Underprescription of medications in older adults: causes, consequences and solutions-a narrative review.

PURPOSE: Under-prescription is defined as the omission of a medication that is indicated for the treatment of a condition or a disease, without any valid reason for not prescribing it. The aim of this review is to provide an updated overview of under-prescription, summarizing the available evidence concerning its prevalence, causes, consequences and potential interventions to reduce it. METHODS: A PubMed search was performed, using the following keywords: under-prescription; under-treatment; prescribing omission; older adults; polypharmacy; cardiovascular drugs; osteoporosis; anticoagulant. The list of articles was evaluated by two authors who selected the most relevant of them. The reference lists of retrieved articles were screened for additional pertinent studies. RESULTS: Although several pharmacological therapies are safe and effective in older patients, under-prescription remains widespread in the older population, with a prevalence ranging from 22 to 70%. Several drugs are underused, including cardiovascular, oral anticoagulant and anti-osteoporotic drugs. Many factors are associated with under-prescription, e.g. multi-morbidity, polypharmacy, dementia, frailty, risk of adverse drug events, absence of specific clinical trials in older patients and economic factors. Under-prescription is associated with negative consequences, such as higher risk of cardiovascular events, worsening disability, hospitalization and death. The implementation of explicit criteria for under-prescription, the use of the comprehensive geriatric assessment by geriatricians, and the involvement of a clinical pharmacist seem to be promising options to reduce under-prescription. CONCLUSION: Under-prescription remains widespread in the older population. Further studies should be performed, to provide a better comprehension of this phenomenon and to confirm the efficacy of corrective interventions.

Inappropriate Use of Proton Pump Inhibitors in Elderly Patients Discharged from Acute Care Hospitals.

BACKGROUND: Proton-pump inhibitors (PPI) are extensively prescribed in older patients. However, little information is available on factors associated to PPI prescribing patterns among older patients discharged from hospital. OBJECTIVE: To evaluate the appropriateness and clinical correlates of PPI prescription at discharge in a population of 1081 older patients discharged from acute care Italian hospitals. DESIGN: We used data from the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) study, a multicenter observational study. The appropriateness of PPI prescriptions was defined according to the Italian Medicines Agency (AIFA) rules. Correlates of overprescribing (i.e prescribing without recognized AIFA indications) and underprescribing (i.e. not prescribing despite the presence of recognized AIFA indications) were investigated by logistic regression analysis. RESULTS: Overprescribing was observed in 30% of patients receiving PPIs at discharge. Underprescribing was observed in 11% of patients not receiving PPIs at discharge. Overprescribing of PPIs at discharge was negatively associated with age (OR=0.88, 95%CI=0.85-0.91), depression (OR=0.58, 95%CI=0.35-0.96), use of aspirin (OR=0.03, 95%CI=0.02-0.06) and systemic corticosteroids (OR=0.02, 95%CI=0.01-0.04). The negative association with number of medications (OR=0.95, 95%CI=0.88-1.03) and overall comorbidities (OR=0.92, 95%CI=0.83-1.02) was nearly significant. Conversely, older age (OR=1.09, 95%CI=1.04-1.14), use of aspirin (OR=24.0, 95%CI=11.5-49.8) and systemic corticosteroids (OR=19.3, 95%CI=11.5-49.8) and overall comorbidities (OR=1.22, 95%CI=1.04-1.42) were independent correlates of underprescribing. CONCLUSION: Overprescribing of PPIs is more frequent in younger patients with lower burden of depression, whilst underprescribing is characterized by older age and greater burden of comorbidity and polypharmacy. Hospitalization should be considered as a clue to identify inappropriate use of PPIs and improve appropriateness of prescribing.

The impact of drug interactions and polypharmacy on antimicrobial therapy in the elderly.

