Midcycle Phase Research Articles

Abstract P3-04-08: Expression of hormone-responsive genes in benign breast tissue varies with menstrual cycle phase and menopausal status

Abstract Background: The expression of many genes is known to be regulated by ambient hormone levels. In a preliminary study of random fine-needle aspirate (rFNA) samples from benign breast tissue, we found several genes that were highly correlated with the serum levels of progesterone (P4) and estradiol (E2). We now present data to further validate these genes as markers of menstrual cycle phase (MCP) and menopausal status (MPS) in benign breast tissue which may allow retrospective classification of archived breast samples with respect to MCP and MPS at the time of sampling. Methods: 240 rFNA samples from healthy women with recorded hormonal data at the time of sampling were analyzed. We divided these subjects by menstrual cycle phase (MCP) and menopausal status (MPS): 41 early follicular: (low circulating E2 and P4); 48 mid-cycle (high E2 and low P4); 31 luteal (moderate E2 and high P4). 120 post-menopausal (low E2 and low P4). 100 ng of RNA from rFNA samples of the breast was reverse transcribed. Amplicons of interest were linearly amplified to 14 cycles for 35 genes related to hormone responsiveness. qPCR reactions were carried out using the TaqMan OpenArray (Applied Biosystems). For each gene of interest, expression levels were normalized to the average expression of GAPDH. Gene expression difference between groups were conducted using the Mann-Whitney Test. P-values from gene expression difference were adjusted via the Benjamini-Hochberg (1995) approach. Results: The mean value of TNFSF11 expression level was 13.19 fold higher in luteal phase subjects than in post-menopausal subjects (p = 0.0003) where there was also the biggest difference of serum P4 level between groups. The expression of DIO2 and MYBPC1 was also significantly higher in luteal phase group than in the post-menopausal group (p = 0.005, p = 0.02, respectively). These 3 genes also demonstrated a higher expression pattern in luteal phase than mid-cycle and follicular phase but analysis is still ongoing. All comparisons between these groups will be presented at the meeting. Conclusion: The expression levels of TNFSF11, DIO2 and MYBPC1 vary with MCP and MPS. These hormone-responsive genes are candidate MCP classifiers which could be applied to archived breast samples to assess whether biomarkers of breast cancer risk are stable across the menstrual cycle, since MCP and MPS variation is likely an important source of biological noise in studies of archived breast biopsy material. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-04-08.

Endometrial thickness measurement throughout a menstrual cycle in non-obese infertile patients with polycystic ovary syndrome

To analyze the changes in the endometrial thickness in infertile polycystic ovary syndrome (PCOS) patients throughout an entire menstrual cycle and compare the changes to those seen in infertile patients without PCOS. This prospective, cross-sectional study was conducted in a total of 58 non-obese, infertile women with PCOS. The endometrial thickness was measured at three different times throughout the menstrual cycle by ultrasound. Age- and body mass index (BMI)-matched control group consisted of 62 non-obese infertile patients without PCOS. Demographic, hormonal and the ultrasonographic measurements of the two groups were compared. Day 3 levels of LH were significantly different between the groups (p=0.013). Ovarian volume measurement was significant between the groups (p=0001). All the endometrial thickness measurements in the early, mid-cycle and late luteal phases were also significantly different; p=0.001 for all. The study demonstrated an increased endometrial stripe measurements throughout a menstrual cycle in infertile patients with PCOS, when compared to infertile patients without PCOS.

