79 fewer hot flashes a day. Forty-six of the trials (74 percent) carried a high risk of bias in three or more domains, and the authors call the evidence suboptimal and heterogeneous. The outcome measured was symptoms, not hormone levels; nothing here says soy moves the numbers on this page.","cites":["franco2016"],"grade":"C"}}],"caveats":[{"text":"Below about 20 to 30 pg/mL, most laboratory estradiol results are noise. The Endocrine Society's position statement puts the limit of quantitation of most direct immunoassays at 30 to 100 pg/mL, says current direct assays cannot accurately measure estradiol below 30 in children and are insensitive below 20 in cycling women, that most commercial assays cannot accurately measure the under-20 values of postmenopausal women, and that against a mass-spectrometry reference the immunoassays showed coefficients of variation from 4 to 49 percent and bias from 26 to 239 percent, with no method under 10 percent bias on every sample. It asks for methods that can measure 0.2 to 2 pg/mL, which is where the levels of elderly women and men sit, often under 5. A postmenopausal estradiol, or a man's, deserves liquid chromatography-tandem mass spectrometry before anyone reads it.","cites":["rosner2013"],"grade":"A"},{"text":"In a cycling woman the cycle day is half the result. By mass spectrometry the early follicular estradiol interval (about 8 to 210 pg/mL) and the LH-peak interval (about 75 to 780) barely overlap, FSH reference ranges describe days 2 to 5 only, and STRAW+10 defines its FSH criteria on early follicular (days 2 to 5) samples. An estradiol drawn on day 12 against a day-3 range, or an FSH drawn on day 20, is a number without a reference. In the late transition the problem compounds: 9 of 23 cycles were anovulatory in the Australian series, and anovulatory and long cycles print follicular-looking values at any calendar day.","cites":["verdonk2019","harlow2012","hale2007"],"grade":"B"},{"text":"Perimenopause swings. STRAW+10 describes early follicular FSH as elevated but variable in the early transition and only sometimes in the menopausal range in the late transition; in SWAN, 44.6 percent of women followed an estradiol path that rose before it fell, and in the Australian series estradiol in ovulatory cycles rose with advancing stage even as anovulatory cycles multiplied, which is why a perimenopausal woman can print a youthful estradiol one month and a postmenopausal one the next. The Melbourne cohort's conclusion stands: there is no single reliable hormonal marker of menopausal status for an individual woman. Symptoms, age and the cycle pattern over months stage the transition; a draw documents one day of it.","cites":["harlow2012","tepper2012","hale2007","burger1999"],"grade":"B"},{"text":"On hormonal contraception or hormone therapy the panel reads the pill. In 28 menopausal women given three cycles of a combined oral contraceptive, 15 of 24 completers (62.5 percent) still had an FSH under 30 mIU/mL on the seventh day of the pill-free interval, and the author concluded that measuring FSH there is not a sensitive test for menopause; estradiol under 20 pg/mL or an FSH-to-LH ratio above 1 on that day did better in this pilot of 28, which is too small to lean on. STRAW+10 adds that tamoxifen may alter FSH and estradiol and make them misleading. A woman on estrogen therapy has an estradiol that reflects her dose and route, and the guidelines do not use it to adjust them.","cites":["creinin1996","harlow2012","stuenkel2015"],"grade":"C"},{"text":"Assays disagree about FSH too, and the famous cutoffs come from particular ones. SWAN's authors note that the absolute FSH concentrations on their analyzer are somewhat higher than values from many clinical laboratories, which is why their postmenopausal plateau near 100 mIU/mL sits above the 54 of the Michigan cohort; STRAW+10's 25 IU/L is stated against current international pituitary standards and said to approximate more than 40 in the older urine-based standards, with the instruction to evaluate the right value for the assay in use. A woman's FSH should be compared with her own earlier values on the same assay before it is compared with a line from a paper.","cites":["randolph2011","sowers2008","harlow2012"],"grade":"B"},{"text":"Almost everything here is association, and the one causal test did not confirm the hoped-for direction. The fracture and coronary findings come