Peripheral Estradiol Levels Research Articles

YB-1 Protein Prevents Age Decline in Plasma Estradiol in 5xFAD Transgenic Aging Female Mice

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the main cause of dementia in the elderly. When looking for new treatments for AD, attention was drawn to the multifunctional Y-box-binding protein 1 (YB-1). Previously, we revealed a positive effect of intranasal administration of YB-1 on learning and spatial memory, along with a decrease in the content of cerebral β-amyloid and the intensity of plaque initiation, with an improvement in the survival of neurons in the cortex and hippocampus of male AD mice. However, AD affects women twice as often as men, so it is of great interest to study the effects of YB-1 on aging females. Estrogens and androgens are necessary for the maintenance of cognitive function during aging and, apparently, may prevent the development of AD. In this work, peripheral levels of estradiol (E2) and cytokines were studied after intranasal administration of YB-1 to aging female 5xFAD transgenic mice and control non-transgenic animals. In intact aging animals of both groups, a violation of the estrous cycle and a decrease in the level of E2 in blood plasma were revealed. Mice treated with YB-1 did not show a characteristic age-related decrease in plasma E2 levels. The introduction of YB-1 did not affect the peripheral level of cytokines. Thus, a novel, previously undescribed effect of YB-1 on plasma E2 levels in aging female mice is shown. These data indicate that YB-1 may be a promising compound in the prevention and treatment of neurodegenerative diseases. However, further experiments are needed to gain insight into the detailed mechanisms of YB-1 action.

Risk Factors for Monozygotic Twins in IVF-ICSI Cycles: a Case-Control Study.

In vitro fertilization (IVF) is associated with a higher incidence of monozygotic twin pregnancies, which are known to be burdened by a higher risk of main obstetric complications. The reasons behind this association are still unclear. In the present study, we therefore investigate the risk factors for monozygotic twinning in pregnancies achieved by IVF. We conducted a multicenter retrospective case-control study. All IVF cycles performed between 2014 and 2019 at the infertility units of two Italian academic institutes were retrospectively reviewed. Only pregnancies obtained with single embryo transfer were eligible. A total of 50 monozygotic twin pregnancies (cases) were identified and matched in a 1:5 ratio to 250 singleton pregnancies (controls) by study center and study period. Monozygotic twin pregnancies were diagnosed by ultrasound. Women experiencing miscarriage could be included provided that the pregnancy loss occurred after a definitive diagnosis of monozygotic twin pregnancy. Demographic, clinical, and embryological characteristics were retrieved from patients' charts. Overall, the incidence of monozygotic twin pregnancies was 1.2% (50 out of 4016 single embryo transfers). At univariate analyses, statistically significant differences emerged for BMI, peripheral levels of estradiol and progesterone at the time of hCG administration, total number of retrieved suitable oocytes, freezing-thawing cycles, and assisted hatching. After performing a multivariate logistic analysis, only assisted hatching remained significantly associated with monozygotic twinning (adjusted odds ratio 2.32, 95%CI 1.03-5.25). Blastomere separation during the passage through this artificial hole or interference with the signaling pathway within the embryo could be the mechanisms involved.

Plasma estradiol-17β, cortisol, and insulin concentrations and serum biochemical parameters surrounding puberty in Japanese Black beef bulls with normal and abnormal semen