Dental Pulp Blood Flow and Its Oscillations in Women with Different Estrogen Status

IntroductionThe skin microcirculation is significantly affected by serum estrogen levels. The objective of this study was to investigate the effects of estrogen serum level changes associated with the menstrual cycle and postmenopause on dental pulp blood flow (PBF) as well as its dynamics. MethodsYoung women at the menstrual phase (low serum estrogen levels) and in the mid-cycle phase of the menstrual cycle (high serum estrogen levels) and postmenopausal women were enrolled in the study. PBF and its oscillations were measured by laser Doppler flowmetry and analyzed by using wavelet transform. Serum levels of estradiol-17β were measured by immunoassay. ResultsPBFs of young women in the menstrual phase and postmenopausal women were mutually similar and significantly lower than those of young women in the mid-cycle period. With respect to the mid-cycle phase, relative amplitude and power were significantly increased in the interval 0.0095–0.02 Hz and decreased in the intervals 0.02–0.06 and 0.06–0.2 Hz in the menstrual phase. A significant decrease in 0.0095–0.02 Hz and increase in 0.02–0.06, 0.06–0.2, 0.2–0.6, and 0.6–1.6 Hz intervals were observed in postmenopause. ConclusionsThe study has shown that the menstrual phase of the menstrual cycle and postmenopause have similar PBF decrease, but PBF oscillations are differently affected in the mid-cycle phase.

Effects of estrogen and progesterone on cerebrovascular responses to euoxic hypercapnia in women

ABSTRACTObjectives To determine the cerebral blood flow response to step changes in end-tidal Pco2 in premenopausal women (n = 10; mean age±standard deviation 27.0±6.4 years) during the follicular (FP), mid-cycle (MC) and luteal (LP) phases of the menstrual cycle.Methods Transcranial Doppler ultrasound was used to measure beat-by-beat averaged peak blood flow velocity () in the middle cerebral artery in response to 20 min of euoxic hypercapnia (end-tidal Po2 = 88 Torr; end-tidal Pco2 = 7.0 Torr above resting values). The responses to euoxic hypercapnia were fitted to a simple mathematical model that included gain terms for the on (Gon) and off (Goff) responses, time constants for the on (τon) and off (τoff) responses, baseline terms and a time delay (Td).Results Serum progesterone levels were significantly greater for LP compared to FP and MC (40.6±13.2 vs. 32.6±1.4 nmol/l (p < 0.001) and 8.8±3.8 nmol/l (p < 0.001), respectively). Serum estrogen concentrations were significantly lower in FP compared to MC and LP (150.9±51.2 vs. 506.5±220.5 pmol/l (p = 0.002) and 589.1±222.8 pmol/l (p < 0.001), respectively). Arterial Pco2 was significantly greater in MC compared to LP (35.0±2.1 and 32.6±1.4 Torr, respectively; p = 0.02). There was a significant increase in Goff during LP compared with FP and MC (3.38±0.68 vs. 2.79±0.82 cm s−1 Torr−1 (p = 0.021) and 2.74±0.90 (p = 0.018) cm s−1 Torr21, respectively). Progesterone and the estrogen/progesterone ratio contributed to the observed differences in Goff.Conclusion There is an increase in Goff during LP that is explained, at least in part, by increases in serum progesterone and estrogen and a decrease in arterial Pco2.

Female urinary proteomics: New insight into exogenous and physiological hormone‐dependent changes

In the frame of a research study on possible urinary markers related to physiological hormones cycle, 33 volunteer, healthy, normotensive fertile women were selected. Clinical parameters and renin-angiotensin-aldosterone system (RAAS) components were also investigated, on the basis of the well-known relation linking sex female hormones and renin and aldosterone levels. A classic proteomic approach was applied to investigate urinary protein changes at different stages of menstrual cycle, specifically mid-cycle phase (G1), luteal phase (G2) and after 2 months of contraceptive therapy (G3). Analysis of urinary proteome was performed by SDS-PAGE, 2-D PAGE, Western blotting, and protein identification by HPLC-MS/MS. In the four comparisons examined (G1 vs. G2; G1 vs. G3; G2 vs. G3 and G(G1+G2) vs. G3), a total of 115 protein spots were differentially represented among the subgroups. Data validation was performed by replicated experiments of immunoblotting. The present work highlights for the first time variations with menstrual cycle or estroprogestin pill of newly discovered, or never related, urinary proteins. In particular, possible protein markers could be useful for further applications in contraceptive target research and RAAS modulation-related topics.