from cohorts of older women; the randomized trials that raised estradiol found fewer hip fractures and more breast cancer, stroke and clots on combined therapy, and no change in all-cause mortality over 18 years. Circulating estradiol after menopause, in the words of the aromatase literature, reflects rather than directs estrogen action, so a low number is a description of where the ovary is, not a target. No trial has treated a woman without symptoms to a chosen estradiol to see whether anything improves.","cites":["cummings1998","zhao2018","manson2013","manson2017","simpson2003"],"grade":"B"}],"seeAPhysician":["Any vaginal bleeding after 12 months without a period, whatever the hormone levels show, since the question is the lining of the uterus and not the ovary.","Periods that stop or become infrequent for four months or more before age 40, which with an FSH above 25 meets the criterion for premature ovarian insufficiency, a diagnosis that carries bone, heart and fertility consequences and a guideline recommendation about replacement that only a physician can weigh with her.","Periods that become irregular before 45 with heavy bleeding, cycles that crowd together or stretch past 60 days, or bleeding between periods, where the cycle pattern is the diagnostic information and where other causes need excluding.","Hot flashes, night sweats, sleep loss, mood change or vaginal symptoms severe enough to interfere with life, at any stage of the transition; these are the symptoms the guidelines treat, and the treatment decision rests on them and on her history, not on a level.","Anyone considering or taking hormone therapy, in any form, including compounded or over-the-counter products, who should hear the benefits and the absolute risks the guidelines list, by her age and years since menopause, before and during use; levels are not how the guidelines dose it.","An FSH that is low or normal in a woman whose periods have stopped and who has headaches, visual change, milky nipple discharge, marked weight change or very low body weight, which points to the pituitary or the hypothalamus rather than the ovary.","Irregular cycles with acne, excess facial or body hair or scalp hair thinning and an LH that runs above FSH, which is a polycystic ovary syndrome assessment rather than a menopause question.","A clearly elevated estradiol in a man or a child, or any sign of early puberty or breast development in a boy, which needs an endocrine evaluation and a mass-spectrometry repeat before anything else."],"openQuestions":["No optimal estradiol for a postmenopausal woman who is not taking estrogen has been defined by any guideline or trial; the fracture cohorts mark harm under about 5 pg/mL, nothing marks a floor above it, and most laboratories cannot measure the range in question.","The timing hypothesis, that estrogen started early in the postmenopause is safer or protective and started late is harmful, is how NAMS and the Endocrine Society read the WHI age subgroups, but it rests on subgroup and observational data and NAMS itself says it has not been definitively supported in randomized trials for cognition; whether early therapy prevents disease rather than treats symptoms is unresolved.","FSH or AMH: AMH predicted the final period better than FSH in SWAN, yet it added only two points to age alone in the pooled analysis and its assays are not standardized, which STRAW+10 lists as its first research priority; what a single AMH should mean to a 42-year-old without symptoms is not settled.","Why the paths differ: four estradiol and three FSH trajectories were found in SWAN, shaped by body mass index and ethnicity, and whether the shape of a woman's path predicts her symptoms, her bone loss or her vascular aging better than her final level is still being worked out.","Whether menopause is an adaptation, as the grandmother hypothesis holds, or the by-product of a lifespan that outran a follicle supply that depletes on a fixed curve, remains argued, and the whale data suggest the trait has evolved more than once."],"questions":[{"q":"What FSH level means menopause?","a":"None on its own. Menopause is diagnosed in retrospect, 12 months after the last period, and the Endocrine Society's guideline says hormone measurements do not add to that diagnosis in a woman with a uterus. The consensus staging system treats an FSH above 25 mIU/mL on a random draw as characteristic of the late transition, the one to three years of 60-day gaps before the final period, and cohorts found FSH averaging about 34 around the final period and about 54 to 100 a year or two after it depending on the assay. A woman in the late transition can print 40 one month and 12 the next. Where the number does carry weight is before 40: an FSH above 25 with four months of missed periods meets the criterion for premature ovarian insufficiency and needs a physician."