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36 original cases, 24 from the Hopital de Sainte-Anne in Paris and 12 from the surrounding region, of ischemic (30) or hemorrhagic (6) strokes in women taking oral contraceptives are reported. The patients were 20-55 years, half under 30; took various types of pills from 10 weeks to 10 years, mean 28 months; 30 of them for contraception but other for migraine, Reclus disease, amenorrhea, sterility, and endometri osis. 27 women had related history: ischemic vascular accident (5), hyp ertension (5), thromboembolism (4), Basedow disease (3), heavy smoking (3), essential comitiality (2), migraine (1), essential hyperlipidemia (1). The women with ischemic strokes were younger, 61% under 30. A 3rd had premonitory symptoms like headache, progressing rapidly to massive hemiplegia in 17, discrete hemiplegia in 11, loss of consciousness in 6, and convulsions in 3. The cerebrospinal fluid was clear in 11 cases tested. Angiography revealed lesions in the internal carotid in 4, sylvian arteries in 9, posterior cerebral in 1, but no anomaly in 8. Only 5 recovered completely: 3 died and 7 retained major neurologic dysfunction. 6 women had hemorrhagic strokes, 2 intracerebral hematomas, and 4 cerebromeningeal hemorrhages. 5 were operated on, 3 with good results and 2 were left with severe neurologic sequelae. The authors insisted that none of these women had been given any preliminary tests or followed with any attention to their related history while taki ng oral contraceptives.
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PMID:[Cerebrovascular accidents and oral contraceptives (reflections a propos of 36 observations)]. 121 91

The forms of administration, mechanisms of action, side effects and complications, and other aspects of female hormonal contraception are set forth in this "lesson" for medical students. Female hormonal contraception has been in use for over 30 years and is used by more than 150 million women worldwide. Oral contraceptives suppress the preovulatory peak of follicle stimulating hormone and luteinizing hormone, preventing ovulation and follicular maturation. Progestins render the cervical mucus impermeable to sperm and modify the endometrium so that it will no longer support implantation. The synthetic estrogen ethinyl estradiol is used in most combined oral contraceptives (OCs). Among the numerous progestins in use are the newer desogestrel, gestodene, and norgestimate, which have fewer androgenic and metabolic effects than did the 1st generation. the different forms of administration of hormonal methods include combined OCs, oral preparations containing low doses of progestin continuously administered or high doses continuously or discontinuously administered. Intramuscular injection of progestins and the so-called "morning after" postcoital pills are less often prescribed. The combined preparations may be monophasic, biphasic, triphasic, or sequential. Sequential preparations should be avoided because of the hyperestrogenic climate they induce. The low-dose progestin preparations are indicated for women with contraindications to synthetic estrogen. They must be taken at the same time each day and have a relatively high rate of side effects, especially ovarian and breast cysts and irregular bleeding. High-dose progestin preparations have significant metabolic effects and are indicated primarily for patients with gynecological problems such as fibromas and endometriosis. Intramuscular injection of medroxyprogesterone acetate every 3 months is effective but has the same side effects as high-dose progestins. It is indicated primarily for patients unable to control their own behavior. The hormonal methods are all highly effective in preventing pregnancy when correctly administered. Side effects may be minor problems, such as nervousness and nausea, that are usually of short duration. the more serious side effects, including modifications of lipid or carbohydrate metabolism, hemostasis, blood pressure, or hepatic functioning and cardiovascular effects, have been reduced with the new lower dosed formulations. Absolute contraindications to hormonal contraception include undiagnosed vaginal bleeding or amenorrhea, history of thromboembolic or cerebral vascular accidents, severe cardiopathy or hypertension, hyperlipidemia, hepatopathy, hormonodependent cancer, pituitary tumors, porphyria, and severe mental problems. Relative contraindications impose the need for careful monitoring and follow-up. The practitioner should be aware of the possibility of interactions between OCs and certain other drugs.
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PMID:[Hormonal contraception]. 160 74