Rapid Cycling Associated With Menstrual Periods in an Adolescent: Electrophysiological Underpinnings for Bipolarity

Rapid Cycling Associated With Menstrual Periods in an Adolescent: Electrophysiological Underpinnings for Bipolarity

Effect of Non-Nucleoside Reverse Transcriptase Inhibitors on Cytokine, Chemokine, and Immunoglobulin Profiles in Serum and Genital Secretions of HIV-Infected Women

Non-protease inhibitor-based antiretroviral therapy (ART) is widely accepted as first-line ART in developing countries. Although reverse transcriptase inhibitor-based regimens have been studied in the peripheral blood, no studies have analyzed alterations in cytokine and chemokine levels, together in peripheral blood and genital secretions. Forty HIV-infected women with CD4 cell counts <200 cells/mm(3), asymptomatic, with no genital tract infection, willing to participate in the study, and adhere to ART were enrolled. Cervicovaginal lavage (CVL) was collected in the mid-cycle phase of menstrual cycle. Patients were initiated with reverse transcriptase-based antiretrovirals. Repeat sampling was performed at 24 weeks. Cytokines and chemokines were measured using ultrasensitive ELISA kits. Viral load declined to undetectable levels in 29 patients in the blood and in 33 cases in the CVL. Proinflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha, interleukin-6 [IL-6], IL-1beta) in the serum and CVL showed a significant decrease in mean levels after therapy. IL-2 levels increased significantly whereas IL-12 and (IFN-gamma decreased in both compartments. Mean levels of IL-4 and IL-10 decreased significantly in the serum. There was direct correlation between serum and CVL levels of IL-2 and IL-10. IL-10 had a negative correlation with CD4% at baseline and 6 months of therapy. Mean levels of all alpha- and beta-chemokines decreased in serum after therapy. In CVL, mean levels of MIP-1alpha, RANTES, and IL-8 reduced and SDF-1alpha increased significantly (P value <0.001). Serum levels of all the cytokines, except IL-2, and all chemokines prior to therapy, were significantly higher than healthy controls. In CVL, mean levels of TNF-alpha, IL-6, IL-1beta, IL-12, IFN-gamma, IL-10, RANTES, and IL-8 were significantly higher, whereas IL-2, MIP-1alpha, and MIP-1beta were significantly lower than healthy controls. The mean levels of proinflammatory cytokines and chemokines significantly decreased in serum and CVL after therapy, possibly due to reduced viral load.

Serum Pattern of Circulating Adipokines throughout the Physiological Menstrual Cycle

This study investigated the serum levels of resistin, adiponectin and leptin during the physiological menstrual cycle. Sixteen women (age: 19-30 years; body mass index: 19.46-24.9) with regular menstrual cycles participated. Fasting blood samples were collected on alternate days throughout a full menstrual cycle. Mean resistin concentrations were slightly higher during the luteal phase (5.30+/-0.23 ng/ml) compared to the follicular (4.68+/-0.07 ng/ml) and midcycle (4.86+/-0.09 ng/ml) phases (p=0.032). Mean leptin concentrations during the follicular phase (18.14+/-0.28 ng/ml) were significantly lower compared to the midcycle (21.79+/-0.29 ng/ml, p=0.006) and luteal phases (23.75+/-0.64 ng/ml, p<0.001). The variation of adiponectin concentrations throughout the menstrual cycle was not significant. According to the results, circulating resistin, likewise leptin concentrations vary significantly during the physiological menstrual cycle presenting with higher values during the luteal phase. This pattern, although its physiological importance is not clear, suggests that resistin, likewise to leptin, may have a role in the regulation of cyclic female reproductive functions. The stable adiponectin concentrations throughout the menstrual cycle indicate that this adipokine probably does not play a considerable role in female reproductive functions.

