Consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of Karnataka, India.

OBJECTIVE: To determine whether consanguinity adversely influences pregnancy outcome in South India, where consanguinity is a common means of family property retention. STUDY DESIGN: Data were collected from a prospective cohort of 647 consenting women, consecutively registered for antenatal care between 14 and 18 weeks gestation, in Belgaum district, Karnataka in 2005. Three-generation pedigree charts were drawn for consanguineous participants. χ (2)-Test and Student's t-test were used to assess categorical and continuous data, respectively, using SPSS version 14. Multivariate logistic regression adjusted for confounding variables. RESULT: Overall, 24.1% of 601 women with singleton births and outcome data were consanguineous. Demographic characteristics between study groups were similar. Non-consanguineous couples had fewer stillbirths (2.6 vs 6.9% P=0.017; adjusted P=0.050), miscarriages (1.8 vs 4.1%, P=0.097; adjusted P=0.052) and lower incidence of birth weight <2500 g (21.8 vs 29.5%, P=0.071, adjusted P=0.044). Gestation <37 weeks was 6.2% in both the groups. Adjusted for consanguinity and other potential confounders, age <20 years was protective of stillbirth (P=0.01), pregnancy loss (P=0.023) and preterm birth (P=0.013), whereas smoking (P=0.015) and poverty (P=0.003) were associated with higher rates of low birth weight. CONCLUSION: Consanguinity significantly increases pregnancy loss and birth weight <2500 g.

What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis?

Pharmacologic osteoporosis therapy, particularly anti-resorptives, is recommended in postmenopausal women with clinical risk factors for fracture. Treatment decisions should be made based on the relative benefit-risk profile in different patient populations. Emerging options [e.g., selective estrogen receptor modulators (SERMs) and denosumab] may hold promise for providing protection from bone loss and for fracture risk reduction.Osteoporosis, the most common clinical disorder of bone metabolism, is characterized by low bone mineral density, deterioration of microarchitecture, and a consequent increase in bone fragility and risk of fracture. Pharmacologic therapy is recommended in postmenopausal women with clinical risk factors for fracture and includes anti-resorptive agents such as bisphosphonates, hormone therapy, SERMs, and calcitonin. The anabolic agent teriparatide (parathyroid hormone) is usually reserved for high-risk patients or those with glucocorticoid-induced osteoporosis. Strontium ranelate, available outside the USA, has both anti-resorptive and anabolic properties. Supplementation with calcium and vitamin D is recommended for all women aged 50 years and older. Bisphosphonates are often considered first-line therapy for osteoporosis and have the largest base of clinical trial data showing efficacy for global fracture risk reduction. Low-dose hormone therapy is appropriate for younger women who are experiencing other menopausal symptoms. In women for whom bisphosphonates are not appropriate or not tolerated or in younger postmenopausal women who have a low risk for hip fracture, SERMs are a suitable treatment option. Calcitonin is designated for patients who are unable or unwilling to tolerate other osteoporosis agents. Emerging options, including newer SERMs (e.g., bazedoxifene and lasofoxifene) and the monoclonal antibody denosumab, may hold promise for providing protection from bone loss and for fracture risk reduction. Because no single agent is appropriate for all patients, treatment decisions should be made on an individual basis, taking into account the relative benefits and risks in different patient populations.

Conducting randomized, controlled trials. Experience with the dysfunctional uterine bleeding intervention trial.

OBJECTIVE: To conduct a randomized, controlled trial (RCT) to examine issues associated with therapeutic alternatives to standard hysterectomy for women with dysfunctional uterine bleeding. STUDY DESIGN: Participants were to be randomly assigned to one of three treatment groups: hysterectomy, endometrial ablation and medical management. Recruitment was targeted at 375 women. RESULTS: Despite multiple recruitment strategies, recruitment was weak, with only five women enrolled after six months. Providers and women screened for eligibility often expressed discomfort with randomization. The protocol was amended to an elective treatment cohort design with a randomization component. Recruitment improved, with 37 women enrolled after four months. CONCLUSION: The success of RCTs may be affected by multiple factors. Acceptance of the protocol by patients and providers is essential. The RCT may present providers with a conflict between the goals of research and of providing optimal individualized care. Thus, RCTs may not always be appropriate for studies designed to examine best treatments in clinical practice, and nonrandomized designs may provide appropriate alternatives in some cases.

Knowledge, beliefs, and risk factors for osteoporosis among African-American and Hispanic women.

