Bioidentical hormones.

After the results of the Women's Health Initiative trials were published, patient and clinician interest in potential alternatives to conventional hormone therapy (HT) has grown. A commonly used alternative therapy involves custom-compounded steroid hormone preparations, formulated by compounding pharmacies. Many postmenopausal women consider the hormones as natural or bioidentical, in contrast to hormones used in conventional HT, which they consider synthetic. In actuality, the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT. To customize formulations, compounding pharmacies frequently use saliva testing to measure hormones. However, there is a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood. Because hormonal custom-compounded formulations are not approved by the Food and Drug Administration (FDA), there are concerns regarding their purity, potency, and quality. Evolving regulatory guidelines by the FDA on oversight of these products should lessen the concerns regarding their safety and efficacy. This review addresses important misconceptions and uncertainties pertaining to BHT, the relationship between salivary and serum/plasma steroid hormone concentrations, the effect of topical progesterone creams on the endometrium, the variability in custom-compounded steroid preparations, and FDA oversight of custom-compounded products.

Circulating androgen levels before and after oophorectomy in premenopausal and postmenopausal women.

OBJECTIVE: This study aimed to determine the effect of oophorectomy on baseline serum levels of androgens and estrogens in premenopausal and postmenopausal women. METHODS: Fourteen premenopausal and 10 postmenopausal women underwent total hysterectomy and bilateral oophorectomy for benign disease of the uterus. Serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), testosterone (T), dihydrotestosterone (DHT), 5α-androstane-3α,17ß-diol-17ß-glucuronide (3α-diol G), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were measured by highly specific immunoassays prior to surgery and 2 weeks afterward. Free T and free E2 were calculated. Differences were determined between preoperative (preop) and postoperative (postop) samples, and between premenopausal and postmenopausal women. RESULTS: In premenopausal women, postop levels of total and free T, DHT, and total and free E2 decreased significantly from preop. Postop levels of DHEAS, A, 3α-diol G, and SHBG were decreased, but not significantly different from preop. In postmenopausal women, postop levels of total and free T and total and free E2 decreased significantly from preop, but there was little change in the other compounds. Significant differences in the mean change from baseline between premenopausal and postmenopausal women were observed only for E1 and total and free E2. CONCLUSION: The significant decrease in serum T in postmenopausal women following oophorectomy adds to the evidence that the postmenopausal ovary continues to produce T.

Circulating maternal and umbilical cord steroid hormone and insulin-like growth factor concentrations in twin and singleton pregnancies.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

Endogenous sex steroid hormones and glucose in a South-Asian population without diabetes: the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study.

AIMS: To examine the associations between endogenous sex steroid hormones (oestradiol, testosterone and sex hormone-binding globulin) with diabetes risk in a South-Asian population living in the USA. METHODS: We used data from the Metabolic Syndrome and Atherosclerosis in South-Asians Living in America pilot study. The analytical sample included 60 women and 45 men of Asian Indian origin living in the San Francisco Bay Area, who were free from diabetes and cardiovascular disease and did not use exogenous sex steroids. Sex steroid hormone levels were assessed by validated conventional radioimmunoassays, and visceral and hepatic adiposity were assessed by computed tomography. We used multivariable regression to examine the association between endogenous sex steroid hormone levels (log-transformed) and fasting glucose and 2-h glucose levels in a series of sex-stratified models adjusted for age, waist circumference, visceral and hepatic adiposity, and insulin resistance. RESULTS: In age-adjusted models, lower levels of sex hormone-binding globulin (ß = -0.18, 95% CI -0.30, -0.06) and higher levels of free testosterone (ß = 0.14, 95% CI 0.02, 0.26) were associated with elevated fasting glucose levels in South-Asian women, whereas lower levels of sex hormone-binding globulin (ß = -0.14, 95% CI -0.26, -0.02) and lower levels of total testosterone (ß = -0.12, 95% CI -0.24, 0.00) were associated with elevated fasting glucose levels in South-Asian men. Adjustment for waist circumference, visceral adiposity and insulin resistance attenuated most of these associations, while adjustment for hepatic adiposity strengthened some of the observed associations. Similar results were found for 2-h glucose levels. CONCLUSIONS: Results were consistent with previous research, which suggests that endogenous sex steroid hormones are a risk factor for diabetes across multiple race/ethnic groups. Additional studies are needed to determine whether visceral fat is a mediator or confounder of associations between sex steroid hormone and glucose levels.