Cyclical Changes in Calcium Metabolism across the Menstrual Cycle in Women with Premenstrual Dysphoric Disorder

Alterations in calcium homeostasis have long been associated with affective disorders. Recently, it has been suggested that abnormalities in calcium metabolism may be responsible for some affective and somatic symptoms in women with premenstrual syndrome. Our objective was to measure fluctuations and group differences in calcium-regulating hormones across the menstrual cycle in women with and without premenstrual dysphoric disorder (PMDD). We conducted a cross-sectional and prospective study of women with and without PMDD. Participating women underwent 2 months of self-assessment symptom screening and 1 month of hormonal evaluation. Calcium-regulating hormones varied significantly across the menstrual cycle in both groups. Total serum, ionized and urine calcium, pH, intact PTH, and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] varied significantly over the menstrual cycle. The PMDD group, when compared with controls, had significantly lower ionized calcium at phase 1 (menses) (1.166 +/- 0.072 vs. 1.182 +/- 0.087 mmol/liter; P = 0.027), significantly lower urine calcium excretion at three of the five phases (late follicular phase 2, midcycle phase 3, and early luteal phase 4), and significantly lower 1,25(OH)(2)D at luteal phase 4 (45.0 +/- 27.5 vs. 50.6 +/- 33.8 pg/ml; P = 0.032). Cyclical fluctuations of the calcium-regulating hormones may help us better understand some of the psychological and somatic features of PMDD. The lack of responsiveness in vitamin D metabolism resulting in a decline in 1,25(OH)(2)D during the luteal phase of the menstrual cycle may serve as the biological trigger for the classical features of PMDD.

Serum fluctuations of total and free tryptophan levels during the menstrual cycle are related to gonadotrophins and reflect brain serotonin utilization

Serotoninergic (5-HT) neurons are suggested to regulate estrous cycle in animal models. In the present study we evaluated whether a relationship exists between the serotoninergic precursors in the central nervous system and the gonadotrophin-ovarian cyclic function. We measured 5-HT precursors [free (FT) and total (TT) tryptophan] and LH, FSH and 17beta-estradiol (E2) levels in the serum of 15 fertile women with normal menstrual cycles during the follicular (cycle days 1-5, 7-11), mid-cycle (cycle days 14-16) and luteal (cycle days 17-19, 22-24) phases. TT and FT were significantly increased in the 7-11 and 17-19 cycle days and were decreased at mid-cycle (P < 0.01), with a cyclic and opposite behaviour when compared to that of FSH and LH. Indeed, correlation analysis through the matrix of mean values showed that LH was negatively correlated to TT (r = -0.636) and FT (r = -0.574), as well as FSH (TT, r = -0.655; FT, r = -0.663), and that TT and FT were positively correlated to each other (r = 0.801; P < 0.001). Furthermore, whilst the two FT peaks reached approximately the same levels in the follicular and luteal phase, TT levels were approximately 30% higher in the luteal than in the follicular phase of the cycle: thus in the first (follicular) phase FT peak was relatively higher than that of TT, whereas the contrary occurred in the second (luteal) phase of the cycle. Both TT and FT levels have cyclic variations throughout the menstrual cycle, being lowest at mid-cycle (14-16 cycle days), concomitant with the highest LH and FSH concentrations, and higher before and after mid-cycle phase, coinciding with the lowest circulating LH/FSH levels. Since TT and FT levels in the plasma have cyclic changes, our study: (i) suggests that a consumption of serum serotonin precursors takes place concomitant with gonadotrophin release during menstrual cycle; (ii) may represent an in vivo model to investigate this relationship in women in different physiopathological conditions.

Role of sialic acid and sulfate groups in cervical mucus physiological functions: study of Macaca radiata glycoproteins

The influence of charged groups in glycoproteins was investigated to assess their effect on the physiological functions of bonnet monkey cervical mucus. The macromolecular glycoproteins from peri-ovulatory, midcycle phase cervical mucus were treated with Pronase, trypsin and chymotrypsin and the enzyme-resistant glycoproteins purified by gel filtration on Sepharose 4B and a high molecular weight component containing carbohydrates, proteins and sulfate groups was recovered in high yield. This material still reacted with an antiserum directed against purified midcycle glycoprotein but not against another antiserum directed against luteal phase purified glycoproteins. Upon treatment with Pronase, trypsin and chymotrypsin, asialoglycoproteins and desulfated asialoglycoproteins released fragments of low molecular sizes, none of which reacted with the anti-midcycle glycoprotein antiserum. Cervical mucus collected from the estrogenic phase displayed a morphology supporting sperm migration, and this mucus retains the same morphology and reacts with the anti-midcycle glycoprotein antiserum following mild treatment with sialidase and subsequently with Pronase. These results imply that charged carbohydrate groups help maintain the structural and functional integrity of the mucus glycoprotein in its biological environment.

