Estimated Ovulatory Years Prior to Menopause and Postmenopausal Endogenous Hormone Levels.

BACKGROUND: Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones. METHODS: Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses' Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated. RESULTS: Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI. CONCLUSIONS: This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone. IMPACT: A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.

Menstrual cycle characteristics and steroid hormone, prolactin, and growth factor levels in premenopausal women.

PURPOSE: Menstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse. METHODS: We assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32-52) from the Nurses' Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models. RESULTS: Early age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference < 12 vs. > 13 years = 11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all p trend < 0.05). Short menstrual cycle length at age 18-22 was associated with higher early-follicular total (< 26 vs. > 39 days = 18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (- 14%), total (- 6%), and free testosterone (- 15%) (all p trend < 0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (< 26 vs. > 31 days = 14%), SHBG (10%), lower luteal estrone (- 8%), progesterone (- 9%), total (- 11%) and free testosterone (- 25%), and androstenedione (- 14%) (all p trend < 0.05). Irregularity of menses at 18-22 was associated with lower early-follicular total (irregular vs. very regular = - 14%) and free estradiol (- 14%), and early-follicular estrone (- 8%) (All p trend < 0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular = - 8%), SHBG (- 3%), higher total (8%), and free testosterone (11%) (all p trend < 0.05). CONCLUSIONS: Early-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year's hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.

The endocrinology of the menstrual cycle.

The ovulatory menstrual cycle is the result of the integrated action of the hypothalamus, pituitary, ovary, and endometrium. Like a metronome, the hypothalamus sets the beat for the menstrual cycle by the pulsatile release of gonadotropin-releasing hormone (GnRH). GnRH pulses occur every 1-1.5 h in the follicular phase of the cycle and every 2-4 h in the luteal phase of the cycle. Pulsatile GnRH secretion stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pituitary gland translates the tempo set by the hypothalamus into a signal, LH and FSH secretion, that can be understood by the ovarian follicle. The ovarian follicle is composed of three key cells: theca cells, granulosa cells, and the oocyte. In the ovarian follicle, LH stimulates theca cells to produce androstenedione. In granulosa cells from small antral follicles, FSH stimulates the synthesis of aromatase (Cyp19) which catalyzes the conversion of theca-derived androstenedione to estradiol. A critical concentration of estradiol, produced from a large dominant antral follicle, causes positive feedback in the hypothalamus, likely through the kisspeptin system, resulting in an increase in GnRH secretion and an LH surge. The LH surge causes the initiation of the process of ovulation. After ovulation, the follicle is transformed into the corpus luteum, which is stimulated by LH or chorionic gonadotropin (hCG) should pregnancy occur to secrete progesterone. Progesterone prepares the endometrium for implantation of the conceptus. Estradiol stimulates the endometrium to proliferate. Estradiol and progesterone cause the endometrium to become differentiated to a secretory epithelium. During the mid-luteal phase of the cycle, when progesterone production is at its peak, the secretory endometrium is optimally prepared for the implantation of an embryo. A diagrammatic representation of the intricate interactions involved in coordinating the menstrual cycle is provided in Fig. 1.

Use of fertility treatment modalities in a large United States cohort of professional women.

OBJECTIVE: To evaluate the use of fertility treatments among a large cohort of women in the United States. DESIGN: Cohort study. SETTING: Nurses' Health Study II. PATIENT(S): Ten thousand thirty-six women who reported having used fertility treatment on biennial questionnaires from 1993-2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Data on patterns of treatment modality were collected via self-report from validated mailed questionnaires. Information on clomiphene, gonadotropin injections alone, and gonadotropin injections as part of intrauterine insemination (IUI) and in vitro fertilization (IVF) was queried. RESULT(S): Most women who reported fertility treatment used clomiphene (94%), with a large majority reporting clomiphene as their only form of treatment (73%). Of women who reported treatment more advanced than clomiphene, 13% had used gonadotropin injections alone, 11% IUI treatment, and 11% IVF. Several subgroups were more likely to use multiple treatment modalities and to initiate treatment with gonadotropins rather than clomiphene, including women living in states with insurance coverage of fertility procedures, with higher household income, younger in age, who remained nulliparous at the study close, and treated after 2000. CONCLUSION(S): Results should be interpreted cautiously, but to our knowledge, this represents the first study of fertility treatment patterns in the United States and could inform public health planning.