Treatment of postmenopausal women with topical progesterone creams and gels: are they effective?

Topical progesterone creams and gels can be obtained over the counter and/or by prescription from custom-compounding pharmacies and are used by thousands of postmenopausal women for hormonal treatment. However, the effectiveness of these preparations for protecting the endometrium from unopposed estrogen is controversial, due largely to the very low serum progesterone levels that are achieved. Despite these low serum levels, salivary and capillary blood levels are very high and a protective endometrium has been reported in a limited number of studies. Topical alcohol-based, but not water-based, gels appear to yield luteal-phase serum progesterone levels but studies with these preparations are scant. Long-term studies with percutaneous progesterone creams and gels are likely to provide valuable information for treatment of postmenopausal women with this popular route of administration.

Effects of aromatase inhibitors and body mass index on steroid hormone levels in women with early and advanced breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are central to the management of oestrogen receptor-positive breast cancer in the adjuvant and metastatic setting. Levels of circulating steroid hormones (SHs) were measured in patients established on AIs to investigate: the influence of body mass index (BMI) in both the adjuvant and metastatic setting; the class of AI utilized in the adjuvant setting (steroidal versus non-steroidal); and differences in SH levels between women treated adjuvantly and those receiving a second-line AI for locally advanced/metastatic disease. METHODS: Plasma levels of androstenedione, 5-androstene-3ß,17ß-diol, dehydroepiandrosterone, oestradiol and testosterone were measured by radioimmunoassay in women with breast cancer who were receiving AIs in either an adjuvant or a metastatic setting. Differences between mean SH levels by class of AI, BMI, and second-line versus adjuvant therapy were assessed. RESULTS: Sixty-four women were receiving AI therapy, 45 (70 per cent) in an adjuvant setting and 19 (30 per cent) were taking a second-line AI. There was no significant correlation between BMI and SH levels. However, BMI was significantly higher in the second-line AI cohort compared with the adjuvant cohort (29.8 versus 26.2 kg/m2 respectively; P = 0.026). In the adjuvant setting, patients receiving a steroidal AI had significantly higher levels of all five hormones (P < 0.050). In the second-line AI cohort, oestradiol levels were significantly higher than in the adjuvant cohort (4.5 versus 3.3 pg/ml respectively; P = 0.022). Multivariable analysis adjusted for BMI confirmed the higher residual oestradiol level in the second-line AI group (P = 0.063) and a significantly higher androstenedione level (P = 0.022). CONCLUSION: Residual levels of SH were not significantly influenced by BMI. However, the significant differences in residual SH levels between the second-line and adjuvant AI cohort is of relevance in the context of resistance to AI therapy, and warrants further investigation.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Metabolic syndrome and insulin resistance in relation to biliary tract cancer and stone risks: a population-based study in Shanghai, China.

BACKGROUND: Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied. METHODS: In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and ß-cell function were assessed, using homeostasis assessment models. RESULTS: Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82-4.15) and biliary stones (OR=1.64, 95% CI=1.24-2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend <0.0001). The observed association persisted among subjects without a history of diabetes. The association between insulin resistance and gallbladder cancer was borderline (P trend=0.06). There was a significant inverse association between ß-cell function and gallbladder cancer risk (P trend <0.001). CONCLUSION: Our findings suggest that metabolic syndrome and insulin resistance have a role in the aetiology of biliary tract cancers and biliary stones, and if confirmed, they imply that lifestyle control of these factors may lower the risk of biliary stones and biliary tract cancer.

Effect of tamoxifen or anastrozole on steroid sulfatase activity and serum androgen concentrations in postmenopausal women with breast cancer.