},{"q":"What is a normal estradiol level for a 45-year-old woman?","a":"It depends on the day of her cycle and where she is in the transition, more than on her age. By mass spectrometry a cycling woman runs about 8 to 210 pg/mL in the first days of a cycle and about 75 to 780 on the day of the LH surge; most laboratories print somewhat different immunoassay figures. In SWAN the median at ages 42 to 52 was 55 pg/mL and the average at the final period itself was 30, but about 45 percent of women followed a path that rose before it fell, so a 45-year-old with 60-day gaps can print anything from a youthful value to a postmenopausal one. If her periods are regular, the number is almost certainly in range; if they are not, the pattern of her cycles over the next months tells more than the draw."},{"q":"Can a blood test tell me if I am in perimenopause?","a":"Not reliably, which is why the guidelines do not use one. Perimenopause is staged by the cycles: a persistent change of seven days or more between consecutive cycle lengths marks the early transition and a gap of 60 days or more marks the late one, with symptoms alongside. FSH rises in the early transition but is, in the consensus wording, elevated but variable, and the Melbourne cohort concluded there is no single reliable hormonal marker of menopausal status for an individual woman. On the combined pill the test is uninterpretable. Anti-Müllerian hormone predicts the final period better than FSH but mostly in women already near it. A diary of cycles and symptoms is the test; a physician reads it, and draws blood when there is a specific question, such as periods stopping before 40."}],"citations":[{"id":"harlow2012","authors":"Harlow SD, Gass M, Hall JE, Lobo R, Maki P, Rebar RW, Sherman S, Sluss PM, de Villiers TJ; STRAW + 10 Collaborative Group","title":"Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging","journal":"Journal of Clinical Endocrinology and Metabolism","year":2012,"pmid":"22344196","doi":"10.1210/jc.2011-3362","type":"consensus","finding":"Staging rests on menstrual criteria (early transition: persistent 7-day or greater difference in consecutive cycle lengths; late transition: amenorrhea of 60 days or longer, lasting 1 to 3 years); an FSH above 25 IU/L on a random draw is characteristic of the late transition (about 40 in older urine-based standards); biomarkers are supportive, not required; FSH rises and estradiol falls until about 2 years after the final period; applicable regardless of age, BMI or lifestyle; PCOS not stageable; a single sample after hysterectomy may mislead.","url":"https://pubmed.ncbi.nlm.nih.gov/22344196/"},{"id":"randolph2011","authors":"Randolph JF Jr, Zheng H, Sowers MR, Crandall C, Crawford S, Gold EB, Vuga M","title":"Change in follicle-stimulating hormone and estradiol across the menopausal transition: effect of age at the final menstrual period","journal":"Journal of Clinical Endocrinology and Metabolism","year":2011,"pmid":"21159842","doi":"10.1210/jc.2010-1746","type":"cohort","finding":"In 1,215 SWAN women with a natural final menstrual period, FSH began rising 6.10 years before it and stabilized 2.00 years after; estradiol began falling 2.03 years before and stabilized 2.17 years after; obesity attenuated and delayed the FSH rise; median FSH 19.25 to 99.30 IU/L and estradiol 55.08 to 18.40 pg/mL from baseline to visit 9; the assay reads FSH higher than many clinical laboratories.","url":"https://pubmed.ncbi.nlm.nih.gov/21159842/"},{"id":"tepper2012","authors":"Tepper PG, Randolph JF Jr, McConnell DS, Crawford SL, El Khoudary SR, Joffe H, Gold EB, Zheng H, et al.","title":"Trajectory clustering of estradiol and follicle-stimulating hormone during the menopausal transition among women in the Study of Women's Health across the Nation (SWAN)","journal":"Journal of Clinical Endocrinology and Metabolism","year":2012,"pmid":"22659249","doi":"10.1210/jc.2012-1422","type":"cohort","finding":"Four estradiol