The associations of semen abnormalities with circulating hormones (estrogens, glucocorticoid, insulin) and common biochemical parameters are unclear in beef bulls. We compared plasma concentrations of estradiol-17β, cortisol, and insulin and serum biochemical parameters surrounding puberty in Japanese Black beef bulls (n = 96) with normal post-thaw or abnormal semen (fresh and frozen). Blood samples were collected monthly from 4 to 24 months of age (n = 50) for the assays of plasma estradiol, cortisol, and insulin and every 3 months from 6 to 21 months of age (n = 92) for the serum biochemical analyses. Semen was collected weekly from 12 months until at least 18 months of age. Fresh semen was evaluated for semen volume, sperm progressive motility, concentrations, and morphological defects. The normal fresh semen was frozen by a standard method and examined for post-thaw sperm motility and fertility, which were evaluated for rates of transferable embryos. Bulls were classified as having either normal fresh semen or abnormal fresh semen (when at least one of the above test items was abnormal for 6 months). The normal fresh semen was categorized as having either normal post-thaw semen or low fertility post-thaw semen. The abnormal fresh semen was categorized as having sperm morphological defects, low motility, or morphological defects plus low motility. Plasma cortisol concentrations in the abnormal fresh semen group were higher than those of the normal fresh semen group (p < 0.0001). Plasma estradiol-17β and insulin concentrations in the low-fertility post-thaw semen group were lower than those of the normal post-thaw semen group (p < 0.0001). Serum aspartate aminotransferase and magnesium concentrations were greater for the abnormal fresh semen group vs. the normal fresh semen group (p < 0.005). These results suggest that fresh semen abnormality in pubertal beef bulls might be associated with increased circulating aspartate aminotransferase, magnesium and cortisol. Low-fertility post-thaw semen could have been involved with the lower peripheral estradiol and insulin levels in beef bulls.

Is the effect of fluoxetine on plasticity related to serotonin transporter or tropomyosin-related receptor kinase B?

The associations of semen abnormalities with circulating hormones (estrogens, glucocorticoid, insulin) and common biochemical parameters are unclear in beef bulls. We compared plasma concentrations of estradiol-17β, cortisol, and insulin and serum biochemical parameters surrounding puberty in Japanese Black beef bulls (n = 96) with normal post-thaw or abnormal semen (fresh and frozen). Blood samples were collected monthly from 4 to 24 months of age (n = 50) for the assays of plasma estradiol, cortisol, and insulin and every 3 months from 6 to 21 months of age (n = 92) for the serum biochemical analyses. Semen was collected weekly from 12 months until at least 18 months of age. Fresh semen was evaluated for semen volume, sperm progressive motility, concentrations, and morphological defects. The normal fresh semen was frozen by a standard method and examined for post-thaw sperm motility and fertility, which were evaluated for rates of transferable embryos. Bulls were classified as having either normal fresh semen or abnormal fresh semen (when at least one of the above test items was abnormal for 6 months). The normal fresh semen was categorized as having either normal post-thaw semen or low fertility post-thaw semen. The abnormal fresh semen was categorized as having sperm morphological defects, low motility, or morphological defects plus low motility. Plasma cortisol concentrations in the abnormal fresh semen group were higher than those of the normal fresh semen group (p < 0.0001). Plasma estradiol-17β and insulin concentrations in the low-fertility post-thaw semen group were lower than those of the normal post-thaw semen group (p < 0.0001). Serum aspartate aminotransferase and magnesium concentrations were greater for the abnormal fresh semen group vs. the normal fresh semen group (p < 0.005). These results suggest that fresh semen abnormality in pubertal beef bulls might be associated with increased circulating aspartate aminotransferase, magnesium and cortisol. Low-fertility post-thaw semen could have been involved with the lower peripheral estradiol and insulin levels in beef bulls.

Adverse Effects of Aromatase Inhibition on the Brain and Behavior in a Nonhuman Primate.