Acute Effect of Alcohol on Estradiol, Estrone, Progesterone, Prolactin, Cortisol, and Luteinizing Hormone in Premenopausal Women

Heavy alcohol consumption is associated with menstrual irregularities, including anovulation, luteal-phase dysfunction, recurrent amenorrhea, and early menopause. In addition, moderate to heavy alcohol intake has been found to increase the risk of spontaneous abortions and breast cancer. These adverse effects could at least in part originate from alcohol-mediated changes in hormone levels. The acute effect of alcohol on the hormone balance in women using oral contraceptives (OC+) and also in nonusers (OC-), was evaluated in 30 OC- and 31 OC+ subjects, representing the whole period of the menstrual cycle. It was also evaluated in 40 OC- and 47 OC+ subjects during the midcycle phase and in 10 OC+ subjects with unknown cycle phase. We found that among subjects who used oral contraceptives, estradiol levels increased and progesterone levels decreased after intake of alcohol (0.5 g/kg). No dose effect (0.34-1.02 g/kg) on progesterone was observed in a substudy on 10 OC+ subjects. With regard to estrone levels, no effect was observed, although a significant increase was found in the estradiol-to-estrone ratio. Among subjects not using oral contraceptives, progesterone levels decreased after intake of alcohol (0.5 g/kg). No effect was found in estradiol, estrone, or the estradiol-to-estrone ratio during midcycle in this study group. A transient elevating effect of alcohol (0.5 g/kg) on prolactin levels was observed in both study groups. We found that alcohol (0.5 g/kg) had no significant effect on luteinizing hormone (LH) levels among subjects not using oral contraceptives, and observed a decline among subjects using oral contraceptives at midcycle. We suggest that the estradiol and progesterone effects are related to decreased steroid catabolism, resulting from the alcohol-mediated increase in the hepatic NADH-to-NAD ratio. The transient effect on prolactin levels may reflect acute changes in opioid and dopamine levels in the hypothalamus. The present findings regarding female sex steroids may be of relevance in the association between moderate to heavy alcohol consumption and the development of breast cancer.

Estrogen improves endothelial function

Purpose: To determine the effect of estrogen on endothelium-dependent relaxation in the cutaneous microcirculation of women. Methods: Three groups of women participated in the study. Group 1 (n = 20) was premenopausal and had a mean age of 39 years (range 24-50 years). Group 2 (n = 9) was postmenopausal and had a mean age of 58 years (range 53-65 years). Group 3 (n = 11) was postmenopausal and taking estrogen replacement therapy; the mean age was 53 years (range 43-58 years). Eleven women in group 1 underwent testing twice, once during menstruation (mean serum estradiol level 73 ± 30 pg/ml) and once during midcycle (mean serum estradiol level 268 ± 193 pg/ml; p = 0.003). Single-point laser Doppler ultrasound and laser Doppler imaging with a scanner were used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (endothelium dependent) and 1% sodium nitroprusside (endothelium-independent smooth muscle relaxant). Results: All three groups were matched for body mass index and fasting glucose, total, high-density lipoprotein, and low-density lipoprotein cholesterol and triglyceride levels. All women had normal blood pressure, and none smoked. Mean serum estradiol levels were 196 ± 170 pg/ml (group 1), 35 ± 12 pg/ml (group 2), and 107 ± 78 pg/ml (group 3) ( p = 0.004). Maximum microvascular vasodilatation (percentage increase over baseline) in response to acetylcholine was reduced in group 2 (93% ± 43%) compared with group 1 (187% ± 63%) and group 3 (142% ± 56%) ( p = 0.001). The response to sodium nitroprusside also was diminished in group 2 (73% ± 27%) compared with group 1 (126% ± 45%) and group 3 (100% ± 32%) ( p = 0.02). Within group 1 the acetylcholine response was higher during the midcycle phase (186% ± 31%) compared with the menstrual phase (147% ± 57%) ( p < 0.05). The sodium nitroprusside response also was higher during the midcycle phase (144% ± 31%) compared with the menstrual phase (94% ± 41%) ( p < 0.05) Conclusion: The results indicate that estrogens might enhance endothelium-dependent and endothelium-independent vasodilatation in the microcirculation of women.(J Vasc Surg 1998;27:1141-7.)