BACKGROUND: In postmenopausal women estrogens can be formed by the aromatase pathway, which gives rise to estrone, and the steroid sulfatase (STS) route which can result in the formation of estrogens and androstenediol, a steroid with potent estrogenic properties. Aromatase inhibitors, such as anastrozole, are now in clinical use whereas STS inhibitors, such as STX64, are still undergoing clinical evaluation. STX64 was recently shown to block STS activity and reduce serum androstenediol concentrations in postmenopausal women with breast cancer. In contrast, little is known about the effects of aromatase inhibitors or anti-estrogens on STS activity or serum androgen levels. PATIENTS AND METHODS: Study 1: Blood was collected from ten postmenopausal women with breast cancer before and after two-week treatment with anastrozole and serum concentrations of androstenediol and other androgens and estrogens were assessed. Study 2: Blood samples were collected from 15 breast cancer patients before and after four-week treatment with anastrozole and 10 patients before and after four-week treatment with tamoxifen. Blood was used to assess STS activity in peripheral blood lymphocytes (PBLs) and serum dehydroepiandrosterone sulfate and dehydroepiandrosterone levels. RESULTS: Neither anastrozole nor tamoxifen had any significant effect on STS activity as measured in PBLs. Anastrozole did not affect serum androstenediol concentrations. CONCLUSION: Anastrozole and tamoxifen did not inhibit STS activity and serum androstenediol concentrations were not reduced by aromatase inhibition. As androstenediol has estrogenic properties, it is possible that the combination of an aromatase inhibitor and STS inhibitor may give a therapeutic advantage over the use of either agent alone.

Effect of statins on estrogen and androgen levels in postmenopausal women treated with estradiol.

OBJECTIVE: A considerable number of postmenopausal women who receive estrogen therapy are also treated for hypercholesterolemia with cholesterol-lowering statins. Statins and steroid hormones can compete for the same steroid-metabolizing enzymes. We investigated whether long-term administration of statins had an effect on serum estrogen and androgen levels in postmenopausal women receiving and not receiving oral estrogen therapy. METHODS: A subgroup analysis from the Estrogen in the Prevention of Atherosclerosis Trial, a randomized, double-blind, placebo-controlled trial, was performed. A total of 222 women were randomized to receive either placebo or 1 mg of oral micronized 17ß-estradiol daily for 2 years. In both the placebo and treatment groups, participants with low density lipoprotein cholesterol levels >160 mg/dl were treated with statins. Blood samples were obtained at baseline and every 6 months during the trial. Serum levels of dehydroepiandrosterone, androstenedione, testosterone, estrone and 17ß-estradiol were measured by radioimmunoassay. RESULTS: Among 86 placebo- and 90 estradiol-treated subjects with baseline and on-trial hormone measurements, no significant differences were observed between the statin-free and statin-treated groups in mean changes from baseline to on-trial levels in any of the androgens or estrogens, whether or not the postmenopausal women were treated with estrogen. CONCLUSION: The results suggest that estrogen therapy and statins can be used simultaneously with no deleterious effects on circulating hormone levels.

Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women.

AIM: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. METHOD: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. RESULTS: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. CONCLUSION: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Variants in circadian genes and prostate cancer risk: a population-based study in China.

Circadian genes influence a variety of biological processes that are important in prostate tumorigenesis including metabolism. To determine if variants in circadian genes alter prostate cancer risk, we genotyped five variants in five circadian genes in a population-based case-control study conducted in China (187 cases and 242 controls). These variants included CRY2 rs1401417:G>C, CSNK1E rs1005473:A>C, NPAS2 rs2305160:G>A, PER1 rs2585405:G>C and PER3 54-bp repeat length variant. Men with the cryptochrome 2 (CRY2)-variant C allele had a significant 1.7-fold increased prostate cancer risk (95% confidence interval (CI), 1.1-2.7) relative to those with the GG genotype. This risk increased to 4.1-fold (95% CI, 2.2-8.0) in men who also had greater insulin resistance (IR) as compared to men with the GG genotype and less IR. In contrast, among men with less IR, the NPAS2-variant A allele was associated with decreased prostate cancer risk (odds ratio=0.5, 95% CI, 0.3-1.0) as compared to the GG genotype. Our findings, although in need of confirmation, suggest that variations in circadian genes may alter prostate cancer risk and some biological processes may modify this effect.

Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men.

