Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation

ABSTRACT

Introduction: Following a historical overview, the ovulation-inhibiting effect of various orally administered estrogen-progestin combinations (combined oral contraceptives [COCs]) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens.

Areas covered: Inhibition of ovulation with progestins alone; estrogens alone; various progestins in combination with ethinyl estradiol; various progestins in combination with natural estrogens (estradiol, estradiol valerate, and estetrol).

Expert commentary: The original idea to achieve ovulation blockage through the administration of steroid hormones involved the use a progestogen (both progesterone and its synthetic homologous). The ability of a progestin to inhibit ovulation depends on the type of compound and on its dosage and a difference of more than 20-fold in activity exists between compounds utilized today in COCs.

Initially, the estrogenic component was present only because it contaminated the first progestin utilized. It was soon found that an estrogen is necessary for proper cycle control. It was also found that the estrogen acts synergistically in inhibiting ovulation. For almost half a century, most COCs contained ethinyl estradiol. Today, also natural estrogens are being employed.

Inhibition of ovulation was complete with all early high dose preparations. Decreasing dosage allowed some ovarian activity to occur, occasionally leading to a mature follicle. Even in this situation, defective corpus luteum formation assured contraceptive protection.     

Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints

The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.     

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis

Introduction: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens.

Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture.

The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel.

Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed.

Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn.

At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.     

17Beta-estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman

Recent publications of the initial outcomes from the Women's Health Initiative (WHI) study of menopausal management have raised concerns over the safety of hormone therapy [1,2]. Every study, no matter how large or well conducted, has biases and limitations that preclude the ability to apply the outcomes to a larger group of individuals not specifically evaluated in the analysis. In particular, the hormonal arms of the WHI evaluated only a single dose of a daily oral regimen of conjugated equine oestrogen 0.625 mg [1,2], combined with medroxyprogesterone acetate 2.5 mg if the subject had a uterus [1]. The failure to evaluate non-oral regimens prevented the evaluation of hormone delivery systems that have been shown to provide similar symptom relief to oral regimens, but with a considerably different physiological impact. The once-weekly transdermal patch (Climara Pro releasing 17beta-estradiol 0.045 mg/day and levonorgestrel 0.015 mg/day has been shown to be highly effective in rapidly reducing the frequency and intensity of vasomotor symptoms and to significantly improve all categories in the quality of life Women's Health Questionnaire [3]. In addition, this transdermal combination system was not associated with any cases of endometrial hyperplasia, adverse impacts on cholesterol or lipid values and was associated with an increasing rate of amenorrhoea over time [3]. The 17beta-estradiol/levonorgestrel transdermal system is approved in the US for the treatment of moderate-to-severe vasomotor symptoms and the prevention and treatment of urogenital atrophy.     

17β-Estradiol/levonorgestrel transdermal system for the management of the symptomatic menopausal woman

Recent publications of the initial outcomes from the Women’s Health Initiative (WHI) study of menopausal management have raised concerns over the safety of hormone therapy [1,2]. Every study, no matter how large or well conducted, has biases and limitations that preclude the ability to apply the outcomes to a larger group of individuals not specifically evaluated in the analysis. In particular, the hormonal arms of the WHI evaluated only a single dose of a daily oral regimen of conjugated equine oestrogen 0.625 mg [1,2], combined with medroxyprogesterone acetate 2.5 mg if the subject had a uterus [1]. The failure to evaluate non-oral regimens prevented the evaluation of hormone delivery systems that have been shown to provide similar symptom relief to oral regimens, but with a considerably different physiological impact. The once-weekly transdermal patch (Climara Pro^?) releasing 17β-estradiol 0.045 mg/day and levonorgestrel 0.015 mg/day has been shown to be highly effective in rapidly reducing the frequency and intensity of vasomotor symptoms and to significantly improve all categories in the quality of life Women’s Health Questionnaire [3]. In addition, this transdermal combination system was not associated with any cases of endometrial hyperplasia, adverse impacts on cholesterol or lipid values and was associated with an increasing rate of amenorrhoea over time [3]. The 17β-estradiol/levonorgestrel transdermal system is approved in the US for the treatment of moderate-to-severe vasomotor symptoms and the prevention and treatment of urogenital atrophy.     

