Effect of continuous combined estrogen and desogestrel hormone replacement therapy on serum lipids and lipoproteins.

OBJECTIVE: To determine the effects of continuous combined hormone replacement therapy with desogestrel and 17 beta-estradiol (E2) on serum lipids and lipoproteins. METHODS: Fifty-seven healthy postmenopausal women of less than 60 years of age were studied prospectively and treated with oral desogestrel 0.15 mg/day and micronized 17 beta-E2 1 mg/day, both taken continuously. Fasting venous blood samples for serum lipids and lipoproteins were taken before and after 6 and 12 months of treatment. RESULTS: Thirty-two women completed the study. Levels of all serum lipids and lipoproteins fell significantly by 6 months and remained low at 12 months. The mean percentage reduction after 12 months of treatment was 12.8% for high-density lipoprotein (HDL) cholesterol, which largely resulted from a reduction in the HDL2 subfraction, which fell by 25.7%. The mean percentage reduction for both low-density lipoprotein (LDL) cholesterol and triglycerides was 7.7%. The median percentage reduction for lipoprotein (a) was 17.6%. CONCLUSIONS: This combination of hormone replacement therapy had profound effects on serum lipids and lipoproteins. According to current concepts, reductions in total and LDL cholesterol, triglycerides, and lipoprotein (a) may reduce cardiovascular disease risk. The reduction in HDL was unexpected, given the rise in HDL that has been demonstrated when desogestrel is combined with ethinyl estradiol in the contraceptive pill. The lowering of HDL observed in this study is undesirable and may be potentially harmful. Our results indicate that when desogestrel 0.15 mg/day is combined with micronized 17 beta-E2 1 mg/day in a continuous manner, the effects of the progestogen on HDL predominate and cause a reduction in HDL and the HDL2 subfraction.

Long-term effects of oral and transdermal hormone replacement therapies on serum lipid and lipoprotein concentrations.

OBJECTIVE: To see whether the short-term changes in serum lipid and lipoprotein concentrations induced by postmenopausal estrogen-progestin therapy are maintained in the long term. METHODS: Sixty-one healthy postmenopausal women were randomized to either oral therapy (continuous conjugated equine estrogens at 0.625 mg/day with sequential dl-norgestrel at 0.15 mg/day for 12 days each cycle) or transdermal therapy (patches delivering continuous 17 beta-estradiol [E2] at 0.05 mg/day with sequential norethindrone acetate at 0.25 mg/day for 14 days each cycle). Twenty-nine healthy postmenopausal women who did not request therapy served as a reference group. Fasting serum lipid and lipoprotein concentrations were monitored for 3 years. RESULTS: Studied in the estrogen-progestin phase, oral and transdermal therapies reduced serum total cholesterol concentrations by 12.1% (P < .001) and 8.4% (P < .001), respectively, and those of low-density lipoprotein (LDL) by 14.2% (P < .001) and 6.6% (P < .01), respectively. These changes, apparent at 3 months, were maintained over 3 years. Serum triglyceride concentrations fell by 2.5% (P < .05) and 16.4% (P < .01), respectively. These decreases were evident after 6 months in both groups but were maintained over 3 years only in the transdermal group. High-density lipoprotein (HDL) concentrations fell in women given oral therapy (7.8%, P < .05) and transdermal therapy (10.7%, P < .001), as well as in untreated women (7.0%, P < .05). CONCLUSIONS: The potentially beneficial effects of estrogen-progestin therapy on serum total and LDL cholesterol and on triglycerides were maintained over 3 years. Interpretation of the potentially detrimental effects on HDL concentrations was hindered by the changes seen in untreated women.

The temporal effect of progestogen on uterine artery pulsatility index in postmenopausal women receiving sequential hormone replacement therapy.

OBJECTIVE: To determine the time relationship between the ingestion of progestogen during sequential hormone replacement therapy (HRT) and impedance to blood flow in the uterine arteries. DESIGN: Nine postmenopausal women who had already received HRT for at least 6 months were treated with either transdermal 17 beta-E2, 0.1 mg/d, or conjugated equine estrogens (Es), 1.25 mg/d, to which norethindrone, 0.7 mg/d, was added for 12 days in a single 28-day cycle of therapy. Transvaginal ultrasonography with color flow imaging was used to measure the pulsatility index (PI) in the uterine arteries every 3 to 5 days over one 28-day treatment cycle. RESULTS: The ingestion of norethindrone increased the mean uterine artery PI by 30% (SE 16.4%). The PI fell significantly within 4 days of ceasing norethindrone. CONCLUSION: Progestogen addition in sequential HRT causes changes in the uterine arterial tone, but the effect subsides within 4 days of progestogen withdrawal.

Paradoxical effects of hormone replacement therapy on breast tenderness in postmenopausal women.

We have studied the effect of HRT on breast tenderness in 61 postmenopausal women randomised to oral or transdermal sequential HRT. An untreated reference group of 29 postmenopausal women was studied concurrently. A questionnaire concerning breast tenderness was administered before and after 10, 12 and 24 weeks of treatment (n = 60) and on 3 occasions at 3-month intervals in the reference group (n = 28). In 10 women with frequent tenderness at baseline, HRT resulted in a reduction at 10 weeks (P < 0.05), which was maintained at 24 weeks (P < 0.05). In contrast, 10 women with infrequent tenderness before treatment reported worsening of tenderness at the 10-week visit (P < 0.01 for transdermal, P < 0.05 for oral), which was not significantly different from the baseline thereafter. These 10 women were older (P < 0.05), and further from the menopause (P < 0.05) than the remaining 40 women who did not develop more frequent tenderness. No significant changes occurred in the reference group. HRT may cause transient breast tenderness, especially in older women and those furthest from the menopause. Paradoxically, it may relieve this symptom in women who have breast tenderness prior to treatment. Breast tenderness should not be considered a contraindication to HRT.