trajectories (slow decline 26.9 percent, flat 28.6, rise/slow decline 13.1, rise/steep decline 31.5) and three FSH trajectories (low 10.6, medium 48.7, high 41.7 percent); obesity raised the odds of a flat estradiol and low FSH path in every ethnic group.","url":"https://pubmed.ncbi.nlm.nih.gov/22659249/"},{"id":"sowers2008","authors":"Sowers MR, Zheng H, McConnell D, Nan B, Harlow S, Randolph JF Jr","title":"Follicle stimulating hormone and its rate of change in defining menopause transition stages","journal":"Journal of Clinical Endocrinology and Metabolism","year":2008,"pmid":"18647816","doi":"10.1210/jc.2008-0482","type":"cohort","finding":"In 629 Michigan women with 5,757 annual FSH values over 14 years, four stages were defined by the rate of FSH change: modest rise to -7 years, major acceleration -7 to -2, acute rise -2 to +1 (mean FSH 34 mIU/mL), plateau from +1 year (mean 54 mIU/mL).","url":"https://pubmed.ncbi.nlm.nih.gov/18647816/"},{"id":"burger1999","authors":"Burger HG, Dudley EC, Hopper JL, Groome N, Guthrie JR, Green A, Dennerstein L","title":"Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women","journal":"Journal of Clinical Endocrinology and Metabolism","year":1999,"pmid":"10566644","doi":"10.1210/jcem.84.11.6158","type":"cohort","finding":"In 150 women measured annually for 6 years through natural menopause, FSH rose from about 2 years before the final period and plateaued by 2 years after, 3 percent higher per year of age and 2 percent lower per kg/m2; estradiol fell on the same schedule, about 9 percent lower per year of age; log FSH and log estradiol correlated at r = -0.73; no single reliable hormonal marker of menopausal status exists for an individual woman.","url":"https://pubmed.ncbi.nlm.nih.gov/10566644/"},{"id":"hale2007","authors":"Hale GE, Zhao X, Hughes CL, Burger HG, Robertson DM, Fraser IS","title":"Endocrine features of menstrual cycles in middle and late reproductive age and the menopausal transition classified according to the Staging of Reproductive Aging Workshop (STRAW) staging system","journal":"Journal of Clinical Endocrinology and Metabolism","year":2007,"pmid":"17550960","doi":"10.1210/jc.2007-0066","type":"cross-sectional","finding":"In 76 women sampled three times a week through one cycle, ovulatory-cycle FSH, LH and estradiol rose with STRAW stage and luteal progesterone fell; 9 of 23 late-transition cycles were anovulatory against 2 of 21 in mid-reproductive age; AMH fell 10- to 15-fold across stages.","url":"https://pubmed.ncbi.nlm.nih.gov/17550960/"},{"id":"verdonk2019","authors":"Verdonk SJE, Vesper HW, Martens F, Sluss PM, Hillebrand JJ, Heijboer AC","title":"Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method","journal":"Clinica Chimica Acta","year":2019,"pmid":"30981845","doi":"10.1016/j.cca.2019.04.062","type":"laboratory","finding":"By an LC-MS/MS method traceable to the CDC reference, in 30 women sampled daily: early follicular 31 to 771 pmol/L, late follicular 104 to 1,742, LH peak 275 to 2,864, early luteal 95 to 1,188, mid-luteal 151 to 1,941, late luteal 39 to 1,769; postmenopausal women (33) under 26 pmol/L; men (64) 12 to 136 pmol/L.","url":"https://pubmed.ncbi.nlm.nih.gov/30981845/"},{"id":"stuenkel2015","authors":"Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ","title":"Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline","journal":"Journal of Clinical Endocrinology and Metabolism","year":2015,"pmid":"26444994","doi":"10.1210/jc.2015-2236","type":"guideline","finding":"Diagnose menopause on clinical criteria of the menstrual cycle (1.1); hormone measurements do not further inform the diagnosis and will not influence management unless fertility is sought; after hysterectomy, repeated FSH and estradiol under 20 pg/mL support but do not confirm; clinicians usually do not measure estradiol to monitor therapy; against custom-compounded hormones, evidence lacking for salivary testing; benefits may exceed risks for most symptomatic women under 60 or within 10 years; not for prevention of coronary disease, breast cancer or dementia; POI and early menopause: therapy until anticipated natural menopause (3.4d).","url":"https://pubmed.ncbi.nlm.nih.gov/26444994/"},{"id":"nams2022","authors":"The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel (Faubion SS, Crandall CJ, Davis L, El Khoudary SR, Hodis HN, Lobo RA, Maki PM, Manson JE, et al.)","title":"The 2022 hormone