Synthetic progestins derived from nortestosterone provide a promising contraceptive alternative for women with contraindications for estrogens. Progesterone and synthetic progestins reduce vasodilatation and edema induced by estrogens and stop estrogen-dependent cellular multiplication in target tissue. Progestins have 2 kinds of contraceptive affect: antigonadotropic action at sufficient doses, and peripheral action at lower doses. The cervical mucus is modified in composition and volume, becoming hostile to sperm; the endometrial mucus atrophies; and tubal motility is slowed. High dose progestins are administered from the 5th or 10th to the 25th cycle day, with the earlier date preferred for women with shorter cycles. They are an ideal method for women with endometrial hyperplasia or benign breast disease or histories of breast or uterine cancer, as well as for women over 40 with dysovulatory cycles. Contraindications to high dose progestins include obesity, hypertension, lipid metabolic anomalies, and diabetes. Low dose progestin-only pills are administered at the exact same time each day including during menstruation. They are attractive for some women because they contain no estrogen, a reduced progestin dose causing fewer headaches and less somnolence, and fewer metabolic effects. Low dose progestins are indicated for lactating women, those with contraindications to estrogens such as obesity, hypertension, hyperlipidemia, and diabetes, and those with renal or cardiac insufficiency with valvulopathy. Low dose progestins are also indicated for nulliparas and other women for whom IUDS are contraindicated. Women using low dose progestins should never take drugs that act as enzymatic inductors, which speed hepatic degradation of steroids and reduce their efficiency. A resulting pregnancy is likely to be extrauterine because of slowed tubal transport. The failure rate of low dose progestins ranges from .9-3%, with higher failure rates among younger women. About 30% of users initially experience spotting, which despite its usual disappearance after 2-3 months of use is the most common reason for discontinuing the method. Low dose progestins have no metabolic or vascular effects, but they may cause a relative hyperestrogenism is some users. Other modes of administration of progestin contraception include continuous high doses, never justified solely for contraception. Trimonthly injections of medroxyprogesterone acetate of norethindrone enanthate provide contraception through a long lasting antigonadotropic effect. Metrorrhagia and amenorrhea are among possible side effects. The method is used primarily in developing countries where its ease of use is a major advantage. Subcutaneous implants releasing continuous doses of levonorgestrel provide contraceptive protection for over 5 years. The cumulative failure rate is 1.7 at 5 years. Metabolic tolerance is good. The major side effect is menstrual irregularity.
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PMID:[Progestational contraception]. 365 94

The present status of oral contraceptive steroids and the IUD, the 2 most effective and increasingly popular contraceptive methods (used by 41.6% of all U.S. married couples practicing contraception in 1970), is presented. Oral steroid contraceptives with varying quantity and activity of estrogen (ethinyl estradiol or mestranol) and progestogen (norethindrone, norethynodrel, ethynodiol diacetate, or norgestrel), are of 3 types: combination, sequential, and minidose progestogen alone. The most effective contraceptive available is the combined oral pill with a pregnancy rate of less than .2 % per 100 women after 1 year. Contraceptive action is exerted primarily through inhibition of ovulation and secondarily by alterations in cervical mucus, endometrial glands, the ovary, and in the oviduct and uterine muscle. In comparison, sequential oral contraceptives are less effective with greater side effects, and should only be used in women with amenorrhea. Effects of oral contraceptives other than contraception include those on the (1) the primary targets of the female reproductive system, (2) on other endocrine oragans and (3) on the remainder of the body. In the first group, changes may include transitory stromal fibrosis in the ovary, enlarged fibromyomata, intermenstrual bleeding or amenorrhea, increased amount of cervical mucus, polypoid hyperplasia of the endocervical glands, breast tenderness, and changes in lactation. Changes in the second category which may occur affect the adrenal glands, hypothalamus, the thyroid (increased thyroid-binding globulin), and pancreas (alterations in glucose metabolism). Effects on the rest of the body may include increase in serum lipids and changed atherogenic index, abnormalities in liver function, thromboembolism (incidence in oral contraceptive users 4.4 times that in non-users), melasma, alterations in the central nervous system with increased incidence of cerebral vascular accidents, hypertension, and increased body weight. Absolute contraindications to oral contraceptive therapy include cancer of the breast and uterus, pregnancy, active liver disease, hyperlipidemia, and history of gestational diabetes, thromboembolic phenomena or coronary artery disease. Relative contraindications include depression, migraine, myomata of the uterus, hypertension, epilipsy, oligomenorrhea and amenorrhea. Reliable epidemiologic data on IUDs from the Cooperative Statistical Program indicated first year pregnancy rate of 2.5%. Problems with the IUD include: 1) pregnancy with device in situ, which is associated with a higher incidence of spontaneous abortion; 2) ectopic pregnancy, which is prevented at a rate of only 90% compared with intrauterine pregnancies prevented in 97-98%; and 3) expulsions (20% of which are unnoticed), the expulsion rate being higher with decreasing age and parity, higher in the first than second year of use, and higher with smaller than larger devices. A major problem is discontinuation for medical reasons (15% rate in the first year), mainly bleeding and pain. Perforation, another serious complication, occurs initially at time of insertion with an incidence of 1 per 2500 insertions for the loop. IUDs were found to produce a sterile inflammatory tissue reaction, which is postulated as the primary causative factor for their contraceptive effect in humans.
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PMID:Current status of contraceptive steroids and the intrauterine device. 459 80