Infectious diseases are more prevalent in older people than in younger adults, and represent a major healthcare issue in older populations. Indeed, infections in the elderly are often associated with higher morbidity and mortality, and may present atypically. Additionally, older patients are generally treated with polypharmacy regimens, which increase the likelihood of drug-drug interactions when the prescription of an antimicrobial agent is needed. A progressive impairment in the functional reserve of multiple organs may affect either pharmacokinetics or pharmacodynamics during aging. Changes in body composition occurring with advancing age, reduced liver mass and perfusion, and reduced renal excretion may affect either pharmacokinetics or pharmacodynamics. These issues need to be taken into account when prescribing antimicrobial agents to older complex patients taking multiple drugs. Interventions aimed at improving the appropriateness and safety of antimicrobial prescriptions have been proposed. Educational interventions targeting physicians may improve antimicrobial prescriptions. Antimicrobial stewardship programmes have been found to reduce the length of hospital stay and improve safety in hospitalized patients, and their use in long-term care facilities is worth testing. Computerized prescription and decision support systems, as well as interventions aimed at improving antimicrobial agents dosage in relation to kidney function, may also help to reduce the burden of interactions and inherent costs.

Treating cancer and no-cancer pain in older and oldest old patients.

Pain is one of the most frequent reasons for consultations in general practice, presenting either alone or associated with some comorbidity. In all care settings for older and oldest old patients, a gap exists between best-practice recommendations and current clinical practice. Clinical manifestations of persistent pain are often complex and multifactorial in the frail population, so the approach to pain management in older persons differs from that for younger people. The purpose of this review is to describe the best approach to assess and manage persistent cancer and no-cancer pain in the elderly, to explain the principles of pain treatment in this so often frail and complex population and compare the different drugs that should be used or avoided in older and oldest old patients considering the agerelated physiologic changes. Considerable emphasis is placed on conditions more common in the elderly such as neuropathic pain or typical subsets of the aging population such as the assessment of pain in people with dementia.

Physical performance measures and polypharmacy among hospitalized older adults: results from the CRIME study.

OBJECTIVE: To investigate the association of polypharmacy and physical performance measures in a sample of elderly patients aged ≥65 years admitted to acute care hospitals. DESIGN, SETTING AND PARTICIPANTS: Prospective study conducted among 1123 hospitalized older adults participating to the CRiteria to Assess Appropriate Medication Use among Elderly Complex Patients (CRIME) project. MEASUREMENTS: Physical performance was measured at hospital admission by the 4-meter walking speed (WS) and the grip strength (GS). Polypharmacy was defined as the use of ≥10 drugs during hospital stay. RESULTS: Mean age of 1123 participants was 81.5±7.4 years and 576 (51.3%) were on polypharmacy. Prevalence of polypharmacy was higher in patients with low WS and GS. After adjusting for potential confounders, participants in the highest tertile of WS were less likely to be on polypharmacy as compared with those in the lowest tertile (OR 0.58; 95% CI 0.35 - 0.96). Similarly, participants in the highest tertile of GS had a significantly lower likelihood of polypharmacy as compared with those in the lowest tertile (OR 0.55; 95% CI 0.36 - 0.84). When examined as continuous variables, WS and GS were inversely associated with polypharmacy (WS: OR 0.77 per 1 SD increment; 95% CI 0.60 - 0.98; GS: OR 0.71 per 1 SD increment; 95% CI 0.56 - 0.90). CONCLUSION: Among hospitalized older adults WS and GS are inversely related to polypharmacy. These measures should be incorporated in standard assessment of in-hospital patients.

Relationship between use of proton pump inhibitors and IGF system in older subjects.

OBJECTIVES: to investigate the effects of proton pump inhibitors (PPIs) on the insulin-like-growth factor 1(IGF-1) system in the elderly. DESIGN: cross-sectional. SETTING: InCHIANTI study. PARTICIPANTS: 938 older subjects (536 women, 402 men, mean age 75.7±7.4 years). MEASUREMENTS: complete data on age, sex, BMI, liver function, medications, dietary intake, IGF-1, IGF-binding protein-1 and -3 (IGFBP-1, IGFBP-3). RESULTS: Participants were categorized by PPI use, identifying 903 PPI non users and 35 users. After adjusting for age, male PPI users (107.0 ± 69.6 vs. 127.1 ± 55.8, p<0.001) and female PPI users (87.6 ± 29.1 vs. 107.6 ± 52.3, p=0.03) had lower IGF-1 levels than non-users. IGFBP-1 levels were similar in the two groups in both sexes. In whole population, after adjustment for age and sex, PPI users had lower IGF-1 levels 81.9 [61.1-113.8] than non-users 110 [77.8-148.6], p=0.02. After further adjustment for BMI, albumin, liver function, C-reactive protein, Interleukin-6, number of medications, ACE-inhibitors use, caloric intake, protein intake, physical activity, glycemia, and IGFBP-1, the use of PPIs remained significantly and negatively associated with IGF-1 levels (ß±SE = -19.60±9.83, p=0.045). CONCLUSION: Use of PPIs was independently and negatively associated with IGF-1 levels.