BACKGROUND: Low prostate cancer incidence and high soy intake in Asian countries suggest a possible protective effect of soy foods against prostate cancer. The goal of this pilot study was to evaluate the feasibility of a randomized, crossover soy trial among men and to investigate the effects of daily soy intake on serum prostate-specific antigen (PSA) and testosterone levels. METHODS: We randomized 24 men to a high or a low soy diet for 3 months. After a 1-month washout period, the men crossed over to the other treatment. During the high soy diet, the men consumed two daily soy servings; during the low soy diet, they maintained their usual diet. During the entire study each man donated four blood samples and five overnight urine samples. Dietary compliance was assessed by soy calendars, 24-h dietary recalls, and urinary isoflavone excretion measured by high-pressure liquid chromatography with photodiode array detection. Blood samples were analyzed for serum testosterone and PSA by radioimmunoassay. When necessary, variables were log transformed. Two sample t-tests compared the two groups before each study period. Mixed models incorporating the repeated measurements were used to evaluate the effect of the soy diet on urinary isoflavone excretion and serum analytes. RESULTS: Twenty-three men aged 58.7+/-7.2 years completed the study. The compliance with the study regimen was high according to self-reported soy food intake and urinary isoflavone excretion. No significant between-group and within-group differences were detected. During the high soy diet, dietary isoflavone intake and urinary isoflavone excretion increased significantly as compared to the low soy diet. A 14% decline in serum PSA levels (P=0.10), but no change in testosterone (P=0.70), was observed during the high soy diet in contrast to the low soy diet. CONCLUSION: The high adherence as shown by three measures of compliance in this pilot trial demonstrated the feasibility of an intervention based on soy foods among free-living men.

Dhea supplementation and cognition in postmenopausal women.

Previous work has suggested that DHEA supplementation may have adverse cognitive effects in elderly women. This article analyzed 24-h measurements of DHEA, DHEAS, and cortisol to determine if cognitive decrease with treatment is mediated by DHEA's impact on endogenous cortisol. It was found that DHEA administration increased cortisol at several hours during the day. In the treatment group, cortisol was positively associated with cognition at study completion. An increase in negative associations between DHEA(S) levels and cognition was found at completion. Increased cortisol does not explain the cognitive deficits associated with DHEA, suggesting a direct negative effect of exogenous DHEA on cognition.

Maternal hormone levels among populations at high and low risk of testicular germ cell cancer.

Ethnic differences in maternal oestrogen levels have been suggested as explaining the significantly higher risk of testicular germ cell tumours (TGCT) of white men than black men in the United States. We therefore examined levels of maternal oestrogens, as well as testosterone and alphafetoprotein (AFP), in 150 black and 150 white mothers in the Collaborative Perinatal Project. Serum levels of estradiol (total, free and bioavailable), estriol, testosterone (total, free and bioavailable), sex hormone binding globulin (SHBG), and AFP were examined during first and third trimesters. We found that the black mothers, rather than the white mothers, had significantly higher estradiol levels in first trimester (P=0.05). Black mothers also had significantly higher levels of all testosterone (P<0.001) and AFP (P<0.001) in both trimesters. In addition, the ratios of sex hormones (estradiol/testosterone) were significantly lower among black mothers. These findings provide little support to the oestrogen hypothesis, but are consistent with higher levels of testosterones and/or AFP being associated with reduced risk of TGCT; alternatively, lower oestrogen/androgen ratios may be associated with reduced risk.

Pregnancy history and cognition during and after pregnancy.

An increasing body of literature confirms anecdotal reports that cognitive changes occur during pregnancy. This article assessed whether prior pregnancy, which alters a woman's subsequent hormonal environment, is associated with a specific cognitive profile during and after pregnancy. Seven primigravids and nine multigravids were compared, equivalent for age and education. No differences between groups were found during pregnancy. After delivery, multigravids performed better than primigravids on verbal memory tasks. After controlling for mood, a significant difference in verbal memory remained. A neuroadaptive mechanism may develop after first pregnancy that increases the ability to recover from some cognitive deficits after later pregnancies.

Androgens modulate beta-amyloid levels in male rat brain.

As a normal consequence of aging, men experience a significant decline in androgen levels. Although the neural consequences of age-related androgen depletion remain unclear, recent evidence suggests a link between low androgen levels and the development of Alzheimer's disease (AD). Here, we test the hypothesis that androgens act as endogenous modulators of beta-amyloid protein (Abeta) levels. To investigate this possibility, brain and plasma levels of Abeta were measured in male rats with varying hormonal conditions. Depletion of endogenous sex steroid hormones via gonadectomy (GDX) resulted in increased brain levels of Abeta in comparison to gonadally intact male rats. This GDX-induced increase in Abeta levels was reversed by DHT supplementation, demonstrating a functional role for androgens in modulating brain levels of Abeta. These findings suggest that age-related androgen depletion may result in accumulation of Abeta in the male brain and thereby act as a risk factor for the development of AD.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.