Breast cancer patients using aromatase inhibitors (AIs) as an adjuvant therapy often report side effects, including hot flashes, mood changes, and cognitive impairment. Despite long-term use in humans, little is known about the effects of continuous AI administration on the brain and cognition. We used a primate model of human cognitive aging, the common marmoset, to examine the effects of a 4-week daily administration of the AI letrozole (20 μg, p.o.) on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell physiology. Letrozole treatment was administered to both male and female marmosets and reduced peripheral levels of estradiol (E2), but unexpectedly increased E2 levels in the hippocampus. Spatial working memory and intrinsic excitability of hippocampal neurons were negatively affected by the treatment possibly due to increased hippocampal E2. While no changes in hypothalamic E2 were observed, thermoregulation was disrupted by letrozole in females only, indicating some impact on hypothalamic activity. These findings suggest adverse effects of AIs on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life.SIGNIFICANCE STATEMENT Aromatase inhibitors (AIs) are used as an adjuvant therapy for estrogen-receptor-positive breast cancer and are associated with side effects, including hot flashes, depression/anxiety, and memory deficits severe enough for many women to discontinue this life-saving treatment. AIs are also used by men, yet sex differences in the reported side effects have not been systematically studied. We show that AI-treated male and female marmosets exhibit behavioral changes consistent with these CNS symptoms, as well as elevated hippocampal estradiol and compromised hippocampal physiology. These findings illustrate the need for (1) a greater understanding of the precise mechanisms by which AIs impact brain function and (2) the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.

Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding

The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4 receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [11C]SB207145 positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p=0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment.

PP.23.02

Objective: Since aldosterone and cortisol levels vary during the menstrual cycle, and are utilised in the interpretation of adrenal venous sampling (AVS) to differentiate unilateral from bilateral primary aldosteronism, outcome of AVS in premenopausal women could possibly be influenced by when the collections are made. We assessed the effect of phase of the menstrual cycle on both adrenal and peripheral venous aldosterone and cortisol levels and on serum female sex steroid levels during AVS. Design and method: In 23 premenopausal women with primary aldosteronism undergoing AVS, levels of aldosterone, cortisol, progesterone, estradiol, LH and FSH levels were compared, depending on whether collected during the follicular or luteal phase Results: Based on results at AVS, 10 women had unilateral over-production of aldosterone, and 13 bilateral. Unilateral aldosterone over-production was observed more frequently in women undergoing AVS during the luteal phase compared with the follicular phase (7/10 = 70% vs 3/13 = 23%; p < 0.05). Simultaneously collected peripheral levels of progesterone (p < 0.0001), estradiol (p < 0.05) and aldosterone (p < 0.05) and bilateral adrenal venous levels of aldosterone (p < 0.01) and cortisol (p < 0.01) were higher in those sampled during the luteal phase. Importantly, higher/lower side adrenal venous aldosterone/cortisol ratios (i.e. lateralization indices) were higher during the luteal phase than follicular [median 11 (range 2.94–96) vs 2 (1.23–35), (p < 0.05)]. Conclusions: The phase of the menstrual cycle during which samples are collected significantly affects the levels of aldosterone and cortisol used to interpret AVS. A risk of false lateralization appears to be present when AVS is performed during the luteal phase, but this requires confirmation with larger patient numbers, ideally with studies in each patient during both phases. Meanwhile, recording of the phase of the cycle during which AVS is performed should be encouraged.

Seasonal Changes in Cell Proliferation in the Adult Sheep Brain and Pars Tuberalis

To adapt to seasonal variations in the environment, most mammalian species exhibit seasonal cycles in their physiology and behavior. Seasonal plasticity in the structure and function of the central nervous system contributes to the adaptation of this physiology in seasonal mammals. As part of these plasticity mechanisms, seasonal variations in proliferation rate and neuron production have been extensively studied in songbirds. In this report, we investigated whether this type of brain plasticity also occurs in sheep, a seasonal species, by assessing variations in cell proliferation in the sheep diencephalon. We administered the cell birth marker 5'-bromodeoxyuridine (BrdU) to adult female sheep in July and December, during long and short photoperiod, respectively. The BrdU incorporation was analyzed and quantified in the hypothalamus, a key center for neuroendocrine regulations, as well as in other structures involved in relaying neuroendocrine and sensory information, including the median eminence, the pars tuberalis of the pituitary gland, and the thalamus. In December, 2-fold and 6-fold increases in the number of BrdU+ nuclei were observed in the hypothalamus and thalamus, respectively, when compared with July. This variation is independent of the influence of peripheral gonadal estradiol variations. An inverse seasonal regulation of cell proliferation was observed in the pars tuberalis. In contrast, no seasonal variation in cell proliferation was seen in the subventricular zone of the lateral ventricle. Many of the newborn cells in the adult ovine hypothalamus and thalamus differentiate into neurons and glial cells, as assessed by the expression of neuronal (DCX, NeuN) and glial (GFAP, S100B) fate markers. In summary, we show that the estimated cell proliferation rates in the sheep hypothalamus, thalamus, and pars tuberalis are different between seasons. These variations are independent of the seasonal fluctuations of peripheral estradiol levels, unlike the results described in the brain nuclei involved in song control of avian species.

