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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 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

Combined oral contraceptives (OCs) have nearly total efficacy when correctly used and good overall tolerance among most women under 40, but there are several significant contraindications to their use. Women with hypertension, hyperlipidemia, diabetes, minor mastopathy, or premenstrual tension should not use OCs containing estrogen. Macroprogestational OCs administered generally 20 days out of 28 are useful when an antiestrogen effect is sought or when metabolic anomalies are to be avoided. An antiestrogen effect may be desired for women over 40 suffering from relative or absolute hyperestrogenism, or for women with premenstrual syndrome, menorrhagia related to endometrial hyperplasia or other menstrual problems, or benign mastopathies. An antiestrogen effect may also be desired to prevent cellular pathologies common after age 40. Some anomalies of metabolism, blood pressure, and coagulation persist in users of combined OCs regardless of the dose or the compounds used in the formulation. Progestins derived from testosterone were the first to be used in contraception and provide good cycle control and antigonadotropic activity, along with a powerful antiestrogen effect. But they may have metabolic side effects and cause signs of hyperandrogenism. Progestins derived from progesterone have been studied in health women and in those with different risk factors. Chlormadinone acetate has been used in women at high vascular risk, and promegestone has been used in women with fibrocystic breast disorders. A study was also done on 36 healthy women for 6 months using nomegestrol acetate. The preliminary results were good but the numbers of women were small, they had no metabolic risk factors, and the treatment periods were short. The results thus cannot be extrapolated to subjects at risk or for use during longer periods. The only observed modifications (essentially declines in apoprotein A1 and elevation of antithrombine) were probably attributable to the decline in average estradiol levels and without significance for risk. A disadvantage of these methods is that they have not been authorized for marketing as contraceptives in France and no Pearl index is available. Although the incidence of menstrual problems is not well known, such problems appear to be relatively frequent. The hypoestrogenism often sought for women with gynecological pathologies is not necessarily desirable for women using these methods because of metabolic problems or age over 40. A sufficient estradiol level protects against premature bone loss and has important metabolic effects including better production HDL cholesterol. 18 women who experienced menstrual problems with macroprogestational contraceptives were given 5 mg/day of nomegestrol acetate in combination with transdermally administered estradiol. Clinical and metabolic tolerance were excellent, and no pregnancies occurred. Further study is warranted.
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PMID:[Macroprogestative contraception: advantages]. 1231 9

Polycystic ovary syndrome (PCOS) is a syndrome, which can be defined as a group of recognisable patterns of symptoms or abnormalities that indicate a particular medical situation. The current definition of PCOS requires the presence of two of the following three conditions: (i) oligo- and/or anovulation; (ii) clinical and/or biochemical signs of hyperandrogenism; and (iii) polycystic ovaries--and the exclusion of other aetiologies. It is generally accepted that the prevalence of PCOS is approximately 5-10%, and that of polycystic ovaries alone is 21-23%. Other features of PCOS are obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes mellitus, dyslipidaemia, cardiovascular disease, obstructive sleep apnoea and infertility. An approach to a patient with possible PCOS should be directed towards making a diagnosis and screening for associated endocrine abnormalities. Therapeutic interventions are directed towards addressing the needs of the patient at present and towards preventing long-term complications of the syndrome. Body mass index, which is a primary mediator in the relationship between PCOS and health-related quality of life in obese PCOS adolescents, may play a similar role in other PCOS patients. Any intervention directed at reducing central obesity will not only improve quality of life but also correct hyperinsulinism and improve fertility and lipid and androgen profiles. It is also the only currently available intervention that can have a lifelong impact on reducing possible long-term complications of the syndrome. Lifestyle modification is the cardinal intervention. Pharmacological treatments are available for specific indications. Infertility can be treated with clomifene (clomiphene citrate), metformin, gonadotropins or surgery to the ovaries. Cyproterone (alone or in combination with ethinylestradiol) and spironolactone are the main drugs used in the treatment of hirsutism. Other drugs that can be considered include flutamide, ketoconazole and finasteride. Women with PCOS require ongoing surveillance to detect impaired glucose tolerance, hyperlipidaemia, endometrial hyperplasia and consequent complications. Obese women, in particular, require regular glucose tolerance testing because of the potential for rapid progression from normal to impaired glucose tolerance and diabetes. The focus of this article is the epidemiology, diagnosis and management of this common endocrine disorder. Diagnostic and co-morbid features are discussed separately to facilitate understanding of PCOS. Symptom-directed strategies, as well as short- and long-term goals of treatment, are outlined.
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PMID:Diagnosis and management of polycystic ovary syndrome: a practical guide. 1674 5