Milk fat globule epidermal growth factor 8 (MFG-E8): a novel protein in the mammalian endometrium with putative roles in implantation and placentation.

OBJECTIVES: MFG-E8 is a novel endometrial protein with conserved functions in tissue remodeling and angiogenesis in non-uterine tissues. Our aims were: 1. To examine the presence of MFG-E8 protein in the human endometrium during the window of implantation, in human endometrial cell lines, in human placental tissue at different gestational ages, and in murine implantation sites during early gestation; and 2. To study the regulation of MFG-E8 mRNA expression in mice implantation sites. STUDY DESIGN: MFG-E8 protein and its receptor integrin αvß3 were detected by immunostaining in human endometrial biopsies obtained from normal volunteers, in human endometrial cell lines (epithelial: Ishikawa and HEC-1A, stromal: HESC, and endothelial: HEEC), in human products of conception from all trimesters of gestation, and in murine implantation and inter-implantation sites dissected on days 5 and 8 post-coitus. MFG-E8 gene expression was assessed by RT-PCR. MAIN OUTCOME MEASURES: Immunohistochemical determination of MFG-E8 in endometrium and products of conception as well as relative MFG-E8 mRNA expression in mice implantation sites. RESULTS: MFG-E8 protein was present almost exclusively in the epithelial compartment of human endometrium. It was also expressed in the cytotrophoblasts and syncytiotrophoblasts outlining chorionic villi of the human placenta at all trimesters of gestation, and in murine implantation sites. MFG-E8 mRNA was significantly up-regulated in murine implantation sites and with increased gestational age. CONCLUSIONS: MFG-E8 expression in the endometrial epithelium as well as in chorionic villi suggests its possible role in endometrial reorganization during the receptive phase and in events related to normal pregnancy in mammals.

Effects of anorexia on mortality among older adults receiving home care: an observation study.

PURPOSE: We describe the prevalence of secondary anorexia in a population of older people living in community and receiving home care. In addition, we examined the relationship between secondary anorexia and mortality. METHODS: We analyzed data from a large collaborative observational study group, the Italian Silver Network Home Care project, that collected data on patients admitted to home care programs. A total of twelve Home Health Agencies participated in such project evaluating the implementation of the Minimum Data Set for Home Care (MDS-HC) instrument. A total of 2757 patients were enrolled in the present study. The main outcome measures were the prevalence of anorexia, weight loss and survival. RESULTS: More than 25% (744 subjects) of the study sample suffered from anorexia. During a mean follow-up of 10 months from initial MDS-HC assessment, 468 patients (17%) died. There was uneven distribution of the risk. After adjusting for age, gender and for all other possible risk factors for death (living alone, physical and cognitive disability, behavior problems, urinary incontinence, pressure ulcer, hearing impairment, congestive heart failure, hypertension, depression, diabetes, renal failure, cancer), subjects with anorexia were more likely to die relative to patients without anorexia (RR, 1.83; 95% CI 1.45-2.31). Even though the risk of mortality was higher among subjects suffering from anorexia and weight loss, the anorexia per se was associated with higher risk compared with subjects without anorexia (RR, 1.45; 95% CI 1.01-2.19). CONCLUSIONS: Anorexia is associated with a significant higher risk of all-cause mortality. The present findings support the possibility that anorexia has an independent effect on survival even among old people receiving home care.