Polycystic ovary syndrome is a diagnosis made in 5%-10% of women between late adolescence and the menopause. Patients may present with oligomenorrhoea or amenorrhoea, anovulation or infertility, hirsutism or acne. Women with the syndrome have at least seven times the risk of myocardial infarction and ischaemic heart disease of other women, and by the age of 40 years up to 40% will have type 2 diabetes or impaired glucose tolerance. Polycystic ovary syndrome is associated with insulin resistance, with consequent hyperinsulinaemia and (frequently) hyperlipidaemia and obesity. Recent research has shown that the application of diabetes management techniques aimed at reducing insulin resistance and hyperinsulinaemia (such as weight reduction and the administration of oral hypoglycaemic agents) can not only reverse testosterone and luteinising hormone abnormalities and infertility, but can also improve glucose, insulin and lipid profiles. The management of polycystic ovary syndrome should now include patient education and attention to diabetes and cardiovascular risk factors such as hyperlipidaemia, obesity, physical exercise, glucose intolerance, hypertension and cigarette smoking.
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PMID:Polycystic ovary syndrome: a new direction in treatment. 986 12

The optimal therapy for pure membranous lupus nephritis (MLN) with nephrotic syndrome remains controversial. While the risk of progressive renal deterioration may be small, persistent heavy proteinuria leads to the complications of oedema, hypoalbuminaemia, hyperlipidaemia, hypercoagulability, and venous thrombosis. We examined prospectively the efficacy and tolerability of a sequential immunosuppressive regimen in a cohort of 20 patients with nephrotic syndrome due to pure MLN (WHO Class Va and Vb). Initial therapy comprised prednisolone (0.8 mg/kg/d p.o.) and cyclophosphamide (2-2. 5 mg/kg/d p.o.). Prednisolone dosage was gradually tapered to 10 mg/d at 6 months, when cyclophosphamide was replaced by azathioprine (2 mg/kg/d p.o.) as maintenance therapy. Within 12 months of therapy 11(55%) patients had complete remission (CR), 7(35%) patients achieved partial remission (PR) (proteinuria reduced from 6.2+/-4.0 to 2.0+/-1.7 g/24 h, P<0.01), and 2 patients failed to respond. Improvements in proteinuria and serum albumin level were observed after 3-6 months of treatment. Non-responders had lower baseline serum albumin compared to complete responders. Renal function remained stable during follow-up for 73.5+/-48.9 months. 8 patients had disease relapse at 47+/-15 months. Early complications (</=12 months) included herpes zoster (40%), minor respiratory or urinary tract infections (25%), mild leukopenia (15%), and transient amenorrhea (14.3%). 4 of the 20 patients developed pulmonary tuberculosis during follow-up, at 35+/-24 months after the diagnosis of MLN. 8 patients had hyperlipidaemia. Haemorrhagic cystitis, permanent amenorrhea, vascular complications, and mortality were not observed. We conclude that this sequential immunosuppressive regimen is effective in 90% of patients with MLN and heavy proteinuria. Prudent consideration of the benefits and potential side-effects is required to determine the optimal management for individual patients.
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PMID:Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression. 1048 33

