Evidence for increased dopaminergic and opioid activity in patients with hypothalamic hypogonadotropic amenorrhea.
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Adult↗
Biomedical subjects
R F Casper
Publications and source records attributed to R F Casper.
Stimulatory effect of 2-hydroxyestradiol on prolactin release in hypogonadal women.
Administration of an intravenous bolus (1.0 mg) or a constant rate infusion (250 microgram/h for 4 h) of 2-hydroxyestradiol (20H-E2) to hypogonadal women, resulted in no discernible alteration in the circulating levels of LH and FSH. In contrast, progressive increments in the release of prolactin were unequivocally detected at 4.5 h after receipt of the bolus and 2.5 h following the initiation of the infusion.
Adult↗
Effects of a superactive luteinizing hormone-releasing factor agonist on gonadotropin and ovarian function during the menstrual cycle.
The effect of a potent luteinizing hormone-releasing factor (LRF) agonist (D-Trp6, Pro9 NEt)-LRF on pituitary gonadotropin release and its concomitant ovarian response was examined in normal women during the early follicular (EFP), late follicular (LFP), and midluteal (MLP) phases. A single subcutaneous injection of 50 micrograms of LRF agonist in subjects during the EFP caused prompt release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to levels comparable to those found during spontaneous midcycle gonadotropin surges, while in LFP subjects gonadotropin levels rose 1 1/2 to 2 times above the levels of midcycle surges. The LH/FSH release in the MLP was almost identical to that found in the EFP. The ovarian response as measured by increasing estradiol levels followed a similar pattern during the 48 hours after injection in all three phases of the cycle. The inappropriate gonadotropin surge induced by LRF agonist in EFP subjects resulted in prolonged follicular phases and anovulation. Three of four subjects in the LFP showed evidence of ovulation in response to the same dose of LRF agonist. The pharmacodynamics of gonadotropin-ovarian responses to this potent LRF agonist reported here should provide an important reference for systemic investigation and rational clinical application.
Adult↗
Menopausal flushes: a neuroendocrine link with pulsatile luteninizing hormone secreation.
Menopausal flush episodes were found to be invariably associated with the initiation of pulsatile pituitary release of luteinizing hormone. This was not accompanied by a significant change in circulating catecholamine or prolactin concentrations. Since pulsatile luteinizing hormone release results from episodic secretion of luteinizing hormone releasing factor by the hypothalamus, these findings suggest a link between the neuroendocrine mechanisms that initiate such episodic secretion and those responsible for the onset of flush episodes.
Climacteric↗
Induction of luteolysis in the human with a long-acting analog of luteinizing hormone-releasing factor.
Subcutaneous injection of 50 micrograms of a long-acting analog of luteinizing hormone-releasing factor on each of two successive days during mid-luteal phase in normally cycling women induced a short luteal phase and premature menstruation. These events were associated with luteolysis, as evidenced by the consistent and parallel premature decline of progesterone and estradiol levels compared with those in control cycles. This finding may prove to be useful in the prevention or interception of implantation.
Corpus Luteum↗
Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects sperm from DNA damage and apoptosis caused by benzo(a)pyrene.
Benzo(a)pyrene (BaP), an aryl hydrocarbon receptor (AhR) ligand present in cigarette smoke and car exhaust, is thought to have negative effects on male reproduction. We hypothesized that BaP damages sperm through AhR activation, phase I enzyme induction, DNA adduct formation, and increased germ cell apoptosis in the testis, and that resveratrol, a natural competitive inhibitor of the AhR found in some red wines, could prevent the adverse effects of BaP on sperm. Male Balb C mice were injected subcutaneously (s.c.) for 5 weeks with a range of BaP doses (0.5 mg/kg to 50 mg/kg). Live sperm were obtained from the vas deferens, counted, and stained to measure annexin-V positive (apoptotic) cells. In a subsequent study, mice were injected for 5 weeks with corn oil (control), BaP (5 mg/kg/week), or BaP plus resveratrol (50 mg/kg/week) (n = 3 per group). Immunohistochemistry (IHC) was performed on testis sections for the determination of CYP1A1, BaP diol epoxide (BPDE) DNA adducts, and apoptosis and the results quantified by using the HSCORE, a semiquantitative scoring system. Our results demonstrated that sperm counts after 5 weeks were inversely correlated to BaP dosage. BaP (0.5 to 5 mg/week) positively correlated with sperm apoptosis while higher doses increased sperm necrosis. CYP1A1 protein was observed mainly in interstitial cells of some testis sections, but there was no significant induction by BaP. BPDE DNA adducts were induced in all components of the seminiferous tubules by BaP and suppressed by resveratrol: median HSCORE (interquartile range) control 61 (52-71.5); BaP 213 (192-248), P = 0.01 compared to control; BaP plus resveratrol 83 (70-90). BaP significantly increased apoptosis, mainly in spermatogonia: medain HSCORE (interquartile range) BaP 189 (161-223) versus control 83 (57-93), P < 0.01; and this effect was abrogated by resveratrol. Median HSCORE for BaP plus resveratrol was 112 (range 99-121). In summary, BaP caused increased sperm cell BPDE DNA adduct formation and apoptosis in the mouse. The natural AhR antagonist, resveratrol diminished BaP-induced DNA adducts and apoptosis in seminiferous tubules.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Rationale for estrogen with interrupted progestin as a new low-dose hormonal replacement therapy.