In Men, Peripheral Estradiol Levels Directly Reflect the Action of Estrogens at the Hypothalamo-Pituitary Level to Inhibit Gonadotropin Secretion

Estradiol inhibits gonadotropin release in men by an action at the hypothalamus and pituitary. Because of the tissue-specific regulation of aromatase, peripheral estradiol levels may not reflect brain estradiol concentrations. We evaluated whether local aromatization of testosterone in the hypothalamus or pituitary is important for gonadotropin release and to what extent circulating estrogens affect gonadotropin levels and peripheral testosterone levels. DESIGN, SUBJECTS, AND INTERVENTIONS: We suppressed aromatase activity in 10 young healthy men with letrozole 2.5 mg once daily, restored plasma estradiol levels with estradiol patches (100 microg/d for the first week, 50 microg/d the second week, 25 microg/d the third week, and no estradiol patch the fourth week) and measured plasma testosterone, estradiol, LH, FSH, and SHBG levels. The mean estradiol and testosterone levels during the study ranged between 68.6 +/- 38.3 and 12.6 +/- 7.21 pg/ml for estradiol and 179 +/- 91 and 955 +/- 292 ng/dl (mean +/- sd) for testosterone. Levels of testosterone, LH, and FSH were inversely related to peripheral estradiol levels. During letrozole use, the mean plasma estradiol level needed to restore testosterone, LH, and FSH levels to baseline levels was not significantly different from the baseline mean estradiol level. Local aromatization of testosterone in the hypothalamo-pituitary compartment is not a prerequisite for expression of the inhibitory action of estrogens on gonadotropin secretion in men. Peripheral estradiol levels directly reflect the inhibitory tone exerted by estrogens on gonadotropin release and are a major determinant of peripheral testosterone, LH, and FSH levels.

Endocrine Function and Oocyte Retrieval After Autologous Transplantation of Ovarian Cortical Strips to the Forearm

In reproductive-age women, one of the common adverse effects of chemotherapy and radiotherapy is premature ovarian failure. In addition, a significant number of women experience early menopause due to oophorectomy performed for benign indications. To develop an ovarian transplantation technique to preserve endocrine function in women undergoing sterilizing radiotherapy and/or chemotherapy, or oophorectomy. Case study of 2 patients in New York who received autologous ovarian transplantation (patient A, November 1999; patient B, April 2000) to the forearm prior to pelvic radiotherapy or after oophorectomy. Patient A is a 35-year-old woman with stage IIIB squamous cell cervical carcinoma and patient B is a 37-year-old woman with recurrent benign ovarian serous cysts. Follicular development evident by ultrasound examination; cyclical production of estradiol and progesterone; restoration of serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels to nonmenopausal range; and disappearance of menopausal symptoms. Menopause was confirmed immediately after the transplantation in both patients by serum follicle-stimulating hormone measurements (patient A, 47 mIU/mL; patient B, 50.7 mIU/mL). In patient A, follicle development was noted by physical and ultrasound examinations approximately 10 weeks after the transplantation. The mean (SE) follicle-stimulating hormone and luteinizing hormone levels decreased to 8.6 (0.4) mIU/mL and 12.8 (0.8) mIU/mL, respectively. The peripheral estradiol levels showed cyclical variation (mean [SE], 115 [9.2] pg/mL [422 (33.8) pmol/L), and during the 18-month follow-up, a dominant follicle developed each month. The estradiol levels from the right cubital vein were consistent with ovarian vein measurements (mean [SE], 1069 [269] pg/mL [3924 (987.5) pmol/L]). Percutaneous oocyte aspirations yielded a mature oocyte. In patient B, ovarian function was demonstrated by ultrasound visualization of a 9-mm follicle by 6 months after transplantation. Thereafter, the patient had spontaneous menstruation every 25 to 28 days. Ovulation was further confirmed by midluteal progesterone measurements (range, 7-10.1 ng/mL; mean [SE], 8.5 [0.9] ng/mL). Patient B's ovarian graft was still functional 10 months after the transplantation. Subcutaneous ovarian transplantation appears to be a relatively simple, novel technique to preserve endocrine function in women undergoing sterilizing cancer therapy or surgery.