New approaches to ovarian stimulation.

Suppression of endogenous hormone production by gonadotrophin-releasing hormone (GnRH) agonists followed by controlled ovarian hyperstimulation (COH) with human gonadotrophins, especially the so-called 'long protocol' has developed from second-line into first-line therapy. Due to this attitude premature luteinization can be safely avoided, enhancing therapeutic efficacy. Recombinant preparations of human follicle stimulating hormone (FSH) have been proven to be effective within COH according to the long protocol. The high purity of these compounds may have clinical advantages. GnRH antagonists could be successfully introduced in COH protocols. Also, daily injections in the midcycle phase according to the 'Lübeck protocol', as single or only dual administrations around day 9 seem to abolish any premature LH rises. Due to their different pharmacological mode of action, based on a classic competitive receptor blockage GnRH antagonists avoid any flare-up period and allow ovarian stimulation to start within the spontaneous cycle. Pregnancy rates are comparable to those after long protocol stimulation. Combination of softer stimulation regimes like clomiphene citrate and low dose HMG with midcycle administration of GnRH antagonists may be the way to a cheap, safe and efficient ovarian stimulation. It seems to be high time for modest forms of ovarian stimulation, lowering burden and risk for our patients.

Hormonal regulation of spermatogenesis in the hypophysectomized rat: cell viability after hormonal replacement in adults after intermediate periods of hypophysectomy.

A quantitative analysis of germ-cell populations in normal, hypophysectomized (Hx), and Hx-hormone-treated animals was undertaken during periods of regression that were characterized as intermediate, between short-term and long-term regression of the testis. Twenty-one groups of adult rats were administered either follicle-stimulating hormone (FSH), growth hormone, thyroid-stimulating hormone (TSH), or testosterone (T) in various doses and combinations. The dosage of T administered was less than that expected to achieve maximum testis weight. Flutamide and Casodex were used to compete with androgen binding to receptors in Hx animals, as it is known that small amounts of androgen are secreted in the absence of pituitary stimulation. Follicle-stimulating hormone, T, and TSH all significantly maintained testis weight as compared with Hx controls, although FSH and T, singly or in combination, were the most effective. Contamination of the TSH preparation with trace amounts of FSH was apparently responsible for the slight maintenance of testis weight. A novel assay for determination of the numbers of viable germ cells was used in a subset of these groups to determine the cellular sites of FSH and T action. Numbers of type A spermatogonia were lowered after Hx and were maintained by either FSH or T or a combination of these hormones. Other phases of germ-cell development most susceptible to FSH and/or T were the successive conversions of type A spermatogonia to intermediate spermatogonia, intermediate spermatogonia to type B spermatogonia, preleptotene spermatocytes to pachytene spermatocytes, and early pachytene spermatocytes to intermediate maturity pachytene spermatocytes during early and midcycle phases of pachytene spermatocyte development. Germ-cell loss during meiosis and virtually every phase of spermatid development was largely prevented by FSH or T or a combination of these hormones. Thus, in testes in advanced stages of regression, both FSH and T were capable of preventing cell loss, suggesting that both hormones can affect the survival of the same cell type. The present study demonstrated that FSH can partially compensate for lowered T levels. The combined administration of FSH and T was more effective in preventing overall cell degeneration than either hormone alone. Unlike the initial phase of spermatogenesis, in which there is a largely midcycle loss of germ cells due to Hx, the loss of cells during testis regression is more widespread and impacts several cell types in more than one stage of the spermatogenic cycle.