OBJECTIVE: This review outlines the basic principles of a novel interrupted progestin hormone replacement therapy (HRT) regimen in which estrogen is given continuously but the progestin is administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent receptor down-regulation and allow estrogen to increase estrogen and progestin sensitivity during the progestin-free periods. METHODS: The reasons for poor patient acceptance of HRT are reviewed. The association of HRT with breast and endometrial cancer is discussed, as are the potential benefits of HRT on the skeleton and the cardiovascular system. Basic research studies in the rat are described that provide supporting evidence for the interrupted progestin regimen. Clinically, we review a pilot study examining symptom control, bleeding rates, and safety of the interrupted progestin regimen as well as preliminary results of the usefulness of this regimen for add-back therapy in GnRH agonist-treated patients. RESULTS: Estrogen and progestin receptor measurements in the rat uterus demonstrate a clear up- and down-regulation in response to estrogen and interrupted progestin but not to the continuous administration of estrogen and progestin or estrogen alone. In addition, we found a significant beneficial effect of a low-dose interrupted HRT regimen on bone mineral content and density in an aged rat model of osteopenia, compared with continuous estrogen and progestin or estrogen alone. These results support the hypothesis that the interrupted progestin HRT increases tissue sensitivity to both estrogen and progestin. Clinical studies demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance. CONCLUSION: The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen-responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance of this new regimen compared to continuous combined HRT.
Animals↗
Fresh and frozen epididymal sperm yield comparable pregnancy rates for intracytoplasmic sperm injection.
To determine if the use of fresh epididymal sperm is superior to frozen-thawed epididymal sperm for intracytoplasmic sperm injection, the authors reviewed the charts on all couples undergoing intracytoplasmic sperm injection at an academic center, using microsurgically aspirated epididymal sperm. Forty-nine couples undergoing intracytoplasmic sperm injection for male factor infertility, due to congenital absence of vas deferens or irreparable post-testicular obstruction were studied. The following parameters were measured: (1) fertilization rate per oocyte injected (two pronuclei at 24 h), (2) chemical pregnancy rate (two consecutively elevated serum b-hCG levels, and (3) clinical pregnancy rate (sonographic identification of fetal heart rate). Fertilization rates were 51 and 41%, chemical pregnancy rates were 27 and 30%, and clinical pregnancy rates were 19 and 27% in the fresh epididymal compared to the frozen epididymal sperm. This study shows no significant difference in outcomes using fresh or frozen epididymal sperm for intracytoplasmic sperm injection. Frozen-thawed sperm guarantees availability of sperm prior to oocyte retrieval.
Adult↗
Regulation of estrogen/progestogen receptors in the endometrium.
Patient acceptance of standard cyclic hormonal replacement therapy (HRT) has been poor. One major cause of non-acceptance is thought to be the resumption of menses as a result of induced withdrawal bleeding. In order to prevent bleeding, continuous combined estrogen and progestin HRT has been utilized. However, most publications report irregular breakthrough bleeding in a majority of patients receiving the continuous HRT regimen. The cause of the irregular bleeding remains unclear at present. It is known that the continuous presence of progestin causes down-regulation of estrogen and progestin receptors and endometrial atrophy. Endometrial atrophy may result in withdrawal of stromal support for blood vessels leading to dilatation and extravasation of blood. In addition, progestin has been implicated in neovascularization, possibly by stimulation of vascular endothelial growth factor (VEGF). Finally, programmed cell death and apoptosis appear to occur in endometrial stroma after prolonged exposure to progesterone and may contribute to breakthrough bleeding. We have developed a novel interrupted progestin HRT regimen in which estrogen is given continuously, but with progestin administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent total receptor down-regulation by allowing estrogen to up-regulate estrogen and progestin receptors during the progestin-free periods. Interrupting the progestin may also prove to be favorable in reducing neo-angiogenesis. Clinically, we have demonstrated low bleeding rates in menopausal women, and in premenopausal women on long-term GnRH-agonist treatment for endometriosis or severe PMS, in whom the interrupted regimen has been used for addback HRT. Further basic and clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance compared to continuous combined HRT.
Aged↗