New trimester-specific reference intervals for clinical biochemical tests in Taiwanese pregnant women-cohort of TMICS.

BACKGROUND: Because there are no published biochemical reference intervals (RI) for pregnant Taiwanese women, we used an established islandwide birth cohort, the Taiwan Maternal and Infant Cohort Study, to establish RIs for important biochemical parameters in women during their 3rd trimester in Taiwan. Additionally, we compared the differences in these biochemical parameters between early third trimester (weeks 28 to 31) and late third trimester (weeks 37 to 40) of pregnant women as well as the differences in them between the third trimester and after delivery. METHODS: Between 2012 and 2015, we recruited a total of 2,136 pregnant women from nine hospitals located in northern (n = 3), central (n = 3), southern (n = 2), and eastern Taiwan (n = 1) to receive regular prenatal health examinations during their third trimester (weeks 28 to 40). After exclusion, samples obtained from 993 eligible pregnant women were analyzed. RESULTS: There were increases in both lower and upper normal limits for blood neutrophil, thyroid profile (triiodothyronine (T3) and thyroxine (T4)), testosterone, estradiol, and progesterone and decreases for RBC, hemoglobin (Hb), alanine aminotransferase (ALT) and creatinine (Cr) during their third trimesters. Women in their late third trimester (n = 378) had higher median RBC, Hb, aspartate aminotransferase (AST), Cr, thyroid-stimulating hormone (TSH), testosterone, estradiol, and progesterone and lower median platelet and insulin, compared with those in their early third trimester (n = 490). Twenty-three of the women had both third trimester and post-pregnancy data. After delivery, the women had lower median AST, ALT, insulin, T3, T4, testosterone, estradiol, and progesterone and higher median Cr, free T4, FSH, and luteinizing hormone (LH), compared to their third trimesters. CONCLUSIONS: Gestation-related changes in important biochemical parameters should be considered when evaluating clinical laboratory values in pregnant women.

Development of anti-immunocomplex specific antibodies and non-competitive time-resolved fluorescence immunoassay for the detection of estradiol.

Detection of circulatory estradiol has widespread use in various clinical applications. Particularly, the use of estradiol-specific antibodies in immunoassays is routinely used, mainly due to the cost efficiency and simplicity of the sample handling process. However, the circulatory levels of estradiol can be extremely low in some conditions, and beyond the current detection limit of existing competitive immunoassays. We describe the generation of anti-immunocomplex specific antibodies derived from synthetic antibody repertoire and the development of high-performance non-competitive immunoassay for the detection of estradiol. Phage display selections were used to isolate new antibodies from synthetic antibody library with the use of existing estradiol specific Fab fragment. The found antibodies were consecutively used to set up a time-resolved fluorescence-based immunoassay (TRFIA), which can be used to detect estradiol with exceptional sensitivity and specificity. The limit of detection and EC50 were shown to be 3.0 pg mL-1 and 32.4 pg mL-1 respectively. Graphical abstract.

In vitro estrogenic activity of representative endocrine disrupting chemicals mixtures at environmentally relevant concentrations.

Exposure to mixtures of endocrine disrupting compounds (EDCs) has been hypothesized to produce potential synergistic or antagonistic effects that can cause undesired effects that are not reflected by the individual compounds. In this study, the estrogenic activities of 11 EDCs of global environmental concern were systematically investigated using the yeast estrogen screen (YES). The contribution of the individual chemical to the total endocrine activity of environmentally relevant mixtures was evaluated. Compared to 17ß-estradiol (E2) as a standard, estrone (E1), estriol (E3), ethinyl estradiol (EE2), bisphenol-A (BPA), and genistein (GEN) showed estrogenic effects, while dibutyl phthalate (DBP), n-butyl benzyl phthalate (BBP), Bis(2-ethylhexyl) phthalate (DEHP), nonyl phenol (NP) and 4-tert-octyl phenol (OP) showed anti-estrogenic effects. The 11 EDCs mixture at a constant environmentally relevant ratio also showed estrogenic activity. The mixtures data were fit to concentration addition (CA), response addition (RA) and interaction (IR) models, respectively. The IR model was not statistically different from the observed value and better predicted results than the CA model for mixtures of all 11 compounds. For the mixtures with the 6 estrogenic compounds only, additive effects were observed, and the data were well predicted by the CA and IR models. Further, in the 11 EDCs mixture the presence of EE2 at an environmentally relevant concentration did not increase the estrogenic activity as compared to a 10 EDCs mixture without EE2.