therapy position statement of The North American Menopause Society","journal":"Menopause","year":2022,"pmid":"35797481","doi":"10.1097/GME.0000000000002028","type":"consensus","finding":"Hormone therapy is the most effective treatment for vasomotor symptoms and genitourinary syndrome and prevents bone loss and fracture; risks differ by type, dose, duration, route, timing and progestogen; favorable benefit-risk under 60 or within 10 years of menopause, less favorable beyond because of greater absolute risks of coronary disease, stroke, venous thromboembolism and dementia; salivary and urine hormone testing to determine dosing unreliable and not recommended, serum testing rarely needed; WHI absolute figures: 9 extra breast cancers and 6 fewer hip fractures per 10,000 per year on combined therapy, stroke about 5 per 10,000 in younger women, dementia 23 per 10,000 when started after 65.","url":"https://pubmed.ncbi.nlm.nih.gov/35797481/"},{"id":"manson2013","authors":"Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, et al.","title":"Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials","journal":"JAMA","year":2013,"pmid":"24084921","doi":"10.1001/jama.2013.278040","type":"rct","finding":"In 27,347 women aged 50 to 79 over 13 years, combined therapy raised coronary disease (hazard ratio 1.18), breast cancer (1.24, 1.28 cumulative), stroke, pulmonary embolism, dementia after 65, gallbladder disease and incontinence, and lowered hip fracture, diabetes and vasomotor symptoms; estrogen alone was more balanced (coronary 0.94, breast cancer 0.79); neither changed all-cause mortality; absolute excess 12 to 38 per 10,000 per year by age on combined therapy, 19 fewer to 51 excess on estrogen alone; not for chronic disease prevention.","url":"https://pubmed.ncbi.nlm.nih.gov/24084921/"},{"id":"manson2017","authors":"Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Chlebowski RT, Howard BV, et al.; WHI Investigators","title":"Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials","journal":"JAMA","year":2017,"pmid":"28898378","doi":"10.1001/jama.2017.11217","type":"rct","finding":"Over 18 years with 7,489 deaths, all-cause mortality was 27.1 percent on hormone therapy and 27.6 percent on placebo (hazard ratio 0.99), cardiovascular 1.00, cancer 1.03; ratio of hazard ratios for ages 50 to 59 versus 70 to 79 was 0.61 during intervention and 0.87 cumulatively.","url":"https://pubmed.ncbi.nlm.nih.gov/28898378/"},{"id":"cummings1998","authors":"Cummings SR, Browner WS, Bauer D, Stone K, Ensrud K, Jamal S, Ettinger B; Study of Osteoporotic Fractures Research Group","title":"Endogenous hormones and the risk of hip and vertebral fractures among older women","journal":"New England Journal of Medicine","year":1998,"pmid":"9731089","doi":"10.1056/NEJM199809103391104","type":"cohort","finding":"In women 65 and older (133 hip and 138 vertebral fracture cases versus controls), undetectable estradiol under 5 pg/mL carried a relative risk of 2.5 for hip and 2.5 for vertebral fracture; SHBG of 34.7 nmol/L or more 2.0 and 2.3; both together 6.9 and 7.9.","url":"https://pubmed.ncbi.nlm.nih.gov/9731089/"},{"id":"ettinger1998","authors":"Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR","title":"Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study of osteoporotic fractures","journal":"Journal of Clinical Endocrinology and Metabolism","year":1998,"pmid":"9661589","doi":"10.1210/jcem.83.7.4708","type":"cross-sectional","finding":"In 274 women 65 and older, estradiol of 10 to 25 pg/mL went with 4.9, 9.6, 7.3 and 6.8 percent greater bone density at hip, calcaneus, radius and spine than under 5 pg/mL (about 0.4 SD adjusted); vertebral deformities less prevalent above 5 (odds ratio 0.4).","url":"https://pubmed.ncbi.nlm.nih.gov/9661589/"},{"id":"zhao2018","authors":"Zhao D, Guallar E, Ouyang P, Subramanya V, Vaidya D, Ndumele CE, Lima JA, Allison MA, et al.","title":"Endogenous Sex Hormones and Incident Cardiovascular Disease in Post-Menopausal Women","journal":"Journal of the American College of Cardiology","year":2018,"pmid":"29852978","doi":"10.1016/j.jacc.2018.01.083","type":"cohort","finding":"In 2,834 MESA postmenopausal women (mean age 64.9) over 12.1 years, per SD of log estradiol the hazard ratios were 0.94 for cardiovascular disease, 0.77 for coronary disease and 0.78 for heart failure; a higher testosterone/estradiol ratio ran 1.19, 1.45 and 