Persistent ex vivo low number and functional in vitro recovery of circulating gammadelta T cells after removal of a cutaneous primary melanoma.

We recently described gammadelta T cells alterations in patients with a cutaneous primary melanoma. To evaluate whether gammadelta T cells alterations persisted after melanoma removal, we performed a follow-up study comparing the number and function of gammadelta T lymphocytes from 19 subjects, 4 years after the removal of a cutaneous primary melanoma, with the data obtained in the same subjects before the surgical intervention and with control donors. The number of circulating gammadelta(+) T cells after melanoma removal was not recovered to the levels found in controls. gammadelta(+) T cells producing TNF-alpha or IFN-gamma were increased after melanoma removal in comparison with the same subjects before surgical intervention or with control donors. After in vitro culture, both the percentage and the expansion of gammadelta T cells were recovered to the values found in controls. In conclusion, the functional capacity of gammadelta T cells was in vitro recovered after melanoma removal, whereas their ex vivo number remained at lower levels than control donors.

Zinc, metallothioneins and immunosenescence.

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of 'second messenger'. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C-carriers) in the IL-6-174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C+carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C-carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6-174G/C locus when associated with those of the MT1A+647A/C locus are useful tools for the choice of old people for zinc supplementation.

Health care for older people in Italy: The U.L.I.S.S.E. Project (Un link informatico sui servizi sanitari esistenti per l'anziano - a computerized network on health care services for older people).

OBJECTIVES: The U.L.I.S.S.E. study is aimed at describing older patients who are cared for in hospitals, home care or nursing homes in Italy. DESIGN: The U.L.I.S.S.E. study is an observational multicenter prospective 1-year study. SETTING: Overall, 23 acute geriatric or internal medicine hospital units, 11 home care services and 31 nursing homes participated in the study. MEASUREMENTS: The patient's evaluation was performed using comprehensive geriatric assessment instruments, i.e. the interRAI Minimum Data Set, while data on service characteristics were recorded using ad-hoc designed questionnaires. RESULTS: The older subjects who are in need of acute and long term care in Italy have similar characteristics: their mean age is higher than 80 years, they have a high level of disability in ADL, an important multimorbidity, and are treated with several drugs. The prevalence of cognitive impairment is particularly high in nursing homes, where almost 70% of residents suffer from it and 40% have severe cognitive impairment. On the other hand, there is a shortage of health care services, which are heterogeneous and fragmented. CONCLUSIONS: Health care services for older people in Italy are currently inadequate to manage the complexity of the older patients. An important effort should be undertaken to create a more integrated health care system.

[Evaluation of stress in surgical trainees: prospective study of heart rate during laparoscopic cholecystectomy]. / Stress des chirurgiens en formation: Etude prospective de la cardio-fréquence lors de cholécystectomies laparoscopiques.

INTRODUCTION: Surgical training is stressful, particularly in the operating room setting. The purpose of the study is to evaluate and quantitate intra-operative stress in surgical trainees. MATERIAL: and methods: Cardiac rate was used as a measure of stress during surgical cases; surgical residents serving as the primary surgeon and assistant during 21 laparoscopic cholecystectomies underwent telemetry monitoring. RESULTS: Intra-operative cardiac rate increased by 4-10%, particularly in the resident serving as primary surgeon. The most stressful moments of the procedure were the draping of the surgical field, trocar placement, clip application, and extraction of the gallbladder. CONCLUSION: This study offers a measure of the stress of surgical residents in the operating room. Heart rate is not the ideal parameter of stress, yet it gives a good idea of the level of stress. The identification of stress-inducing factors may help residents to deal with difficult situations.

Dietary antioxidants as potential pharmacological agents for ischemic stroke.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Circulating homocysteine levels in sustained and white coat hypertension.