Expression of platelet-derived endothelial cell growth factor and its mRNA in uterine endometrium during the menstrual cycle.

Steroid hormones, e.g. progesterone and oestradiol, may be responsible for the production and expression of a variety of angiogenic growth factors present in endometrial tissue. The expression of platelet-derived endothelial cell growth factor (PD-ECGF) in neovascularization after regression of the microvessels in the endometrium was examined. PD-ECGF protein expression in the endometrium during the menstrual cycle was determined by a sandwich enzyme immunoassay. Transcription levels of PD-ECGF were measured by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) Southern blot technique. The data show that levels of PD-ECGF protein and mRNA in uterine endometrium did not alter during the proliferative phase prior to ovulation. During the midcycle phase a sharp transient fall in mRNA levels accompanied by a gradual drop in protein levels was observed. After ovulation transcription of PD-ECGF recovered with a sharp increase in mRNA levels which persisted during the ovulatory phase. PD-ECGF protein levels were temporarily low after ovulation, but increased remarkably through the late secretory phase. PD-ECGF expression in the endometrium seems to be inversely correlated with oestradiol concentrations during the menstrual cycle.

Hormone profiles under ovarian stimulation with human menopausal gonadotropin (hMG) and concomitant administration of the gonadotropin releasing hormone (GnRH)-antagonist Cetrorelix at different dosages

The premature LH surge in ART programs seems to be avoided by daily administration of the GnRH-antagonist Cetrorelix during the midcycle phase in controlled ovarian hyperstimulation with hMG. The dosage necessary for sufficient suppression of the pituitary gland is not yet defined. To elucidate this question three daily dosages (3, 1, 0.5 mg) were administered and the hormone profiles obtained as well as the number of oocytes retrieved, the fertilization rate, and the consumption of HMG were compared. No premature LH surge could be observed at any of the three dosages administered. Both gonadotropins were deeply suppressed. The fertilization rates of the oocytes obtained were 45.3% in the 3-mg group, 53.1% in the 1-mg group, and 67.7% in the 0.5-mg group. The average uses of hMG ampoules were 30 in the 3-mg group, 27 in the 1-mg group, and 26 in the 0.5-mg group. Cetrolix, 0.5 mg/day, administered during the midcycle phase of controlled ovarian hyperstimulation with hMG is enough to prevent completely the premature LH surge. Perhaps even lower dosages would be sufficient. Regarding fertilization rates and use of hMG, the lower dosage seems to be the most favorable.

Menstrual cycle, arousal-induction, and intelligence test performance.

Regularly menstruating students (aged 19 to 25 yr.) were tested in the morning under high and low arousal-induction conditions (with time-pressure instructions vs without time-pressure instructions) during either midcycle (n = 16 or menstruation phase (n = 16) to study the interactive effects of menstrual phases and time-pressure stress-induced arousal on intelligence test scores on Raven's Standard Progressive Matrices and Hundal's General Mental Ability Test. A crossover interactive effect of menstrual phase and stress-induced arousal was found on performance of the Hundal test, suggesting that performance of subjects who were tested during the midcycle phase (putatively High Basal Arousal) was impaired under the time-pressure instructions condition (High-induced Arousal) as compared to performance under the without time-pressure instructions condition (Low-induced Arousal), with the reverse pattern of effects being true for subjects who were tested during the menstruation phase. Scores on Hundal's test conform to the Yerkes-Dodson (1908) law which relates arousal to task performance and suggests that the menstrual cycle and performance on the intelligence test was arousal-based. No effects, however, were observed for Raven's Matrices, raising the possibility that task characteristics may mediate the relationship between arousal and performance.