Premenopausal endogenous steroid hormones and breast cancer risk: results from the Nurses' Health Study II.

INTRODUCTION: Prior research supports an association between endogenous sex steroids and breast cancer among postmenopausal women; the association is less clear among premenopausal women. METHODS: We evaluated the associations between estrogens, androgens, progesterone and sex hormone binding globulin (SHBG) and breast cancer in a nested case-control study in the Nurses' Health Study II. Between 1996 and 1999, 29,611 participants provided blood samples; 18,521 provided samples timed in early follicular and mid-luteal phases of the menstrual cycle. A total of 634 women, premenopausal at blood collection, developed breast cancer between 1999 and 2009 and were matched to 1,264 controls (514 cases and 1,030 controls with timed samples). We used conditional logistic regression controlling for breast cancer risk factors for overall analyses; unconditional logistic regression additionally controlling for matching factors was used for subgroup analyses. RESULTS: In analyses of premenopausal estrogens including breast cancers diagnosed both before and after menopause, there was no association between follicular estradiol, estrone and free estradiol and risk of either total or invasive breast cancer. Luteal estradiol was positively associated with estrogen receptor positive (ER+)/progesterone receptor positive (PR+) cancers (5th vs. 1st quintile odds ratio (OR): 1.7 (95% confidence interval (CI): 1.0 to 2.9), Ptrend = 0.02). Luteal estrone, free estradiol and progesterone were not associated with risk. Androgens were suggestively or significantly associated with risk when the sample was restricted to invasive tumors (for example, testosterone: OR: 1.4 (1.0 to 2.0), Ptrend = 0.23) and ER+/PR+ disease (testosterone: OR: 1.7 (1.1 to 2.6) Ptrend = 0.10; dehydroepiandrosterone sulfate (DHEAS) OR: 1.3 (0.8 to 2.0) Ptrend = 0.05). SHBG was not associated with breast cancer risk. The results varied by menopausal status at diagnosis, with follicular estradiol suggestively positively associated with breast cancers in women premenopausal at diagnosis (OR: 1.1 (0.9 to 1.3) and significantly inversely associated with postmenopausal disease (OR: 0.6 (0.4 to 0.9); Pheterogeneity < 0.01). CONCLUSIONS: Androgens were associated with modestly increased risk of breast cancer in this population, with stronger associations for invasive and ER+/PR+ disease. Luteal phase estradiol levels were suggestively associated with ER+/PR+ tumors but no other strong associations were observed with estrogens. Associations with follicular phase estrogens may vary by menopausal status at diagnosis, but case numbers were limited. Additional studies to confirm the role of premenopausal hormones in the etiology of both premenopausal and postmenopausal breast cancer are needed.

Role of decreased androgens in the ovarian response to stimulation in older women.

Ovarian testosterone increases the response of antral follicles to stimulation, declines with age, and has effects mediated or potentiated by insulin-like growth hormone I (IGF-I). Increased circulating insulin and IGF-I, exogenous testosterone, and increased local ovarian testosterone concentrations due to aromatase inhibition or exogenous luteinizing hormone/human chorionic gonadotropin are all associated with an increased ovarian response to gonadotropins. These factors should be further investigated alone or in combination for enhancing oocyte yield with fertility treatments, particularly in older reproductive-age women.

Office gynecology in the internet age.

Historically, the stethoscope is representative of the type of medical tool that dominated the clinician-patient interaction. In the future, electronic tools will dominate the clinician-patient interaction. Most electronic tools will be accessed through the internet. The internet will become a key portal for enhancing the doctor-patient relationship.

Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among premenopausal women.