1.31.","url":"https://pubmed.ncbi.nlm.nih.gov/29852978/"},{"id":"rosner2013","authors":"Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME","title":"Challenges to the measurement of estradiol: an endocrine society position statement","journal":"Journal of Clinical Endocrinology and Metabolism","year":2013,"pmid":"23463657","doi":"10.1210/jc.2012-3780","type":"consensus","finding":"Most direct immunoassays have a limit of quantitation of 30 to 100 pg/mL, cannot accurately measure postmenopausal values under 20 pg/mL and are insensitive below 20 in cycling women; immunoassays against GC/MS showed CVs of 4 to 49 percent and bias of 26 to 239 percent; elderly women and men often under 5 pg/mL; calls for a universal standard, age-, sex- and stage-specific ranges, and methods for 0.2 to 2 pg/mL; estradiol acts on skin, vessels, bone, muscle, coagulation, liver, fat, kidney, gut, brain, lung and pancreas.","url":"https://pubmed.ncbi.nlm.nih.gov/23463657/"},{"id":"finkelstein2020","authors":"Finkelstein JS, Lee H, Karlamangla A, Neer RM, Sluss PM, Burnett-Bowie SM, Darakananda K, Donahoe PK, et al.","title":"Antimullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women's Health Across the Nation","journal":"Journal of Clinical Endocrinology and Metabolism","year":2020,"pmid":"31965189","doi":"10.1210/clinem/dgz283","type":"cohort","finding":"In 1,537 SWAN women (mean age 47.5), AMH predicted the final period within 24 months better than FSH; AMH under 10 pg/mL gave a 51 to 79 percent probability of the final period within 12 months by age; above 100 pg/mL a 97 to 90 percent probability of not reaching it.","url":"https://pubmed.ncbi.nlm.nih.gov/31965189/"},{"id":"depmann2018","authors":"Depmann M, Eijkemans MJC, Broer SL, Tehrani FR, Solaymani-Dodaran M, Azizi F, Lambalk CB, Randolph JF Jr, et al.","title":"Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis","journal":"Journal of Clinical Endocrinology and Metabolism","year":2018,"pmid":"30032277","doi":"10.1210/jc.2018-00724","type":"meta-analysis","finding":"In 2,596 regularly cycling women (1,077 reached menopause), age alone predicted time to menopause with a C-statistic of 84 percent and age plus AMH 86 percent; for early menopause (45 or younger) AMH raised it from 52 to 80 percent; individual predictions remained imprecise.","url":"https://pubmed.ncbi.nlm.nih.gov/30032277/"},{"id":"panay2024","authors":"Panay N, Anderson RA, Bennie A, Cedars M, Davies M, Ee C, Gravholt CH, Kalantaridou S, et al.; ESHRE, ASRM, CREWHIRL, and IMS Guideline Group on POI","title":"Evidence-based guideline: premature ovarian insufficiency","journal":"Human Reproduction Open","year":2024,"pmid":"39660328","doi":"10.1093/hropen/hoae065","type":"guideline","finding":"Prevalence of premature ovarian insufficiency now estimated at 3.5 percent; only one elevated FSH above 25 IU/L is required for diagnosis, with AMH testing or repeat FSH where there is diagnostic uncertainty; 145 recommendations covering sequelae and hormone therapy.","url":"https://pubmed.ncbi.nlm.nih.gov/39660328/"},{"id":"taylor1997","authors":"Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld D, Hall JE","title":"Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome","journal":"Journal of Clinical Endocrinology and Metabolism","year":1997,"pmid":"9215302","doi":"10.1210/jcem.82.7.4105","type":"cross-sectional","finding":"Among 61 women with PCOS defined by oligomenorrhea and hyperandrogenism, sampled every 10 minutes for 8 to 12 hours, 75 percent had an elevated pooled LH and 94 percent an elevated LH-to-FSH ratio after excluding recently ovulatory women; LH fell with rising body mass index and body fat.","url":"https://pubmed.ncbi.nlm.nih.gov/9215302/"},{"id":"ehbccg2011","authors":"Endogenous Hormones and Breast Cancer Collaborative Group; Key TJ, Appleby PN, Reeves GK, Roddam AW, Helzlsouer KJ, Alberg AJ, Rollison DE, et al.","title":"Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies","journal":"British Journal of Cancer","year":2011,"pmid":"21772329","doi":"10.1038/bjc.2011.254","type":"cross-sectional","finding":"In 6,291 postmenopausal women from 13 prospective studies, obese versus thin women had estradiol 47 percent higher (82 percent with purified assays), free estradiol 89 percent higher and SHBG 46 percent lower; smokers of 15 or more cigarettes a day and drinkers of 20 g or more a day had higher levels of all sex hormones; estradiol in the first