The choice of currently available oral contraceptives (OCs) includes combined formulations in varying dosages and monophaic, biphasic, or triphasic form, sequential pills, synthetic progestin-only pills in macro or microdose, and injectable synthetic progestins. Before the advent of microdose pills, products were characterized by progestin or estrogen dominance. Rumors that microdose pills do not completely inhibit ovulation have hindered their acceptance in France, but research has shown that they inhibit ovarian secretions as effectively as more strongly dosed products. Their les profound inhibition of the hypothalamo-pituitary axis raises hopes of a lessened incidence of postpill amenorrhea. Progestin-only microdose pills allow considerable ovarian estrogen secretion, creating a veritable iatrogenic luteal insufficiency. Following the suppression of mestranol, the only estrogen used in OCs is ethinyl estradiol (EE). The only 19-norsteroid progestins which are fixed directly to the progesterone receptors are norethindrone and norgestrel; others such as lynestrenol, ethynodiol diacetate and norethindrone acetate are prohormones. Menstrual problems are among the most frequent side effects of minidose combined pills, but their incidence had dimished with the appearance of biphasic pills and the triphasic pills should offer even greater improvements. The frequency of thromboembolic venous accidents is firectly correlated to the estrogen dose of OCs, but arterial accidents and possibly arterial hypertension appear to be linked to the progestin dose. Synthetic progestins appear to diminish the high density lipoprotein (HDL) fraction of cholesterol and disturb glucose tolerance, while synthetic estrogens augment the HDL fraction of cholesterol and the very low density lipoprotein (VLDL) fraction of triglycerides, modify some coagulation factors, and elevate the plasma level of angiotensinogene. Dose levels and chemical structures of the constituents influence the metabolic effects of pill formulations. In current practice, minidose products are preferred because they cause fewer metabolic changes and are less likely to entail vascular risks. Sequential pills are prescribed for 1 cycle following induced abortion but are not used for long periods because they are not 100% effective, they carry a risk of endometrial hyperplasia, and they appear to increase risks of venous thromboembolism. A combination of 50 mcg EE and 2 mg cyproterone acetate may be prescribed for acne, and minidose combination pills may be used in case of fibroma or endometriosis. In case of contraindications to estrogen, a microdose or injectable progestin can be prescribed if their shortcomings are kept in mind. The current popularity of macrodose progestin-only pills in France has more to do with fashion than with science. All hormonal contraception should be avoided for women at risk, including smokers and those with hyperlipidemia or a family history of vascular accidents.
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PMID:[How to choose an oral contraceptive in 1984]. 1226 9

This is the discussion after a presentation by E. BAULIEU on combined oral contraceptives (ibid; 4(4)1972); it emphasized tumors, blood lipids, and management of typical problems with the pill. It was agreed that the pill does not cause breast cancer, despite the nodules reported in Beagles, but the discussants came to no concensus on the possibility of ovarian cysts and pituitary adenoma. DE GENNES described his 33 cases of vascular accidents in pill users of whom 24 had hyperlipidemia, usually (80%) of the "mixed" type 3 (i.e. high cholesterol and triglycerides). About 2% of women have abnormal plasma lipids, defined as total lipids over 9 g/1, triglycerides over 1.35 g/1, cholesterol over 2.7 g/1. Among the 33 cases, pure hypercholesteremia was underrepresented; premonitory signs (usually migraine) were only present in some cases of cerebrovascular accident, not in cardiac infarction or pulmonary embolism; the parous women had had no trouble in pregnancy. Other topics discussed included diabetes, glucose tolerance tests, hypertension, amenorrhea, menopause, and whether and when to interrupt oral contraception. The conference was concluded with a summary of the status of French legislation on contraception. The French Assembly had not authorized funds for family planning centers, nor for a national office of information, because they considered France too underdeveloped for such an antinatalist policy.
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PMID:[Combined oral contraceptives]. 1230 30