Although white coat hypertension has been widely studied in the last years, its risk profile is not yet completely clear. The aim of this study was to evaluate circulating homocysteine levels, an emerging cardiovascular risk factor, in subjects with white coat and sustained hypertension. We selected 31 sustained hypertensive subjects, 31 white coat hypertensive subjects and 31 normotensive subjects matched for age, gender, body mass index and occupation. Women were also matched for menopausal status. Subjects with smoking habit, dyslipidaemia and diabetes mellitus were excluded from the study. White coat hypertension was defined as clinical hypertension and daytime ambulatory blood pressure <135/85 mmHg. Blood samples were drawn after a fasting period of 12 h for routine laboratory tests and homocysteine determination. Homocysteine levels were evaluated by fluorescence polarization immunoassay. Creatinine, glucose, cholesterol and triglycerides were not different among the groups. White coat hypertensive subjects had significantly lower homocysteine levels than sustained hypertensive patients (8.2+/-2.0 vs 12.6+/-3.9 micromol/l, P=0.0003). No significant difference was observed between white coat hypertensive and normotensive subjects regarding this parameter (8.2+/-2.0 vs 7.6+/-1.9 micromol/l, P=0.9). In conclusion, our data show that middle-aged white coat hypertensive subjects without other cardiovascular risk factors have lower circulating homocysteine levels than sustained hypertensive patients suggesting that they are at lower cardiovascular risk.

Functional status and clinical correlates in cognitively impaired community-living older people.

We describe the prevalence of cognitive impairment in a population of community-living older people, its association with functional decline, and degree of comorbidity. In addition, we examined the relationship between different levels of cognitive impairment and mortality. We conducted an observational study of 1787 patients aged 65 years and above with any degree of cognitive impairment. Patient data were collected with the Minimum Data Set for Home Care. More than 50% of patients had some level of cognitive impairment, which correlates with the degree of physical frailty. On the contrary, patients with cognitive impairment appear to have fewer comorbid conditions and are less likely to receive medications than patients with normal cognitive status. In particular, hypertension, congestive heart failure, chronic obstructive pulmonary disease, cancer, diabetes mellitus, and osteoporosis are found more frequently among patients with normal mental status compared with those showing some level of cognitive defects. Yet, more severe cognitive impairment is associated with a higher mortality rate. Demented patients are characterized by a high prevalence of functional disability and by increased mortality. This increased morbidity and mortality rate is associated with a lower prevalence of comorbid clinical conditions and drug use, relative to patients with normal cognitive performance. The present findings support the possibility that severe cognitive impairment has an independent effect on survival.

The birth of ocular pharmacology in the 20th century.

Nineteenth century ophthalmology, characterized by significant gains in diagnostic techniques, provided the basis for great advancements in treatment during the 20th century. Drug therapy at the turn of the century was empiric, palliative, and often toxic. The development of ocular pharmacology during the 20th century provided the basis for a rational therapeutic approach to ocular disease. Foremost among the therapeutic developments were antibiotics, due to their potential to cure conditions that frequently resulted in blindness. Second, other therapeutic classes provided palliative therapy for chronic diseases, and thus decreased morbidity. For example, drugs specifically targeting many different aspects of glaucoma have had remarkable success controlling intraocular pressure and forestalling development of blindness. In addition, other new approaches provided palliative therapy for nonblinding conditions and effective adjuncts to surgical procedures. Antiallergy and anti-inflammatory drugs greatly increased patient comfort and facilitated treatment of allergic and inflammatory reactions. Local anesthetics and analgesia reduced patient discomfort during surgery. Other adjunct drugs improved surgical outcomes by reducing inflammation and infectious complications. The 21st century will undoubtedly provide novel approaches to address many of today's therapeutic dilemmas. Photodynamic therapy, growth factors, antisense technology, and genetic-based therapies all show great promise. Many of the conditions that are only treated palliatively today will be curable in the next century using many of these pharmacological advances.

Comorbidity and cancer in the aged: the geriatrician's point of view.

Demographic trends in Italy and Western countries show a progressive aging of the population, which concerns the 80+ segment. The aging population is characterized by increased comorbidity and functional decline. The "frail elderly", who has problems in a variety of areas, including the physical, cognitive, psychological, social and economic ones, represents the paradigm of the emerging demographic and epidemiologic reality. In oncology, there is increasing awareness of the impact of comorbidity on cancer management in the elderly (including both screening and treatment). The Comprehensive Geriatric Assessment represents the only answer to such problems, allowing to improve the quality of life, prolong survival and maintain functional status.