The purpose of this work was to develop and conduct a needs and risk instrument to assess knowledge of osteoporosis risk factors, identify beliefs and attitudes about this disease, and delineate the presence and/or absence of healthy behaviors associated with osteoporosis among African American and Hispanic women. The survey findings suggest that African-American and Hispanic women are not well-versed in behaviors that would promote and maintain optimal bone mass. Consequently, they are not practicing appropriate lifestyle and dietary habits to decrease their risk of osteoporosis. Such behaviors include inadequate physical activity, inadequate calcium intake, cigarette smoking, and long-term steroid use. Less than 10% of women in the study were getting adequate daily dietary calcium intake, with only 13% taking daily calcium supplements to augment this deficit and less than one-half of women exercising at a minimal level (20 minutes/3 times a week). Women in this study also had limited knowledge about osteoporosis, perceived this condition to be less of a health threat as compared to breast cancer, heart disease, diabetes, and Alzheimer's disease, and very few had the perception that being Hispanic or African American was a factor to consider in assessing their risk of osteoporosis. Our findings suggest that osteoporosis education and prevention initiatives are needed, specifically for African-American and Hispanic women, to promote healthy behaviors, identify women at-risk, and encourage early diagnosis and treatment.

Androgen excess in women.

There exists a growing body of evidence in women that links androgen excess to increases in cardiovascular disease and reproductive site neoplasia. Ten to fifteen percent of women exhibit clinical signs and symptoms of hyperandrogenism wherein more extensive evaluation is warranted. Women with adult acne, android-type obesity, and alopecia often have been treated for cosmetic reasons without regard to the underlying pathophysiology. Adverse changes in insulin resistance, lipids, and apoproteins favor earlier progression of diabetes for some patients and an unfavorable cardiovascular risk profile for most. Patients with polycystic ovarian syndrome (PCOS) often present to different health providers with different complaints that include excessive facial hair, obesity, hypertension, impaired glucose tolerance, dysfunctional uterine bleeding, or infertility. First-line treatment options, after excluding ovarian or adrenal tumors, include use of non-androgenic OCs until pregnancy is desired. Early identification of patients allows for use of risk-reduction strategies, which may affect clinical outcomes.

Quality of life during sequential hormone replacement therapy -- a placebo-controlled study.

OBJECTIVE -- The purpose of the study was to determine the efficacy of sequential 17 beta-estradiol and norethindrone acetate (Trisequens) in the relief of vasomotor symptoms by comparing the quality of life data from questionnaires, number and severity of symptoms, and the dropout rate versus placebo treatment. STUDY DESIGN -- Women 40 to 60 years old, who spontaneously complained of menopausal symptoms, were randomly allocated to four consecutive cycles with Trisequens (n = 40) or placebo (n = 42). Analysis of variance and two-tailed tests (P < .05) for all comparisons were used. RESULTS -- The mean number of pretreatment vasomotor symptoms per day was 7 (1.3 severe) for Trisequens and 6 (1.8 severe) for placebo, whereas posttreatment a reduction to 1.3 (0.1 severe) versus 4.2 (1.8 severe), respectively, was observed. Quality of life scores, utilizing the Kupperman Scale, 3-Factor Green Index, and Beck Depression Inventory all produced statistically significant differences (P = 0.0015, 0.0037, 0.0026, 0.0003, 0.0242, respectively). The dropout rate difference between groups was significant (P = 0.028): 12 from the Trisequens group and 23 from the placebo group. CONCLUSION -- Trisequens significantly improves vasomotor symptoms. Quality of life rating scales provide additional data to support the utility of sequential estrogen/progestin treatment for menopause therapy.

Effects of sex steroids on women's health: implications for practitioners.

Androgen excess in women is manifested typically by clinical features that may include hirsutism, acne, central obesity, male-pattern baldness, upper torso widening, increased waist-to-hip ratio, clitoral hypertrophy, and deepening of the voice. The differential diagnosis includes androgen-producing ovarian and adrenal neoplasms, Cushing's syndrome, polycystic ovary syndrome, and the intake of exogenous androgens. Physicians treating patients for one symptom of androgen excess must be alert for other symptoms and signs. The cosmetic manifestations of androgen excess belie the serious health risks associated with this condition, including cardiovascular disease, intravascular thrombosis, and insulin resistance. Prompt clinical recognition of androgen excess, understanding of the androgen-related biochemical abnormalities underlying the risks associated with this condition, and implementation of risk modification can reduce the incidence of associated morbidity and mortality. An interdisciplinary approach to management is strongly recommended. Risk reduction strategies include correction of dyslipidemias, low-dose aspirin for primary prevention of myocardial infarction, maintenance of ideal weight, smoking cessation, exercise, use of oral contraceptives containing a low-androgenic progestin, and postmenopausal estrogen replacement. Combination oral contraceptives containing low-androgenic progestins are effective not only in reducing signs of androgen excess but also in potentially retarding the progression of long-term sequelae such as cardiovascular disease.