Aromatase inhibitors and their use in the adjuvant setting.

Over the past decade several novel aromatase inhibitors have been introduced into clinical practice. The discovery of these drugs followed on from the observation that the main mechanism of action of aminoglutethemide was via inhibition of the enzyme aromatase, thereby reducing peripheral levels of estradiol in post-menopausal patients. The second-generation drug 4-hydroxyandrostenedione was introduced in 1990, and although its use was limited by its need to be given parenterally, it was found to be a well-tolerated form of endocrine therapy. The third-generation inhibitors include vorozole, letrozole, anastrozole and exemestane, the former three being non-steroidal inhibitors, the latter being a steroidal inhibitor. All these compounds are capable of reducing estrogen levels to within 5%-10% of baseline levels compared with 20%-30% base line levels in the case of 4-hydroxyandrostenedione. Studies are currently in progress to determine the value of these third-generation aromatase inhibitors in the adjuvant setting. These studies include head-to-head comparison of aromatase inhibitor with tamoxifen, sequential aromatase inhibitor after tamoxifen and first-line aromatase inhibitor followed by adjuvant tamoxifen. Current issues revolve around the toxicity of these compounds in terms of effects on the cardiovascular system and bone.

Estradiol and testosterone in specific regions of the human female brain in different endocrine states

Post-mortem concentrations of estradiol and testosterone were measured in 17 brain areas, serum and fat in 6 fertile and 5 postmenopausal women. Steroid concentrations were measured with radioimmunoassay after extraction of brain tissue with ethanol and purification with celite chromatography. There were regional differences in brain concentrations of both steroids. The highest levels of estradiol and testosterone were noted in the hypothalamus, preoptic area and substantia nigra. These findings may assist in the interpretation of functional animal studies where the hypothalamus-preoptic area and the nigrostriatal dopamine system have proved to be target areas for estradiol. When compared to postmenopausal women, estradiol concentrations were significantly higher in the brains of fertile women, which indicates that peripheral serum levels of estradiol are reflected in the brain. This study has yielded information about steroid levels in different endocrine states and could provide a frame of reference for studies of estradiol and testosterone mediated effects on the central nervous system.

Endometrial blood flow response to estrogen replacement therapy and tamoxifen in asymptomatic, postmenopausal women: a transvaginal Doppler study.

This study was conducted to evaluate endometrial blood flow characteristics in response to estrogen replacement therapy (ERT) and tamoxifen in asymptomatic postmenopausal women, and to correlate the resistance index (RI) with plasma estradiol levels. Transvaginal color Doppler ultrasound examinations were performed in 30 asymptomatic, postmenopausal women who demonstrated thin endometria (< 0.5 cm). Ten healthy women receiving ERT and ten women with breast cancer receiving tamoxifen comprised the study groups. Ten postmenopausal women free of any hormonal treatment comprised the control group. Blood flow response was assessed by visualization of arterial waveforms in the endometrial region. Resistance indices were calculated for analysis and correlated with peripheral blood levels of estradiol. All postmenopausal women treated with tamoxifen or ERT showed continuous forward end-diastolic flow velocities, while the menopausal women without treatment demonstrated partial forward end-diastolic flow. Resistance index values of non-treated women were invariably higher (mean 0.89, range 0.85-0.91) than in those on tamoxifen (mean 0.79, range 0.54-0.90; p < 0.05), while the lowest RI was obtained in women taking ERT (mean 0.66, range 0.54-0.90; p < 0.05). The plasma concentrations of estradiol in women on ERT were found to be significantly higher than those of the tamoxifen and control groups. The observed data suggest that ERT and tamoxifen modify normal postmenopausal endometrial perfusion. Tamoxifen had a weaker estrogenic effect on the endometrial blood flow resistance, and ERT enhanced endometrial blood perfusion through vasodilatation.