Endogenous estrogens and estrogen metabolism are hypothesized to be associated with premenopausal breast cancer risk but evidence is limited. We examined 15 urinary estrogens/estrogen metabolites and breast cancer risk among premenopausal women in a case-control study nested within the Nurses' Health Study II (NHSII). From 1996 to 1999, urine was collected from 18,521 women during the mid-luteal menstrual phase. Breast cancer cases (N = 247) diagnosed between collection and June 2005 were matched to two controls each (N = 485). Urinary estrogen metabolites were measured by liquid chromatography-tandem mass spectrometry and adjusted for creatinine level. Relative risks (RR) and 95% confidence intervals (CI) were estimated by multivariate conditional logistic regression. Higher urinary estrone and estradiol levels were strongly significantly associated with lower risk (top vs. bottom quartile RR: estrone = 0.52; 95% CI, 0.30-0.88; estradiol = 0.51; 95% CI, 0.30-0.86). Generally inverse, although nonsignificant, patterns also were observed with 2- and 4-hydroxylation pathway estrogen metabolites. Inverse associations generally were not observed with 16-pathway estrogen metabolites and a significant positive association was observed with 17-epiestriol (top vs. bottom quartile RR = 1.74; 95% CI, 1.08-2.81; P(trend) = 0.01). In addition, there was a significant increased risk with higher 16-pathway/parent estrogen metabolite ratio (comparable RR = 1.61; 95% CI, 0.99-2.62; P(trend) = 0.04). Other pathway ratios were not significantly associated with risk except parent estrogen metabolites/non-parent estrogen metabolites (comparable RR = 0.58; 95% CI, 0.35-0.96; P(trend) = 0.03). These data suggest that most mid-luteal urinary estrogen metabolite concentrations are not positively associated with breast cancer risk among premenopausal women. The inverse associations with parent estrogen metabolites and the parent estrogen metabolite/non-parent estrogen metabolite ratio suggest that women with higher urinary excretion of parent estrogens are at lower risk.

A prospective study of dietary fat consumption and endometriosis risk.

BACKGROUND: Endometriosis is a prevalent but enigmatic gynecologic disorder for which few modifiable risk factors have been identified. Fish oil consumption has been associated with symptom improvement in studies of women with primary dysmenorrhea and with decreased endometriosis risk in autotransplantation animal studies. METHODS: To investigate the relation between dietary fat intake and the risk of endometriosis, we analyzed 12 years of prospective data from the Nurses' Health Study II that began in 1989. Dietary fat was assessed via food frequency questionnaire in 1991, 1995 and 1999. We used Cox proportional hazards models adjusted for total energy intake, parity, race and body mass index at age 18, and assessed cumulatively averaged fat intake across the three diet questionnaires. RESULTS: During the 586 153 person-years of follow-up, 1199 cases of laparoscopically confirmed endometriosis were reported. Although total fat consumption was not associated with endometriosis risk, those women in the highest fifth of long-chain omega-3 fatty acid consumption were 22% less likely to be diagnosed with endometriosis compared with those with the lowest fifth of intake [95% confidence interval (CI) = 0.62-0.99; P-value, test for linear trend (Pt) = 0.03]. In addition, those in the highest quintile of trans-unsaturated fat intake were 48% more likely to be diagnosed with endometriosis (95% CI = 1.17-1.88; Pt = 0.001). CONCLUSION: These data suggest that specific types of dietary fat are associated with the incidence of laparoscopically confirmed endometriosis, and that these relations may indicate modifiable risk. This evidence additionally provides another disease association that supports efforts to remove trans fat from hydrogenated oils from the food supply.

The association of plasma androgen levels with breast, ovarian and endometrial cancer risk factors among postmenopausal women.

Although androgens may play an etiologic role in breast, ovarian and endometrial cancers, little is known about factors that influence circulating androgen levels. We conducted a cross-sectional analysis among 646 postmenopausal women in the Nurses' Health Study to examine associations between adult risk factors for cancer, including the Rosner/Colditz breast cancer risk score, and plasma levels of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). All analyses were adjusted for age, laboratory batch and other cancer risk factors. Free testosterone levels were 79% higher among women with a body mass index of > or =30 vs. <22 kg/m(2) (p-trend <0.01) and 25% higher among women with a waist circumference of >89 vs. < or =74 cm (p-trend = 0.02). Consuming >30 g of alcohol a day vs. none was associated with a 31% increase in DHEA and 59% increase in DHEAS levels (p-trend = 0.01 and <0.01, respectively). Smokers of > or =25 cigarettes per day had 35% higher androstenedione and 44% higher testosterone levels than never smokers (p-value, F-test = 0.03 and 0.01, respectively). No significant associations were observed for height or time since menopause with any androgen. Testosterone and free testosterone levels were approximately 30% lower among women with a hysterectomy vs. without (both p-values < 0.01). Overall breast cancer risk was not associated with any of the androgens. Thus, several risk factors, including body size, alcohol intake, smoking and hysterectomy, were related to androgen levels among postmenopausal women, while others, including height and time since menopause, were not. Future studies are needed to clarify further which lifestyle factors modulate androgen levels.