PIP: 5-10% of all women have an androgen excess syndrome. Androgen excess signs and symptoms include hirsutism, acne, central obesity, male-pattern baldness, upper torso widening, increased waist-to-hip ratio, clitoral hypertrophy, and deepening of the voice. Physicians must be able to recognize these signs and symptoms. Presence of these signs and symptoms calls for a screening history and physical examination. Differential diagnoses of androgen excess in women include endogenous and exogenous causes. Endogenous-related diagnoses are those of ovarian origin (primary tumors, metastatic tumors, polycystic ovary syndrome, ovarian stromal hyperthecosis, androgen excess in pregnancy, and abnormal gonadal or sexual development) and those of adrenal origin (Cushing's syndrome/disease, late-onset congenital adrenal hyperplasia, and tumors). Exogenous causes of androgen excess include Danazol, Phenytoin, Diazoxide, Hexachlorobenzene, Hexachlorophene, Minoxidil, Cyclosporin, testosterone and other androgens, anabolic steroids, synthetic progestins (the pill), and Metapyrone. When physicians treat patients for one symptom of androgen excess, they should watch for other signs and symptoms. Serious health risks associated with androgen excess include cardiovascular disease, intravascular thrombosis, and insulin resistance. Physicians must be aware that timely clinical recognition of androgen excess, knowledge of androgen-related biochemical abnormalities underlying the risks linked to androgen excess, and risk modification behavior reduces associated morbidity and mortality. Risk reduction strategies are correction of dyslipidemias, low-dose aspirin for primary prevention of myocardial infarction, maintenance of ideal weight, smoking cessation, exercise, use of combined oral contraceptives (OCs) with a low-androgenic progestin, and postmenopausal estrogen replacement. OCs also slow progression of long-term sequelae (e.g., cardiovascular disease).

Oral contraceptives and cardiovascular risk. Taking a safe course of action.

Although a prospective, longitudinal study on the long-term cardiovascular effects of oral contraceptives has yet to be performed, available data are useful in determining a safe course of action while physicians await definitive answers. Exogenous sex steroids produce important effects on lipid metabolism. Early intervention against cholesterol is important in reducing cardiovascular risk. Current users of high-dose formulations, particularly older women who smoke, are at greatest risk for cardiovascular complications, especially myocardial infarction. Low-dose oral contraceptives have more modest effects on lipid metabolism, but important differences in the potency of progestins remain. Fortunately, recent studies among users of lower-dose oral contraceptive formulations fail to show an increase in cardiovascular morbidity and mortality. Nonetheless, prudent physicians will avoid oral contraceptives that may adversely affect lipoprotein metabolism, such as those containing progestins with high androgenic and antiestrogenic potency.

PIP: The cardiovascular effects of oral contraceptives, as predicted by studies on serum lipid changes in users, are based on the progestin dose, androgenic potency and biologic effect of the estrogen in the pill. Women suffer 250,000 deaths per year in the U.S. resulting from cardiovascular disease, almost half as many as men. They have the same risk factors: high cholesterol, high blood pressure and smoking, and also have more risk from diabetes than men do. The serum HDL, especially HDL2, correlates closely and inversely with heart disease risk. Exogenous estrogens raise HDL and HDL2, and lower LDL, conferring protection against coronary disease, in direct proportion to dose. Progestins usually have adverse effects, in proportion to dose, but progestin potency and type also determine their effects. The estrane progestins norethindrone, norethindrone acetate and ethynodiol diacetate are less potent and much less androgenic, while the gonanes norgestrel and especially levonorgestrel are 5-20 times as potent and androgenic. Each pill needs to be considered as a unit. Several comparative studies are reviewed, corroborating the prediction that pills with higher progestin potency have adverse effects on serum lipids, compared to those with higher estrogen effect. For new lower dose multiphasics, the effects either way are minimal, but HDL2 is still significantly lowered by pills containing levonorgestrel. Progestin-only pills lower HDL2 17- 21%. It is prudent to follow and treat the long-term effects of oral contraceptives on blood lipids.

[Clinical evidence of the minimal androgenic activity of norgestimate]. / Preuve clinique de l'activité androgénique minimale du norgestimate.