Are we going to increase the use of antidepressants up to that of benzodiazepines?

Objective The present study compared recent trends in benzodiazepine and antidepressant consumption in Italy and projected their global sales in the future. We investigated whether the increasing use of antidepressants is associated with a progressive reduction in benzodiazepine use.Methods Data concerning actual quantities of benzodiazepines and antidepressants dispensed in Italy from 1995 to June 2003 were obtained from IMS Health. For each agent, the number of defined daily doses (DDDs) per 1000 inhabitants per day and the annual expenditure in Euros was calculated.Results During the 9-year period, benzodiazepine consumption remained substantially stable, accounting for 50 DDDs/1000 per day in 2003. In the same period, antidepressant consumption dramatically rose, from 9 DDDs/1000 per day in 1995 to 26 DDDs/1000 per day in 2003, an increase of nearly three times. While the use of tricyclic antidepressants declined by one-third and that of other older agents remained substantially stable, the use of selective serotonin-reuptake inhibitors and newer agents (venlafaxine, mirtazapine, reboxetine) increased by 623%. Global consumption of antidepressants was projected to increase still further, and, in 2007, the total sales of antidepressants were projected to be similar to the total sales of benzodiazepines. The value of benzodiazepine sales increased from 322 million to 565 million Euros, an increase of 43%; similarly, the value of antidepressant sales increased from 186 million to 569 million Euros, an increase of 67%.Conclusions In Italy, the consumption of benzodiazepines was not affected by the increased prescribing of selective serotonin-reuptake inhibitors and newer antidepressants.     

Use of postmenopausal hormone therapy since the Women's Health Initiative findings

PURPOSE: To assess how use of postmenopausal hormone therapy (PHT) has changed since the Women's Health Initiative (WHI) trial was halted early due to an excess risk of stroke and other adverse outcomes. To estimate whether use of alternative drugs to treat menopausal symptoms (e.g., selective serotonin reuptake inhibitors [SSRIs], soy) has increased. METHODS: Women were interviewed in the Slone Survey, a random-digit-dial (RDD) survey of current medication use in a representative national sample. Information was obtained on PHT including dose, route, and reason for use, and on use of alternative drugs to treat menopausal symptoms. There were 3853 women aged >or=50 years, interviewed from 1/2001 to 6/2004. RESULTS: The average weekly prevalence of PHT declined 57%, from 28% in the first half of 2002 to 12% in the first half of 2004. Use declined for conjugated estrogens (CE) and for other estrogens, taken either alone or with progestin. The decrease exceeded 50% in most strata of age, race, education, and region. The proportion of PHT users taking 0.3 mg CE did not change. Comparing prevalence in 2004 with prevalence in 2002, there was no material increase in use of black cohosh (2.0% in 2004) or soy (2.0%) and use of SSRIs was somewhat lower (8.9%). CONCLUSIONS: These population-based usage data demonstrate a large decline in PHT use among women of postmenopausal age. The proportion of CE users taking lower doses has not increased. On a population basis, millions fewer women are using PHT in 2004 than before the WHI results were published, but there has been no appreciable increase in use of alternative therapies for menopausal symptoms over the same period.     

Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals

For over 30 years various combinations of synthetic estrogens and progestins have been used in oral contraceptive formulations. Ethinyl estradiol (EE) and norethindrone acetate (NA) are common synthetic hormones used in oral contraceptives such as Loestrin, Brevicon, Ortho-Novum, Norlestrin, and Norinyl. In recent years these oral contraceptives have been considered for development in other therapeutic indications. Given the use of these agents for other clinical indications with different and larger target populations, an updated comprehensive review of the toxicology literature of estrogens and progestins is warranted. This review will summarize available data on the pharmacology and toxicology of estrogens and progestins with an emphasis on the specific synthetic hormones EE and NA. Ethinyl estradiol and norethindrone acetate alone or in combination, possess low acute and chronic toxicity. In some studies, EE and/or NA increased the incidence of specific tumors in susceptible strains of rodents and dogs, but not monkeys. These agents are not teratogenic when given in combination. Alone EE and NA have clastogenic properties. Overall, the animal data demonstrates that long-term exposure to EE and NA formulations pose very little health risks to humans.     

1 101份抗高血压药处方相互作用调查与评价

目的：筛查抗高血压药物之间以及与其他药物之间的相互作用，分析发生相互作用的原因，为临床合理联合使用抗高血压药物提供依据。方法：对我院门诊药房2003年上半年每月(随机抽取一天)含有抗高血压药物的处方使用合理用药软件系统进行分析统计。结果：所筛查的1101份处方中有94份发生了相互作用，发生率为8．5％，其中与ACEI类药物有关的相互作用有80份，抗高血压药物之间发生相互作用的仅有5份；有两份发生相互作用处方的反应程度为严重。结论：大部分抗高血压药物的使用比较合理，但ACEI类药物的使用应谨慎，特别是联合使用发生相互作用，且反应程度为严重的更应引起临床医师的重视。     

Hormone therapy for the management of menopausal symptoms: pharmacotherapy update

Nearly 50 million women each year are projected to reach menopause by 2030. Many of these women will experience vasomotor symptoms such as night sweats and hot flashes as they enter the menopausal transition. Up until the release of the findings of the Women's Health Initiative (WHI) studies, women were frequently prescribed hormone therapy (HT) to alleviate bothersome and sometimes debilitating menopausal symptoms as well as to prevent osteoporosis and coronary heart disease (CHD). Although the WHI studies were the first large, randomized, controlled trials that contradicted what was historically believed about the benefits of HT in postmenopausal women, important limitations including baseline demographics of WHI participants and investigation of only one HT strength/dosage form exist. HT may be a reasonable pharmacotherapy option for the management of menopausal symptoms following complete patient evaluation by experienced clinicians. Updated recommendations addressing management of menopausal symptoms, a new HT product containing the spironolactone-analogue drospirenone (DRSP), and discontinuation methods of HT are also discussed in this review.     

门诊口腔粘膜病临床用药调研

目的了解口腔粘膜病的主要病种及临床用药特点。方法从2002年6、7月我院所有门诊处方中挑选口腔粘膜病处方,统计处方诊断所涉及的病种及处方数量、金额,并分析处方数量排名前3位的口腔粘膜病用药情况。结果处方诊断所涉及的病种共计30多种,处方数量排名前3位的口腔粘膜病依次是口腔扁平苔藓、复发性阿弗他溃疡和口腔念珠菌病;口腔粘膜病的治疗体现出了同病异治、异病同治、局部疾病全身治疗和中西医结合治疗的特点。结论我院口腔粘膜病患者的病种涵盖了几乎所有种类的口腔粘膜病,合理用药在口腔粘膜病的治疗中发挥着重要作用。     

我院儿科门诊抗生素用药分析

目的:为了了解目前儿科门诊抗生素的使用情况,促进临床抗生素的合理使用,提供参考.方法:随机抽取2003年7月～9月门诊西药处方11703张,统计抗生素处方占处方总数的百分比,两种口服抗生素联合用药和两种注射抗生素联合用药方式,前10位两种注射抗生素联用品种以及前10位两种口服抗生素联用品种.结果:含有抗生素的处方占处方总数的64.75%,口服抗生素处方占含抗生素处方的34.99%,注射抗生素处方占含抗生素处方的65.01%.结论:抗生素使用率较高,剂量偏大,个别联合用药方式有的无理论根据,有的明显不合理,有的甚至属滥用.