The standardization of nonsterile compounding: a study in quality control and assessment for hormone compounding.

Sterile and nonsterile compounding of medication has attracted much attention over the last few years due to the onset of various infections and negative compounding practices. This paper reports on the standardization of compounded hormones utilizing the Wiley Protocol, which provides nonsynthetic bioidentical estradiol, progesterone, dehydroepiandrosterone, and testosterone in a transdermal topical cream base for women and men in a standardized dosing regimen. Here, we present data from 2008 through 2012, which details the process of standardization and quality testing of the hormones through submission of random compounded samples for quality control and assessment. Pharmacies delivering the Wiley Protocol were required to follow the same compounding formulation, as well as submit random samples for quarterly testing. Sample concentrations were tested using high-performance liquid chromatography. We found that pharmacies that submitted samples had a 91% passing rating with a percent of target of 98.6% +/- 8.4%. It was also determined that pharmacies that prepared more compounded cream had a higher passing rating than those that prepared limited quantities. We found that standardization across multiple pharmacies could be achieved through quarterly testing of submitted samples by a third-party laboratory when following necessary procedures as defined by the Wiley Protocol. It was also determined that experience and training were a critical factor in the mixing of compounded prescriptions, with high consistency and accuracy providing patient safety.

Challenges and improvements in testosterone and estradiol testing.

Assays that measure steroid hormones in patient care, public health, and research need to be both accurate and precise, as these criteria help to ensure comparability across all clinical and research applications. This review addresses major issues relevant to assay variability and describes recent activities by the US Centers for Disease Control and Prevention (CDC) to improve assay performance. Currently, high degrees of accuracy and precision are not always met for testosterone and estradiol measurements; although technologies for steroid hormone measurement have advanced significantly, measurement variability within and across laboratories has not improved accordingly. Differences in calibration and specificity are discussed as sources of variability in measurement accuracy. Ultimately, a combination of factors appears to cause inaccuracy of steroid hormone measurements, with nonuniform assay calibration and lack of specificity being two major contributors to assay variability. Within-assay variability for current assays is generally high, especially at low analyte concentrations. The CDC Hormone Standardization (HoSt) Program is improving clinical assays, as evidenced by a 50% decline in mean absolute bias between mass spectrometry assays and the CDC reference method from 2007 to 2011. This program provides the measurement traceability to CDC reference methods and helps to minimize factors affecting measurement variability.

Estradiol valerate and dienogest: a novel four-phasic oral contraceptive pill effective for pregnancy prevention and treatment of heavy menstrual bleeding.

Estradiol valerate and dienogest have been combined to create a novel four-phasic oral contraceptive pill effective for both pregnancy prevention and treatment of heavy menstrual bleeding. This formulation represents the only oral contraceptive pill available in the USA containing an estrogen component that is biologically active as the endogenous estrogen 17ß-estradiol. This medication was developed out of efforts to replace the most common estrogen in contraceptive pills, ethinyl estradiol, which is known to be a potent inducer of hepatic protein synthesis. Estradiol valerate has been available since the 1970s in oral and injectable forms indicated for the treatment of menopausal climacteric symptoms. Dienogest has been used in other oral contraceptive pills for over 10 years. Previous attempts to develop an oral contraceptive pill with natural estradiol or estradiol valerate were unsuccessful due to poor cycle control. A novel dynamic-dosing regimen was devised to improve the bleeding pattern. This medication has been shown in several clinical trials to have good contraceptive efficacy and cycle control. Recent studies have also demonstrated that this medication is effective for the treatment of heavy menstrual bleeding. However, compared with other oral contraceptive pills, this medication is associated with a higher frequency of absent withdrawal bleeding. Furthermore, the dynamic dosing regimen requires relatively complex instructions for users who miss pills.

Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy.

OBJECTIVE: To identify if there are certain cutoff levels for P and or the P/E(2) ratio on the day of hCG that would be defined as detrimental for occurrence of pregnancy in women with normal ovarian reserve undergoing cleavage-stage embryo transfer (ET). Secondarily, to determine if these same cutoffs might have the same potential negative effect in women undergoing blastocyst ET. DESIGN: Prospective cohort study including two randomized cohorts. SETTING: Private and university fertility centers. PARTICIPANT(S): A total of 240 women undergoing long agonist protocol with at least four grade 1 day 3 embryos. INTERVENTION(S): Women were randomized in a 1:1 ratio to undergo day 3 or day 5 embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) was the primary outcome. RESULT(S): Using receiver operator characteristics, cutoffs for P and P/E(2) ratio were 1.5 ng/mL and 0.55, respectively. Patients with P ≤ 1.5 ng/mL and P/E(2) ≤ 0.55 undergoing cleavage-stage ET had higher CPR. Using multiple regression, P/E(2) ratio was the only independent predictor for pregnancy. The P and P/E(2) cutoffs were not correlated with CPR in blastocyst transfers. CONCLUSION(S): Progesterone >1.5 ng/mL and P/E(2) >0.55 affect the CPR in women undergoing cleavage-stage, but not blastocyst ET. P/E(2) ratio is the only independent prognosticator for cycle outcome in women undergoing cleavage-stage ET.

New quantification method for estradiol in the prostatic tissues of benign prostatic hyperplasia using liquid chromatography-tandem mass spectrometry.

Estrogen is suspected to play a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. To clarify the role of estradiol (E2) in the prostatic tissues (prostatic tissue E2) during the development of prostatic disorders, we developed a new sensitive and specific quantification method for prostatic tissue E2 using liquid chromatography-tandem mass spectrometry (LC-MS/MS). For the solid-phase extraction, E2 was purified by anion-exchange through an Oasis MAX cartridge. In addition, after the formation of 3-pentaflurobenzyl-17beta-pyridinium-estradiol derivative (E2-PFBPY), E2-PFBPY was purified by cation-exchange through an Oasis WCX cartridge. These processes in the LC-MS/MS method improved the specificity and sensitivity for prostatic tissue E2 measurement, compared to the radioimmunoassay (RIA) method. The validation tests showed that intra-day and inter-day precisions were both within +/-15% (except for 15.5% of the inter-day precision of the lowest concentration), with the accuracy ranging from 88 to 110%. The quantification limit of this assay was 0.15pg/tube in our method, which was 80-fold more sensitive than that of the RIA method. With the use of our present method, the median E2 levels in the prostatic tissues in patients with BPH (n=20, median age: 71 years) were 12.0pg/g tissue (95% confidence interval=9.1-22.6pg/g tissue). Furthermore, the E2 levels increased significantly with aging. These results showed that our present method would be useful for elucidating the role of prostatic tissue E2 in the development of prostatic disorders with a small amount of tissue samples.

Biochemical reference intervals for sex hormones with a new AutoDelfia method in aged men.

BACKGROUND: Our aim was to establish sex hormone reference intervals measured with a new AutoDelfia immunoassay method for aged men free of medication and/or conditions known to influence sex hormone levels. METHODS: The reference population consisted of 466 individuals between 64 and 97 years (mean 72 years) and a mean body mass index (BMI) of 26.9 kg/m(2). RESULTS AND CONCLUSIONS: Because age correlated significantly with most sex hormones studied, we calculated reference intervals for three age groups (64-69, 70-74 and > or =75 years). In clinical practice, single ranges can be used for men aged 64 years or over for testosterone, estradiol and follicle-stimulating hormone (FSH) with the AutoDelfia method. For free testosterone and luteinizing hormone (LH), separate reference intervals should be used for men aged 64-74 years and those aged 75 years or over. For sex hormone-binding globulin, two separate reference intervals by age (64-69 and > or =70 years) are also needed for aged men. LH and FSH reference ranges should be judged with caution, because they may be too high due to cases of subclinical hypogonadism included in the reference population.