Preserved pituitary response under ovarian stimulation with HMG and GnRH antagonists (Cetrorelix) in women with tubal infertility

Objective: To examine the pituitary response in patients undergoing short-term application of the GnRH antagonist Cetrorelix in the mid-cycle phase for hypophysial suppression of premature LH surges within an IVF-program. Design: Twenty patients suffering from primary or secondary tubal infertillty were stimulated with hMG from cycle day 2. From day 7 till ovulation induction Cetrorelix was administered in two different dose regimens (15 patients 3 mg s.c. daily; 5 patients 1 mg s.c. daily). Three hours before ovulation induction a GnRH test was performed using 25 μg of native GnRH and the pituitary response examined by measurement of the serum LH concentration after 30 min. Results: Premature LH surges could be avoided in the 3-mg group and in the 1-mg group, respectively. Due to this, none of the cycles had to be cancelled. Oestradiol profiles and ultrasound demonstrated a satisfactory follicular maturation. All patients showed pronounced suppression of the serum LH levels before ovulation induction. The mean increase of serum LH due to the performed GnRH test was 10 mIU/ml for the 3-mg group, while the average maximum in the 1-mg group was about 32.5 mIU/ml. Conclusions: The pituitary response is preserved by the treatment with the GnRH antagonist Cetrorelix. The extent of suppression of the adenohypophysis, as expressed by the different reactions on GnRH test, can be modulated by the dosage administered. This should allow ovulation induction by GnRH or one of its agonists instead of hCG, which could be beneficial in patients at high risk of Ovarian Hyperstimulation Syndrome (OHSS) and those suffering from Polycystic Ovary Disease (PCOD).

Some effects of prematurely elevated concentrations of progesterone on luteal and follicular characteristics during the oestrous cycle in heifers

The aim of this study was to characterise the luteal and follicular response to artificially elevated concentrations of progesterone during the metoestrous phase of the oestrous cycle of heifers. An intravaginal controlled internal drug releasing (CIDR) device containing 1.9 g progesterone was inserted at either Day 1 of the cycle (oestrus designated Day 0) for 4 days (T1; n=12), or on Day 4 for 5 days (T4; n=11). A third group of heifers (CTRL; n=13) remained untreated. The diameters of the corpus luteum (CL) and all follicles of at least 5 mm were recorded daily in ovaries of eight heifers from each group by transrectal ultrasonography throughout the cycle. A blood sample was collected daily from every heifer to determine the concentrations of progesterone and luteinising hormone (LH) in sera. Two of the heifers with elevated progesterone levels from Day 1 had ‘short’ cycles which were characterised by ovulation of the first dominant follicle following the premature demise of the CL. These data are considered separately from the general analysis. Progesterone concentrations of heifers in both treatment groups were elevated ( P<0.05) during the period of CIDR insertion, but were not different at the mid-cycle phase compared with untreated contemporaries. A sustained decline to basal concentrations of progesterone occurred earlier ( P<0.05) in heifers treated from Day 1. Elevated progesterone concentrations were associated with decreased ( P<0.05) mean concentrations of LH on Days 4 and 5 in heifers of the T1 group, but only on Day 5 in the T4 group. The average diameter of the corpus luteum (CL) of treated heifers from Days 8 to 18 was less than in untreated heifers (Days 11–13 and 16–18, P<0.05). Heifers in the T1 group had either one or two waves of follicle turnover, with a mean inter-oestrus interval of 8 days and 18 days, respectively. In contrast, heifers in other groups had some two-wave but mostly three-wave cycles and mean inter-oestrus intervals of about 21 days. Premature elevation of progesterone reduced ( P<0.05) the size of the first dominant follicle in both treated groups of heifers. Administration of progesterone during the early and late metoestrous phase of the oestrous cycle in heifers reduced the diameters of the CL and the first dominant follicle. Elevation of progesterone from Days 1 to 5, but not from Days 4 to 9, reduced the lifespan of the CL to produce ‘short’ and ‘shortened’ cycles, with either one or two follicle waves, respectively.