year after menopause averaged 64.4 pmol/L.","url":"https://pubmed.ncbi.nlm.nih.gov/21772329/"},{"id":"schoenaker2014","authors":"Schoenaker DA, Jackson CA, Rowlands JV, Mishra GD","title":"Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents","journal":"International Journal of Epidemiology","year":2014,"pmid":"24771324","doi":"10.1093/ije/dyu094","type":"meta-analysis","finding":"Across 46 studies in 24 countries, mean age at natural menopause was 48.8 years; smoking was associated with a 1-year reduction (weighted mean difference -0.91 years); education went with later menopause; overweight and physical activity modestly and less conclusively with later menopause.","url":"https://pubmed.ncbi.nlm.nih.gov/24771324/"},{"id":"campbell2012","authors":"Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, et al.","title":"Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial","journal":"Journal of Clinical Oncology","year":2012,"pmid":"22614972","doi":"10.1200/JCO.2011.37.9792","type":"rct","finding":"In 439 overweight postmenopausal women over 12 months, estradiol fell 16.2 percent with diet, 4.9 percent (not significant) with exercise and 20.3 percent with both; free estradiol fell 21.4 and 26.0 percent; SHBG rose 22.4 and 25.8 percent; greater weight loss gave stronger effects.","url":"https://pubmed.ncbi.nlm.nih.gov/22614972/"},{"id":"mctiernan2004","authors":"McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, et al.","title":"Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial","journal":"Cancer Research","year":2004,"pmid":"15087413","doi":"10.1158/0008-5472.can-03-3393","type":"rct","finding":"In 173 sedentary overweight postmenopausal women, 12 months of moderate exercise (171 minutes a week) lowered estradiol 7.7 percent at 3 months, no longer significant at 12 months; women who lost 2 percent or more body fat had estradiol 13.7 percent lower than controls.","url":"https://pubmed.ncbi.nlm.nih.gov/15087413/"},{"id":"dorgan2001","authors":"Dorgan JF, Baer DJ, Albert PS, Judd JT, Brown ED, Corle DK, Campbell WS, Hartman TJ, et al.","title":"Serum hormones and the alcohol-breast cancer association in postmenopausal women","journal":"Journal of the National Cancer Institute","year":2001,"pmid":"11333294","doi":"10.1093/jnci/93.9.710","type":"rct","finding":"In a controlled feeding crossover of 51 postmenopausal women through 8-week periods of 0, 15 and 30 g alcohol a day, estrone sulfate rose 7.5 and 10.7 percent and DHEAS 5.1 and 7.5 percent; estradiol and the other hormones did not change significantly.","url":"https://pubmed.ncbi.nlm.nih.gov/11333294/"},{"id":"franco2016","authors":"Franco OH, Chowdhury R, Troup J, Voortman T, Kunutsor S, Kavousi M, Oliver-Williams C, Muka T","title":"Use of Plant-Based Therapies and Menopausal Symptoms: A Systematic Review and Meta-analysis","journal":"JAMA","year":2016,"pmid":"27327802","doi":"10.1001/jama.2016.8012","type":"meta-analysis","finding":"Across 62 randomized trials with 6,653 women, phytoestrogens were associated with 1.31 fewer daily hot flashes and a 0.31 lower vaginal dryness score, no significant change in night sweats; soy isoflavones 0.79 fewer hot flashes; 74 percent of trials at high risk of bias.","url":"https://pubmed.ncbi.nlm.nih.gov/27327802/"},{"id":"creinin1996","authors":"Creinin MD","title":"Laboratory criteria for menopause in women using oral contraceptives","journal":"Fertility and Sterility","year":1996,"pmid":"8752618","doi":"10.1016/s0015-0282(16)58394-0","type":"cross-sectional","finding":"In 28 menopausal women given three cycles of a combined oral contraceptive, 15 of 24 completers (62.5 percent) still had FSH under 30 mIU/mL on day 7 of the pill-free interval; FSH there is not a sensitive test for menopause; estradiol under 20 pg/mL or FSH:LH above 1 on that day did better.","url":"https://pubmed.ncbi.nlm.nih.gov/8752618/"},{"id":"hansen2008","authors":"Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA","title":"A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause","journal":"Human Reproduction","year":2008,"pmid":"18192670","doi":"10.1093/humrep/dem408","type":"laboratory","finding":"Stereological counts of non-growing follicles in 122 normal ovaries from birth to age 51 were best fit by a power function in which follicles decay faster with increasing age, with no sudden change in rate; the model matched observed ages at menopause, with much