The aim for improving the progestogen component of oral contraceptives is both to increase their selectivity by obtaining a highly effective contraceptive action and to decrease the side effects related to the existing progestogens. The androgenic activity of the existing progestogens modifies the lipid metabolism, particularly a decrease in the high density lipoprotein (HDL) level, which increases the risks of cardiovascular diseases. Thus, the discovery of a progestogen with good anti-ovulatory and minimal androgenic properties would constitute an important progress in the field of oral contraception. Norgestimate (NGM) is a new progestogen presenting an exceptional profile of biological activity, and has proved to be extremely selective, as observed during the clinical trials. The studies described below have been carried out in order to confirm clinically the low androgenic activity of NGM. In two clinical trials, Norgestimate (0.25 mg) associated with 0.035 mg of ethinyloestradiol (NGM 0.25/35) was compared to norgestrel (0.30 mg) associated with 0.030 mg of ethinyloestradiol (Lo/Ovral). In the first trial (1,261 women), the following observations were made: an important increase in the HDL level compared to the base levels in the subjects taking NGM 0.25/35, and an important decrease in the HDL level in those taking Lo/Ovral. The low density lipoprotein (LDL) level increased slightly in the NGM 0.25/35 group, while a higher increase was observed in the Lo/Ovral group. Moreover, the LDL/HDL ratio translates a more favourable lipid profile in the NGM 0.25/35 group, since the values are lower than those observed for the Lo/Ovral group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlorpromazine-induced immunopathy: progressive increase in serum IgM.

Long-term chlorpromazine therapy has been associated with the asymptomatic development of a high incidence of antinuclear antibodies, coagulation inhibitors, and increased serum levels of IgM. The purpose of this study has been to characterize the natural history of this chlorpromazine-induced (CPZ) immunopathy. To this end we carried out a prospective study of schizophrenic patients with the immunopathy to compare the effect of continuing CPZ versus switching to haloperidol therapy. Although no marked differences were noted between the 2 groups at the end of 5 years, 6 of 29 patients who continued to receive CPZ, as compared to none of 14 patients on haloperidol, had progressive elevations of serum IgM. In spite of a high incidence of antinuclear antibodies, none of the patients developed a lupus-like syndrome. One patient, however, who had been maintained on CPZ for more than 15 years, developed Waldenström macroglobulinemia, as characterized by an IgM monoclonal gammopathy and a lymphocyte immunoglobulin heavy and kappa light chain gene rearrangement. Another CPZ-treated patient developed immune thrombocytopenia. Based on the potential serious sequelae of prolonged stimulation of the immune system by CPZ, we recommend that patients who develop an increase in serum IgM while on CPZ be switched to other types of anti-psychotic medications.

Clinical evidence of the minimal androgenic activity of norgestimate.

The goal in improving the progestational component of oral contraceptives (OCs) is to enhance the selectivity of the progestin by achieving a high degree of contraceptive efficacy while decreasing undesirable side effects associated with existing progestational agents. The androgenic activity of current progestins results in changes in lipid metabolism, particularly decreased levels of high-density lipoprotein cholesterol (HDL), which have been associated with an increased risk of coronary heart disease (CHD). A progestin with high antiovulatory activity and minimal androgenicity would offer a clear therapeutic advantage in oral contraception. Norgestimate (NGM) is a new progestin with a unique profile of biological activity that has demonstrated a high level of selectivity in preclinical assays. The present studies were conducted to confirm clinically the low androgenic activity of NGM. Norgestimate (0.25 mg) in combination with 0.035 mg ethinyl estradiol (NGM 0.25/35) was compared with 0.30 mg norgestrel combined with 0.030 mg ethinyl estradiol (Lo/Ovral) in two multicenter clinical studies. In the first study (1,261 women), HDL levels were significantly increased from baseline levels in NGM 0.25/35 subjects but were significantly decreased in Lo/Ovral subjects. Increases in low-density lipoprotein cholesterol (LDL) levels were moderate in the NGM 0.25/35 group and pronounced in the Lo/Ovral group. A favorable lipid profile in NGM 0.25/35 subjects was also reflected in the LDL/HDL ratios, which were significantly lower in the NGM 0.25/35 subjects than in the Lo/Ovral subjects. Sex hormone binding globulin (SHBG) binds androgens, preventing clinical expression of androgenic activity. As a result, elevations in SHBG levels reduce bioactive (unbound) androgen levels and decrease the potential for androgenic side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral contraceptives: a reassessment.