Geographic distribution of reproductive endocrinology and infertility (REI) fellowships in the United States.

OBJECTIVE: To examine in detail the geographic distribution of reproductive endocrinology and infertility (REI) fellowships in the United States. DESIGN: Ecological. SETTING: University-based REI fellowship program. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number and location of REI fellowship positions. RESULT(S): A significant association was found between the number of REI fellowship positions and the number of categorical postgraduate year-1 (PGY-1) obstetrics and gynecology (OBGYN) residency positions within states. No association was observed among the land area, population, or population density within states. However, despite the fact that in the East, as in the United States overall, there was no association between population density and number of fellowships, West of the Mississippi River, as the population density increased, the number of REI fellowships increased linearly (test for heterogeneity = 0.007). CONCLUSION(S): First-year REI fellowship positions in the United States are correlated with the number of categorical PGY-1 OBGYN residency positions within a state. The geographically uneven distribution of fellowship positions may limit the choices for OBGYN residents wishing to pursue further training in REI.

Update in female reproduction: a life-cycle approach.

CONTEXT: Female reproduction spans a developmental life arc from fetal life and childhood, through puberty to the reproductive years, and, finally, ovarian follicle depletion and the onset of menopause. OBJECTIVE: This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause. SYNTHESIS: During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause. CONCLUSIONS: The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction.

Physical activity and inactivity in relation to sex hormone, prolactin, and insulin-like growth factor concentrations in premenopausal women - exercise and premenopausal hormones.

An association between physical activity and premenopausal breast cancer risk may be due, in part, to relationships with sex hormones or growth factors. Therefore, we assessed whether MET-h/week of total physical activity (moderate-to-vigorous intensity), walking, or vigorous physical activity, and h/week of standing or sitting were associated with plasma concentrations of several hormones. We examined levels of estrogens, androgens, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and growth hormone (GH) in 565 premenopausal women, ages 33-52 years, from the Nurses' Health Study II (NHSII). About 87% of women had both timed follicular and luteal samples; other women had one untimed sample. In general we observed few associations between sex hormone or IGF levels and measures of physical activity or inactivity. However, free testosterone was modestly inversely associated with total physical activity (p-trend = 0.02). Luteal estradiol, free estradiol, and estrone also were inversely associated with total physical activity (p-trend = 0.10, 0.04, 0.01, respectively); however, the trend was substantially attenuated when excluding women with anovulatory cycles or irregular cycles. These cross-sectional results suggest that physical activity and inactivity have limited associations with premenopausal sex hormone and growth factor levels, except possibly luteal estrogens.

Dietary patterns, the Alternate Healthy Eating Index and plasma sex hormone concentrations in postmenopausal women.

To evaluate the association between overall diet and sex hormones concentrations, we collected blood from 578 postmenopausal women ages 43 and 69 years in 1989 or 1990. Food intake was measured in 1990 via a food frequency questionnaire. We calculated the Alternate Healthy Eating Index (AHEI), and dietary patterns were identified by factor analysis. The cross-sectional association between diet and estrogens, sex hormone binding globulin (SHBG) were evaluated with linear regression and adjusted for energy and other potential confounders. We found a higher AHEI score was associated with lower concentrations of estradiol, free estradiol, and higher concentrations of SHBG. The prudent pattern, with higher intakes of fruits, vegetables, and whole grains, was not associated with any sex hormones. The Western pattern, which represents higher intakes of red and processed meats, refined grains, sweets and desserts, was associated with a higher level of estradiol and lower concentrations of SHBG. Further adjustment for BMI attenuated these results except for free estradiol (5th vs. 1st quintile = 0.09 vs. 0.11 pg/mL, p for trend = 0.03). In addition, the AHEI was inversely associated with estradiol among those with BMI > 25, and Western pattern with SHBG among those with BMI < 25. In conclusion, we observed inverse associations between the AHEI score and several estrogens, and it was positively associated with plasma levels of SHBG. In contrast, the Western pattern was positively associated with estrogen levels and inversely with SHBG. However, these associations appeared to be largely accounted for by BMI.