Detection of arrhythmogenic cellular magnesium depletion in hip surgery patients.

The use of high-dose magnesium infusions in critically ill and surgical patients is increasing. This practice is associated with considerable risk of toxicity, as no reliable criteria are currently available to detect significant intracellular magnesium depletion. We have evaluated, before and after surgery, 33 elderly patients with hip fracture, by 24-h Holter ECG monitoring, Doppler echocardiography and serum chemistry; lymphocyte magnesium was measured using atomic absorption spectrophotometry. The severity of ventricular arrhythmias increased, and serum and mononuclear magnesium concentrations decreased significantly after surgery. Decreases in either serum magnesium concentrations > 0.125 mmol litre-1 or cellular magnesium > 6 nmol mg-1, but not serum or lymphocyte absolute magnesium concentrations, were associated with postoperative development of repetitive arrhythmias. Variations in serum magnesium concentrations correlated with intracellular decreases, and yielded good accuracy in predicting the postoperative worsening of arrhythmias. Thus perioperative differences in serum magnesium concentrations reflected intracellular variations and allowed us to identify patients with clinically relevant cellular magnesium depletion.

Cell surface localization of a novel non-genomic progesterone receptor on the head of human sperm.

Cell surface receptors for progesterone were visualized in human sperm using fluorescein isothiocyanate-progesterone 3-(O-carboxymethyl) oxime-bovine serum albumin (FITC prog CMO BSA). The receptors were confined to the head and not the midpiece or tail. FITC prog CMO BSA was also an effective stimulus to elevate intracellular free calcium in human sperm as detected by fura-2 fluorescence. The elevation of intracellular free calcium is a stimulus for the acrosome reaction, a process which is necessary to occur for sperm to fertilize the egg. It is proposed that progesterone, which is present in the female reproductive tract, can bind to progesterone receptors located in the plasma membrane of the sperm head and elicit an influx of Ca2+ into the underlying cytoplasm and or acrosome and induce the acrosome reaction and facilitate fertilization.

Cell surface-binding sites for progesterone mediate calcium uptake in human sperm.

Recent studies (e.g. Blackmore, P. F., Beebe, S. J., Danforth, D. R., and Alexander, N.) (1990) J. Biol. Chem. 265, 1376-1380) have shown that in human sperm, progesterone produces a rapid increase in intracellular free calcium ([Ca2+]i) and an induction of the acrosome reaction (e.g. Osman, R. A., Andria, M. L., Jones, A. D., and Meizel, S. (1989) Biochem, Biophys. Res. Commun. 160, 828-833). In this study, the location of progesterone receptors on the cell surface of human sperm was identified using progesterone immobilized on bovine serum albumin (BSA) (progesterone 3-(O-carboxymethyl)oxime:BSA) as well as progesterone and its 3-O-carboxymethyloxime derivative. Using fluorescence microscopy, BSA-fluorescein isothiocyanate was shown to be excluded from intact sperm, thus validating the use of progesterone 3-(O-carboxymethyl)oxime:BSA to identify cell surface-binding sites for progesterone. The immobilized progesterone and the 3-O-carboxymethyloxime derivative rapidly increased [Ca2+]i and were full agonists, although they were approximately 1.5 orders of magnitude less potent than progesterone. They also displayed an identical time course to increase [Ca2+]i as free progesterone, and the entire increase in [Ca2+]i was due to the influx of Ca2+. This progesterone-mediated response displayed different steroid receptor characteristics since the very potent inhibitors of genomic progesterone responses, RU38486 and ZK98.299, were very ineffective at inhibiting the progesterone-mediated increase in [Ca2+]i. Also the synthetic progestins megestrol, medroxyprogesterone acetate, norgestrel, norethynodrel, norethindrone, R5020, and cyproterone acetate did not mimic the effects of progesterone to increase [Ca2+]i. It is proposed that a distinct nongenomic cell surface receptor for progesterone exists in human sperm.