High-resolution reference ranges for estradiol, luteinizing hormone, and follicle-stimulating hormone in men and women using the AxSYM assay system.

OBJECTIVES: High-resolution reference ranges are essential for reproductive hormones due to the significant day-to-day variation seen with these analytes. DESIGN AND METHODS: The performance of AxSYM assays for estradiol, luteinizing hormone (LH), and follicle-stimulating hormone was evaluated. RESULTS: These studies validate the performance of each assay, permitting high-resolution reference ranges to be established. CONCLUSIONS: The high-resolution reference range data provided herein for both normally cycling females and males should be applicable to a wide variety of clinical situations.

Survey of estrogenic activity in fish feed by yeast estrogen-screen assay.

Fishes have been used as laboratory animal for research of estrogenic endocrine disrupters by many researchers. However, much less attention was paid to the possibility that compounds with estrogenic activity are present in fish diets. In order to examine this possibility, we measured the estrogenic activity in commercial fish feed by in vitro yeast estrogen-screen (YES) assay based on the binding ability of tested compounds to estrogen receptors. Estrogenic activity was detected in all the commercial fish feed examined (0.2-6.2 ng estradiol equivalent/g fish feed), some phytoestrogens (genistein, formononetin, equol and coumestrol; relative activity to estradiol, 8.6 x 10(-6)-1.1 x 10(-4) by giving a value of 1.0 to estradiol) and some androgens (testosterone, 11-ketotestosterone and 5 alpha-dihydrotestosterone; relative activity to estradiol, 3.0 x 10(-6)-1.2 x 10(-4)). Therefore, it is possible that these compounds could affect the results of in vivo estrogen assay, such as vitellogenin production in male fish, especially when fish are fed commercial feed.

Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina.

OBJECTIVES: We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND: Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS: Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2 supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS: The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2 augmented FMD (3.5 +/- 0.6*, 8.9 +/- 0.7 and 4.0 +/- 0.5* on days 1, 3 and 5, respectively; *p < 0.01 vs. day 3). The serum E2 levels on days 1, 3 and 5 were 22.7 +/- 2.8*, 96.2 +/- 9.2 and 30.7 +/- 7.1* pg/ml, respectively (*p < 0.01 vs. day 3). CONCLUSIONS: The present results demonstrated for the first time, to our knowledge, that E2 supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.

[Estradiol Reference Standard (Control 001) of National Institute of Health Sciences].

The raw material of tocopherol was tested for the preparation of "Estradiol Reference Standard (Control 991)". Analytical data obtained were: melting point, 178.5 degrees C: UV spectrum, lambda max of 281 nm and specific absorbance in ethanol at lambda max = 77.7; IR spectrum, same as that of the Estradiol Reference Standard (Control 964); optical rotation, [alpha]D20 = +79.5 degrees; thin-layer chromatography, one impurity was detected; high-performance liquid chromatography (HPLC), total amount of impurities estimated to be less than 0.6%; loss on drying, 3.3%; assay, 100.2% by UV spectrophotometry and 99.9% by HPLC. Based on the above results, the raw material was authorized as the Estradiol Reference Standard (Control 001) of the National Institute of Health Sciences.

[Estradiol Reference Standard (Control 961) of National Institute of Health Sciences].

The raw material for estradiol was examined for preparation of the "Estradiol Reference Standard (Control 961)" of National Institute of Health Sciences. Analytical data obtained were as follows: melting point, 179.1 degrees C; UV spectrum, lambda max = 281 nm; IR spectrum, the same as that of the Estradiol Reference Standard of National Institute of Health Sciences (Control 931); optical rotation, [alpha]20D = +79.5 degrees; thin-layer chromatography, one impurity was detected; high-performance liquid chromatography (HPLC), a trace amount of three impurities were detected; loss on drying, 3.17%; assay, 99.4% by UV spectrophotometry and 99.0% by HPLC. Based on the above results, the raw material was authorized as the Estradiol Reference Standard (Control 961) of National Institute of Health Sciences.