Changes in rabbit corpus luteum progesterone secretion and cellular morphology following unilateral luteectomy or ovariectomy.

The objective of this study was to determine whether removal of corpora lutea (CL) from one ovary (unilateral luteectomy; ULL) or removal of the entire ovary (unilateral ovariectomy; ULO) of pseudopregnant rabbits would cause compensatory growth and progesterone production by the contralateral ovary. Pseudopregnancy was induced in rabbits with hCG (Day 0). On the first day of pseudopregnancy, one group of rabbits received a sham operation (controls), another group underwent ULL, and a third group underwent ULO. On Day 11 of pseudopregnancy, each rabbit underwent laparotomy, the ovarian artery and vein were cannulated, and the ovary(ies) was removed and perfused in vitro for 6 h. The mean CL weight increased by 33% in the ULL group and by 28% in the ULO group as compared to sham-operated controls. Peripheral estradiol and progesterone levels in sham-operated control, ULL, and ULO groups were similar. Ovarian venous estradiol levels were similar in the control and ULL groups, but were significantly increased in the remaining ovary of the ULO group. Both ovarian venous progesterone in vivo and progesterone secretion in vitro increased significantly in contralateral ovaries from ULL and ULO rabbits as compared to sham-operated controls. Progesterone secretion by ovaries perfused in vitro increased significantly in the contralateral ovary of the ULL and ULO groups. Mean number of luteal cells per CL increased significantly in the ULL group, but not in the ULO group. In contrast, luteal cell volume increased significantly in the ULO, but not in the ULL group. The stimuli responsible for increased progesterone production following ULL and ULO result in morphological changes in the remaining CL.(ABSTRACT TRUNCATED AT 250 WORDS)

Follicular development and oocyte maturation after stimulation with gonadotropins versus leuprolide acetate/gonadotropins during in vitro fertilization

Follicular development and oocyte maturation were compared in 22 patients stimulated with human menopausal gonadotropins/human chorionic gonadotropin (hCG, group I) and in 52 women also treated with the gonadotropin-releasing hormone agonist (GnRH-a) leuprolide acetate (LA, group II). Suppression of endogenous leutinizing hormone (LH) surges by LA allowed delayed hCG administration, resulting in higher peripheral estradiol levels, more retrieved oocyte cumulus corona complexes, and greater numbers of cryopreserved embryos. Reduction in spontaneous LH surges in the GnRH-a cycles may have allowed time for larger follicular fluid (FF) volume accumulation during all phases of oocyte cumulus corona complex maturation, restoring synchrony between FF volume and oocyte cumulus corona complex maturity.

Morphometric studies of the endometrium, the Fallopian tube and the corpus luteum during contraception with the 300 μg norethisterone (NET) minipill

Biopsy specimen from endometrium, Fallopian tube and corpus luteum were obtained from 35 women treated with 300 μg norethisterone daily and from 10 untreated, normally menstruating women. Peripheral levels of LH, progesterone and estradiol were measured. In the norethisterone-treated women four different ovarian reactions were identified. Ovarian activity was completely suppressed (Type A) in 3 women, follicular activity only (Type B) in 10 women, follicular activity was followed by insufficient luteal function (Type C) in 12 women, and peripheral estradiol and progesterone levels compatible with normal ovulation (Type D) in 10 women. The histology of the endometrium varied between atrophy (3 subjects), suppressed proliferation (9 subjects), proliferation (8 subjects), irregular secretory changes (12 subjects) and apparently normal secretory activity (3 subjects). When the histology of endometrium and Fallopian tube was compared with the peripheral hormonal levels and the corpus luteum steroid production in vitro, no correlation was found. Nor was a correlation found between the histologic changes of corpus luteum, endometrium and Fallopian tube. Thus, these target organs seem to react independently to norethisterone treatment.