between-woman variation unexplained by age.","url":"https://pubmed.ncbi.nlm.nih.gov/18192670/"},{"id":"ellis2018","authors":"Ellis S, Franks DW, Nattrass S, Currie TE, Cant MA, Giles D, Balcomb KC, Croft DP","title":"Analyses of ovarian activity reveal repeated evolution of post-reproductive lifespans in toothed whales","journal":"Scientific Reports","year":2018,"pmid":"30150784","doi":"10.1038/s41598-018-31047-8","type":"laboratory","finding":"In most species the reproductive system ages with the soma; of 16 toothed whale species with ovarian data, three (short-finned pilot whales, belugas, narwhals) show a significant post-reproductive lifespan, doubling with killer whales the known nonhuman mammals; phylogenetic reconstruction suggests several independent origins.","url":"https://pubmed.ncbi.nlm.nih.gov/30150784/"},{"id":"foster2012","authors":"Foster EA, Franks DW, Mazzi S, Darden SK, Balcomb KC, Ford JK, Croft DP","title":"Adaptive prolonged postreproductive life span in killer whales","journal":"Science","year":2012,"pmid":"22984064","doi":"10.1126/science.1224198","type":"cohort","finding":"In multigenerational records of two killer whale populations, postreproductive mothers increased the survival of their offspring, particularly older male offspring.","url":"https://pubmed.ncbi.nlm.nih.gov/22984064/"},{"id":"hawkes1998","authors":"Hawkes K, O'Connell JF, Jones NG, Alvarez H, Charnov EL","title":"Grandmothering, menopause, and the evolution of human life histories","journal":"Proceedings of the National Academy of Sciences of the United States of America","year":1998,"pmid":"9448332","doi":"10.1073/pnas.95.3.1336","type":"review","finding":"Long postmenopausal lifespans distinguish humans from all other primates and may have evolved with mother-child food sharing that let aging females raise their daughters' fertility, increasing selection against senescence; with Charnov's assembly rules this also accounts for late maturity, small size at weaning and high fertility.","url":"https://pubmed.ncbi.nlm.nih.gov/9448332/"},{"id":"kachel2011","authors":"Kachel AF, Premo LS, Hublin JJ","title":"Grandmothering and natural selection","journal":"Proceedings of the Royal Society B: Biological Sciences","year":2011,"pmid":"20739319","doi":"10.1098/rspb.2010.1247","type":"laboratory","finding":"In simulated populations the inclusive fitness benefits of grandmothering were too small to affect the evolution of longevity across a wide range of conditions, because selection is weak near or beyond the end of reproduction; grandmothers could favor a shorter reproductive period by lowering weaning age.","url":"https://pubmed.ncbi.nlm.nih.gov/20739319/"},{"id":"simpson2003","authors":"Simpson ER","title":"Sources of estrogen and their importance","journal":"Journal of Steroid Biochemistry and Molecular Biology","year":2003,"pmid":"14623515","doi":"10.1016/s0960-0760(03)00360-1","type":"review","finding":"After menopause estradiol is made in fat, bone, vascular endothelium and smooth muscle and brain and acts locally, so circulating levels reflect rather than direct estrogen action; ovarian CYP19 is driven by FSH through promoter II, adipose and bone CYP19 by promoter I.4 under glucocorticoids and cytokines.","url":"https://pubmed.ncbi.nlm.nih.gov/14623515/"},{"id":"brinton2015","authors":"Brinton RD, Yao J, Yin F, Mack WJ, Cadenas E","title":"Perimenopause as a neurological transition state","journal":"Nature Reviews Endocrinology","year":2015,"pmid":"26007613","doi":"10.1038/nrendo.2015.82","type":"review","finding":"The symptoms of perimenopause are largely neurological, reflecting disruption of estrogen-regulated thermoregulation, sleep, circadian rhythm and sensory processing; the brain's estrogen receptor network uncouples from its bioenergetic system during the transition.","url":"https://pubmed.ncbi.nlm.nih.gov/26007613/"}],"written":"2026-10-10","updated":"2026-10-10","reviewed":true,"reviewedOn":"2026-10-12","related":{"essays":["plastics-bpa-and-hormone-disruption"],"glossary":["SHBG","Bioidenticals","Reference range"],"symptoms":["perimenopause","hormonal-imbalance","pms-or-cycle-issues","poor-sleep"],"entries":["shbg","testosterone-men","ferritin","vitamin-d","tsh","cortisol","dhea-s"]},"url":"https://taggehealth.com/labs/estradiol-fsh","author":"Daniel Tagge, MD","publisher":"Tagge Health","license":"Free to read and cite with attribution to the URL above."}