17 beta-estradiol and norethisterone acetate in low doses as continuous combined hormone replacement therapy.

OBJECTIVES: To evaluate low doses of 17 beta-estradiol (E2) and norethisterone acetate (NETA) as continuous combined hormone replacement therapy (HRT) in their effects on vasomotor symptoms, bleeding episodes, endometrial histology and mastalgia. METHOD: Sixty postmenopausal women were randomly allocated to three treatment groups and were given 1 mg E2 and 0.25 mg NETA (A), 1 mg E2 and 0.5 mg NETA (B) and 2 mg E2 and 1.0 mg NETA (C) in daily doses. The treatment period was 1 year. RESULTS: A similar statistically significant reduction of climacteric symptoms (P < 0.05) was found in all groups. Bleedings, mainly as spottings, occurred most commonly during the first treatment months. Fewer bleeding episodes and a higher percentage of amenorrhea was noted in group B compared to the other groups but did not reach statistical significance. All endometrial biopsies showed atrophy. Women in group A and B had less severe mastalgia (P < 0.05) compared to group C, given higher doses of steroids. CONCLUSION: Postmenopausal women taking 1 mg of E2 plus 0.5 mg NETA as continuous combined HRT reported a marked reduction of climacteric complaints and good bleeding control. No endometrial proliferation was detected after 1 year of treatment. This type of therapy may be beneficial especially for elderly women, in whom bleeding may be annoying.

Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis.

OBJECTIVE: To investigate whether the addition of low-dose estrogen-P combination hormone replacement therapy (HRT) to GnRH agonist (GnRH-a) treatment for endometriosis reduces the pharmacologic side effects of such treatment without reducing efficacy and to determine the endocrinologic changes during treatment. DESIGN: Prospective, randomized, double-blind, placebo-controlled, comparative study of two drug regimens: 3.6 mg goserelin acetate in a 28-day SC depot formulation once monthly for 6 months plus either a combination of 2 mg 17 beta-E2 and 1 mg norethisterone acetate (NET) 1 mg or matching placebo tablets once daily for 6 months. SETTING: Multicenter study in three tertiary referral centers at university teaching hospitals and two central hospitals. PATIENTS: Women with laparoscopically confirmed symptomatic endometriosis were included in the study. RESULTS: Of the total of 109 patients screened, 93 were recruited and 88 patients were randomized to either the HRT or the placebo group. Four women were withdrawn because of various medical reasons, and 76 patients were followed-up for a total of 12 months. In terms of efficacy, there was no difference between the two drug regimens for objective or subjective response. There were significantly less postmenopausal symptoms in the patients treated with goserelin plus HRT compared with those treated with goserelin plus placebo. CONCLUSION: Goserelin diminished significantly the symptoms and laparoscopic scores of endometriosis. The addition of HRT did not reduce the efficacy of goserelin but diminished the postmenopausal symptoms during treatment.

Relationship between serum estradiol concentration and IGF-I, IGF-II and IGF-binding proteins in patients with premature ovarian failure on short-term estradiol therapy.

OBJECTIVE: Insulin-like growth factors (IGFs) exert stimulatory effects on follicular growth and development, and early embryogenesis. In view of this, we studied the effect of short-term estradiol treatment, as used in preparing the uterus for embryo implantation, on the serum concentrations of IGFs and their binding proteins (IGFBP) in patients with premature ovarian failure (POF). PATIENTS AND METHODS: Twenty-four patients with POF, enrolled in an assisted reproduction program, were treated with increasing doses of estradiol up to 8 mg daily for 6 weeks. Blood was sampled for measurement of serum estradiol, IGF-I, IGF-II, and IGFBP 1, 2 and 3 at various times during estradiol treatment. RESULTS: There was no significant correlation between serum estradiol concentrations and the serum concentrations of IGF-I and IGF-II. As expected, IGF-I and IGF-II concentrations in serum correlated positively with the serum concentration of IGFBP-3, the major IGF-binding protein in serum. CONCLUSION: The results of this study suggest that estradiol therapy as used to prepare the uterus for implantation has no significant effect on serum IGF-I and IGF-II concentrations, and therefore probably does not influence, via an IGF-mediated mechanism, the success of implantation and early embryonic development.