Endometrial carcinoma is the most common malignant tumor of the female genitals in developed countries. The differences noted in epidemiology, presentation, and biological behaviors of endometrial carcinoma suggest that there are two fundamentally different pathogenic types of the disease: type I (estrogen related, endometrioid type) and type II (non-estrogen related, non-endometrioid type). The first type is more common and represents about two-thirds of cases. It occurs in women with hyperlipidemia, obesity, and signs of hyperestrogenism, including anovulatory uterine bleeding, infertility, late onset of menopause, ovarian stromal hyperplasia, and endometrial hyperplasia. The second type occurs in the absence of these features. Pathohistologically, type I tumors are composed of endometrioid carcinoma whereas type II tumors are composed of serous or clear cell carcinoma. Atypical hyperplasia is recognized as the precursor for the endometrioid type of endometrial carcinoma and endometrial intraepithelial carcinoma (EIC) as the precursor of serous carcinoma, the most common non-endometrioid type of endometrial carcinoma. In endometrioid type of endometrial carcinoma, it appears that PTEN mutation may be central to the initiation of endometrial proliferative lesions by which damage in other genes is then accumulated (e.g., DNA mismatch repair genes, K-ras, p53) in the progression to carcinoma. In contrast to endometrioid type, p53 mutations appear to be important in the conversion of atrophic endometrium to EIC and serous adenocarcinoma. Endometrial intraepithelial neoplasia (EIN) has been a recently defined precursor for the endometrioid type of endometrial carcinoma.
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PMID:[Endometrial carcinoma and precursor lesions]. 1764 68

Polycystic ovary syndrome is now a well-recognized condition affecting 6%-25% of reproductive-aged women, depending on the definition. Over the past 3 decades, research has launched it from relative medical obscurity to a condition increasingly recognized as common in internal medicine practices. It affects multiple systems, and requires a comprehensive perspective on health care for effective treatment. Metabolic derangements and associated complications include insulin resistance and diabetes, hyperlipidemia, hypertension, fatty liver, metabolic syndrome, and sleep apnea. Reproductive complications include oligo-/amenorrhea, sub-fertility, endometrial hyperplasia, and cancer. Associated psychosocial concerns include depression and disordered eating. Additionally, cosmetic issues include hirsutism, androgenic alopecia, and acne. This review organizes this multi-system approach around the mnemonic "MY PCOS" and discusses evaluation and treatment options for the reproductive, cosmetic, and metabolic complications of this condition.
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PMID:Polycystic ovary syndrome: update on diagnosis and treatment. 2485 38

Polycystic ovary syndrome (PCOS) affects 8-10 percent of reproductive-aged females, making it the most common state of endocrine dysfunction in women. Patients with PCOS are often treated for the signs and symptoms of the condition without consideration for the underlying syndrome, causing frustration for many affected patients. Abnormal uterine bleeding, endometrial hyperplasia and cancer, hirsutism and other skin changes, obesity, glucose intolerance, hypertension, and hyperlipidemia often accompany the syndrome, making it imperative to address these issues. The keys to diagnosis and treatment are understanding the diagnostic criteria of hyperandrogenism, ovulatory dysfunction, polycystic ovaries and the metabolic syndrome, while aiming treatment at controlling the symptoms and causes of the syndrome. In 2013, the Endocrine Society released its clinical guidelines, Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. This gives clear diagnostic criteria, and treatment goals aimed at the etiology of the syndrome: to decrease hyperandrogenic symptoms, management of underlying metabolic abnormalities, prevention of endometrial hyperplasia and carcinoma, and improvement of ovulation.
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PMID:Polycystic Ovarian Syndrome: A Primer. 2613 26