Mitochondriopathies (MCPs) are either due to sporadic or inherited mutations in nuclear or mitochondrial DNA located genes (primary MCPs), or due to exogenous factors (secondary MCPs). MCPs usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Although several proteins with signalling, assembling, transport, enzymatic function can be impaired in MCP, most frequently the activity of the respiratory chain (RC) protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. MCPs represent a diagnostic challenge because of their wide variation in presentation and course. Systems frequently affected in MCP are the peripheral nervous system (myopathy, polyneuropathy, lactacidosis), brain (leucencephalopathy, calcifications, stroke-like episodes, atrophy with dementia, epilepsy, upper motor neuron signs, ataxia, extrapyramidal manifestations, fatigue), endocrinium (short stature, hyperhidrosis, diabetes, hyperlipidaemia, hypogonadism, amenorrhoea, delayed puberty), heart (impulse generation or conduction defects, cardiomyopathy, left ventricular non-compaction heart failure), eyes (cataract, glaucoma, pigmentary retinopathy, optic atrophy), ears (deafness, tinnitus, peripheral vertigo), guts (dysphagia, vomiting, diarrhoea, hepatopathy, pseudo-obstruction, pancreatitis, pancreas insufficiency), kidney (renal failure, cysts) and bone marrow (sideroblastic anaemia). Apart from well-recognized syndromes, MCP should be considered in any patient with unexplained progressive multisystem disorder. Although there is actually no specific therapy and cure for MCP, many secondary problems require specific treatment. The rapidly increasing understanding of the pathophysiological background of MCPs may further facilitate the diagnostic approach and open perspectives to future, possibly causative therapies.
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PMID:Mitochondriopathies. 1500 63

PCOS is a metabolic syndrome that exists throughout the world with much clinical heterogeneity. PCOS is now appreciated as encompassing two interrelated metabolic phenomena--insulin resistance and hyperandrogenism. Patients present with oligo-amenorrhea and clinical hyperandrogenism, and the diagnosis is based on clinical grounds with few laboratory tests necessary. Because patients are at higher than normal risk for diabetes, glucose intolerance, and hyperlipidemia, and perhaps at higher risk for coronary heart disease, newly diagnosed patients with PCOS should be evaluated for glucose intolerance and hyperlipidemia. The cornerstone of therapy today includes weight management, and further therapeutic intervention is focused on reproductive and cardiovascular health and treatment of insulin resistance. Clinical case continued The 17-year-old mentioned in the beginning of this article probably does have PCOS. She fits the clinical criteria: oligo-ovulation and hyper-androgenism (the acne and hirsutism). In addition, she is obese, which is also associated with PCOS. Her TSH and prolactin were normal, and as her presentation was not suggestive of an adrenal tumor or congenital adrenal hyperplasia (she had mild hirsutism, and those diagnoses are associated with more severe hyperandrogenism), no further laboratory evaluation was deemed necessary. Once the diagnosis was made, she was screened for lipid abnormalities and for glucose intolerance. Her LDL was 150, HDL 35; oral glucose tolerance test (OGTT) was normal. A pregnancy test was negative, and she was started on OCPs. Devoting herself to exercise and dietary change, she lost 10 pounds in her first 3 months after diagnosis. Her hirsutism and acne have improved with the OCPs and weight loss, and her menses are regular. She has elected to defer oral insulin sensitizers until her weight loss has stabilized. Findings PCOS is common in reproductive-aged women. Diagnosis is clinical and is supported by lab findings; there is significant clinical heterogeneity. Insulin resistance is likely central to the pathophysiology along with androgen excess. Health implications include infertility, diabetes, endometrial cancer, hyperlipidemia, and possibly coronary heart disease. Treatment is evolving and includes weight loss, OCPs, and insulin sensitizers.
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PMID:Polycystic ovary syndrome: a review for primary providers. 1502 92


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