Comparative effectiveness of somatotropin and anabolic steroids in feedlot steers.

Crossbred steers (n = 252, BW = 379 +/- 28 kg) were allotted to 42 pens in a 2 x 3 factorial arrangement of treatments: control or steroid implant (STR; estradiol benzoate+progesterone [three lighter blocks reimplanted on d 84] and trenbolone acetate [reimplanted on d 63]), and either 0, 80, or 160 mg/wk of recombinant bovine somatotropin (bST). Steers were adapted to the finishing diet (12% roughage equivalent, 13% CP) before the start of the experiment and fed for 84 or 119 d. Blood samples were taken on d 0, 14, 28, 56, and 84 for plasma urea N (PUN), serum somatotropin (ST), plasma insulin-like growth factor I (IGF-I), and plasma amino acid assay. Few interactions were noted (P > .1). Gain was increased by both treatments: 1.30 vs 1.66 kg/d for control vs. STR (P < .001) and 1.44, 1.49, and 1.51 kg/d (linear, P = .07) for 0, 80, and 160 mg of bST/wk, respectively. Gain efficiency was also improved: 169 vs 205 g/kg (P < .001) and 177, 189, and 195 g/kg (linear, P < .001), respectively. Average PUN was decreased (P < .001) 29% by STR and decreased 17 and 29% by 80 and 160 mg of bST/wk, respectively (linear, P < .001). Somatotropin decreased mean serum ST compared with controls; STR increased ST 36% compared with controls. Average plasma IGF-I was increased (P < .001) 12% by STR and 13 and 19% (linear, P < .001) by 80 and 160 mg of bST/wk, respectively. Both STR and bST influenced (P < .05) plasma amino acid profiles. Indicators of carcass fatness were decreased linearly (P < .05) by bST; STR implant tended to decrease carcass fatness and increase longissimus muscle area, which was related to carcass weight. The anabolic effects of STR and bST were found to be additive and possibly independent in feedlot steers.

A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese women. I. Contraceptive efficacy and sid effects.

A phase III clinical study was carried out among 5680 fertile Chinese women to evaluate efficacy and side effects of three monthly injectable contraceptives: Mesigyna, Cyclofem and Chinese Injectable No. 1. When used in a once-a-month treatment schedule (part 1 of study), the effectiveness of Chinese Injectable No. 1 was unacceptably low; 36 pregnancies occurred during the first 1743 women-months of use, 16 before the second injection. The study was restarted with a revised injection schedule for Injectable No. 1: two injections separated by 9 +/- 1 days during the first month and subsequent injections given 10-12 days after the onset of bleeding, or if no bleeding occurred, 28 days after previous injection. In part 2 of the study, 988, 990 and 992 subjects were provided Mesigyna, Cyclofem and Injectable No. 1, respectively. Life-table pregnancy rates at one year were 0.41%, 0% and 0.77% (p < 0.05), respectively; the overall discontinuation rates at one year were 13.9%, 19.1% and 20.4% (p < 0.001). Discontinuation rates for bleeding problems were significantly different between the groups: discontinuation rates for amenorrhea were 0.58%, 3.71% and 0.68% (p < 0.001) for Mesigyna, Cyclofem and Injectable No. 1; for other bleeding problems, the rates were 4.88%, 8.38% and 12.64% (p < 0.001). There were no significant differences between the groups regarding discontinuation for other medical or non-medical reasons. Mean weight changes after one year of use were small: 0.73, 0.86 and 0.17 kg for the three groups, respectively. Both Mesigyna and Cyclofem were very effective for contraception, but Mesigyna appeared to be tolerated slightly better with regard to cycle control; the modified dose regimen for Injectable No. 1 also gave a low pregnancy rate but was associated with higher rates of discontinuation.