Follicular development and oocyte maturation after stimulation with gonadotropins versus leuprolide acetate/gonadotropins during in vitro fertilization

Follicular development and oocyte maturation were compared in 22 patients stimulated with human menopausal gonadotropins/human chorionic gonadotropin (hCG, group I) and in 52 women also treated with the gonadotropin-releasing hormone agonist (GnRH-a) leuprolide acetate (LA, group II). Suppression of endogenous leutinizing hormone (LH) surges by LA allowed delayed hCG administration, resulting in higher peripheral estradiol levels, more retrieved oocyte cumulus corona complexes, and greater numbers of cryopreserved embryos. Reduction in spontaneous LH surges in the GnRH-a cycles may have allowed time for larger follicular fluid (FF) volume accumulation during all phases of oocyte cumulus corona complex maturation, restoring synchrony between FF volume and oocyte cumulus corona complex maturity.

Morphometric analysis of the endometrium of infertile patients in relation to peripheral hormone levels

In an attempt to identify factors that may be responsible for reproductive failure, we compared endometrial biopsies taken from infertile patients during the luteal phase of spontaneous cycles (n = 18) with those taken after ovarian stimulation (n = 18). Morphometric analyses were performed and compared with peripheral estradiol (E 2 ) and progesterone levels at the time of supposed implantation. In stimulated cycles the number of glands per square millimeter was positively correlated to the E 2 level. The morphometric data point to a measurable difference between the study groups, indicating an insufficient secretory transformation of the tissue in infertile women when compared with a group of fertile women. The observations suggest that hormonal stimulation occasionally results in impaired development of the endometrial glands.

Zoladex: Endocrine and therapeutic effects in post-menopausal breast cancer

The endocrine and therapeutic effects of the LHRH agonist Zoladex have been assessed in 28 post-menopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had no previous hormone therapy. There were two partial responses and two patients with stable disease for more than 6 months in the former group, and one partial response and two with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue. Six out of seven patients who received tamoxifen after progression of disease on Zoladex showed a response. Peripheral oestradiol levels were measured, and they fell after 1 month from 33 pmol l-1 (+/- 20, s.d.) to 22 pmol l-1 (+/- 11, s.d.) (P less than 0.005). Responders and non-responders showed similar changes in oestradiol. Oestrone levels did not change significantly. These results suggest that Zoladex acts indirectly via changes in peripheral hormones, rather than directly on LHRH receptors on the tumour.

Zoladex: Therapeutic Effects in Postmenopausal Breast Cancer

The endocrine and therapeutic effects of the luteinising hormone-releasing hormone (LHRH) analogue, Zoladex, have been assessed in 28 postmenopausal women with advanced breast cancer. Fourteen had responded to previous hormone therapy and 14 had received no previous hormone therapy. Zoladex treatment resulted in 2 partial responses and 2 patients with stable disease for more than 6 months in the former group, and 1 partial response and 2 with stable disease for more than 6 months in the latter group. Toxicity was minimal. All responses occurred in soft tissue disease. Peripheral oestradiol levels fell after 1 month of Zoladex from 33 pmol/l (+/- 20 SD) to 22 pmol/l (+/- 11 SD) (p less than 0.005) and both responders and nonresponders showed similar changes in oestradiol. Oestrone levels did not change significantly. Six out of 7 patients who received tamoxifen after progression of disease on Zoladex, showed a response. These results suggest that Zoladex acts indirectly via changes in peripheral hormone levels rather than directly on LHRH receptors on the tumour.