Cardiovascular risks attributable to oral contraceptive use may now be subdivided into those that appear to be secondary to the estrogen component, i.e., venous thrombosis, pulmonary embolism, and those linked to the progestin component, i.e., small vessel disease including myocardial infarction and cerebrovascular accident. It appears that venous risk is attributable to subtle changes in clotting factors, while arterial risk may be secondary to changes in glucose and lipid metabolism. In order to determine which women are at greatest risk from oral contraceptive use, Spellacy et al. has developed a risk scoring form that aids in the screening process. After excluding women with an absolute contraindication to pill use, women at greatest risk for cardiovascular disease related to oral contraceptive use are those with a family history of hyperlipidemia, gestational or overt diabetics, hypertensives, and smokers over the age of 35. The gradual reduction by manufacturers of the steroid content of oral contraceptives appears to have lessened the incidence of adverse effects. Our current knowledge of risk factors permits the clinician to reduce exposure to oral contraceptive-related mortality by as much as 86 per cent. As we continue to search for ways to reduce risk among oral contraceptive users, it is important to note that more than 25 per cent of women are still taking formulations containing 50 micrograms of estrogen. It becomes the responsibility of the practicing physician to "step-down" these patients to lower-dose preparations such as the multiphasics. Such preparations also represent optimal therapy for first-time pill users.

PIP: The risks and benefits of the newer oral contraceptives are evaluated, considering cancer, teratogenicity, drug interactions, cardiovascular risks, and carbohydrate metabolism. Oral contraceptives confer the lowest mortality risk of all contraceptives, except sexual abstinence, in all women under 30 and in nonsmokers through age 40 in developed countries. In less developed countries where maternal mortality can be as high as 5-10%, the risks of even nonmedically supervised oral contraceptives are dwarfed. The pill protects against ovarian cancer even after the pill is discontinued because it suppresses ovulation, and endometrial cancer because it blocks estrogen receptors. The relationship of oral contraception to breast cancer is still in dispute, but no good evidence exists for increased risk, especially with new low- dose pills. There may be a slightly increased risk of cervical cancer, although it is difficult to separate out other risk factors co-existing in pill users, such as earlier sexarche, more partners and more frequent screening. The incidence of pelvic inflammatory disease, functional ovarian cysts and ectopic pregnancy is reduced by pills. There is only 1 report of increased incidence of congenital heart disease in infants whose mothers took pills during pregnancy. Drug interactions are common, and must be managed by the physician. Among currently popular pills, only the norgestrel and levonorgestrel-containing multiphasic pills are said to decrease HDL2 and impair glucose tolerance, because they are androgenic enough to overcome the low dose of estrogen.

Oral contraceptives. Assessment of benefits.

Use of oral contraceptives has been shown to reduce the risk of gynecologic conditions that cause significant mortality, including ovarian cancer, endometrial cancer and ectopic pregnancy. Additionally, its use has been linked to quality-of-life issues, such as the prevention of pelvic inflammatory disease, benign breast disease and functional ovarian cysts, as well as to dysmenorrhea, premenstrual syndrome and iron deficiency anemia. Such information should be conveyed to women of reproductive age during their contraceptive counseling session.

Bipolar affective disorder, lithium carbonate and Ca++ ATPase.

Erythrocyte membrane Ca++ ATPase levels were investigated in 10 men treated with lithium carbonate for bipolar affective disorder. With regard to Ca++ ATPase activity, which is intimately associated with the active Ca++ transport mechanism of the red cell membrane, it is interesting to note that the Ca++ ATPase activities of bipolar disorder patients were found to be depressed at 2 hours after the administration of lithium. These data are discussed in terms of the physiology of bipolar affective disorder and lithium carbonate.

Pancreatic duct arteriovenous fistula and the metastatic fat necrosis syndrome.

This report summarizes the course of a patient with asymptomatic chronic pancreatitis associated with hemorrhage into the pancreatic duct and metastatic fat necrosis. Retrograde cannulation of the pancreatic duct and superior mesenteric arteriography established the presence of a pseudocyst with a pancreatic duct-arteriovenous (DAV) fistula as the cause of the syndrome. Ligation of feeder vessels with external drainage of the cyst as the initial surgical procedure stopped the bleeding but failed to prevent recurrence of the pancreatic duct-venous fistula. A pancreaticoduodenectomy with resection of the cyst and fistula was required to arrest destruction of distant tissues. Although serum and urine amylase concentrations were markedly elevated, serum lipase levels were normal throughout the patient's course. Elevation of serum lipase does not seem to be a necessary condition for the development of the metastatic fat necrosis syndrome.