Women's views on and adherence to low-molecular-weight heparin therapy during pregnancy and the puerperium.

BACKGROUND: Non-adherence to prescribed medication represents a significant factor associated with treatment failure. Pregnant women identified at risk of venous thromboembolism are increasingly being prescribed low-molecular-weight heparin (LMWH) during pregnancy and the puerperium. It is important to understand women's views on and adherence to LMWH during pregnancy and the puerperium, so that women gain maximum benefit from the treatment. OBJECTIVES: To monitor women's adherence to enoxaparin, when prescribed during pregnancy and the puerperium, and explore their beliefs about the enoxaparin therapy prescribed. PATIENTS/METHODS: A prospective cohort study involving 95 nullparous and multiparous women prescribed enoxaparin for recognized antenatal indications. Adherence to enoxaparin was assessed through self-completion of a diary, additionally verified through laboratory tests. An adapted beliefs about medication questionnaire was administered to women during their pregnancy. RESULTS: Women were highly adherent to enoxaparin: antenatally, mean percentage adherence 97.92%; postnatally, mean percentage adherence 93.37% (paired t-test, P = 0.000). In the cohort of women we followed, their perceived necessity for enoxaparin therapy outweighed any concerns they had regarding enoxaparin antenatally, necessity-concerns differential 2.20. In some women, however, this perceived necessity does decrease postnatally. CONCLUSIONS: Our results suggest that most women prescribed enoxaparin are highly adherent to their therapy during the antenatal period and that women's antenatal beliefs about enoxaparin are able to predict a decrease in postnatal adherence. Our results have important clinical implications, particularly when women are initiated on LMWH just during the postnatal period.

The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy.

BACKGROUND: The metabolism of estrogen contained within hormone replacement therapy (HRT) is influenced by the route of administration, and this may affect the risk of venous thromboembolism. Thrombin generation, a global coagulation assay, is a marker of hypercoagulability and is of potential use in determining the thrombotic risk associated with particular HRT administration routes. OBJECTIVES: To determine whether any effect of oral and transdermal HRT on thrombin generation is related to the plasma estrogen profile. METHODS: We investigated the effects of oral, transdermal and no HRT (controls) in 52, 39 and 52 postmenopausal women, respectively, on thrombin generation, standard markers of thrombophilia, estradiol level and estrone level. RESULTS: All parameters of thrombin generation were altered in women using oral HRT as compared with controls (P<0.001 for all comparisons). No such differences were found in women using transdermal HRT. Estrone levels correlated with peak thrombin generation (R=0.451, P<0.001) in women using oral HRT, but there was no correlation in women using the transdermal route. CONCLUSIONS: Thrombin generation is significantly increased in women who use HRT administered by the oral route. This is probably mediated by the hepatic first-pass metabolism of estrone, the main metabolite of oral estradiol, which is avoided by the transdermal route. The effect of estrone on thrombin generation may provide the explanation for the higher thrombotic risk seen in women using oral rather than transdermal HRT.

Alternatives to HRT in prevention and treatment.

Oestrogen hormone replacement therapy remains the first choice for the treatment and prevention of osteoporosis in postmenopausal women, but for patients who are unsuitable for this therapy, which of course includes men, other satisfactory treatments are available. Several placebo-controlled studies have demonstrated that bisphosphonates and calcitonin prevent bone loss or perhaps increase bone density over 2-3-year periods, and reduce the rate of fracture. It is not known whether these treatments will increase bone density over longer periods of time. Cyclical etidronate has recently become licensed in the UK for use in the treatment of osteoporosis, and it is hoped that other bisphosphonates and intranasal calcitonin will soon be added to the available treatments. Fluoride appears to increase bone density but, at doses above a very narrow therapeutic window, it increases the fracture rate, either because of bone redistribution, formation of poor quality bone or a toxic effect on osteoblasts. At present, fluoride remains a treatment to be used only under expert supervision or within the context of controlled clinical trials. Anabolic steroids may be of value in selected elderly patients with osteoporosis. The patient may be able to contribute to the prevention of osteoporotic fracture by exercising, which will improve dexterity and may have a small effect to increase bone density, and by avoiding the factors that predispose to falls, such as icy paths and excess alcohol. Changes in the diet are unlikely to play a major role in the maintenance of bone density in women living in the Western world.

Management of the menopause.

The management of the peri- or postmenopausal patient, whether symptomatic or asymptomatic, involves a careful assessment of the problems and expectations of each patient and the matching of appropriate treatment to their needs. The effects of the menopause and its treatment on the patient's immediate and long-term health must be taken into account. This may involve consideration of aspects of medical topics as diverse as gynaecological endocrinology, bone metabolism, oncology and cardiology. Although the benefits of oestrogen therapy are well established the response to therapy must be carefully monitored. Vigilance in the monitoring and seeking out of adverse effects both in individuals and populations must continue to ensure that any problems with this form of therapy are detected at the earliest possible stage.

Differences in the pattern visual evoked potential between pregnant and non-pregnant women.

It has been proposed that latencies of some components of the pattern-reversal visual evoked potential (PRVEP) are shorter in women than in men because of differences in levels of circulating sex steroids. Pregnancy is a time when serum levels of oestrogen and progestogen are considerably greater than in the non-pregnant state. Whole and half field PRVEP latencies and amplitudes have been compared in 16 pregnant and 38 healthy non-pregnant women. The mean P100 latencies for all responses were shorter in the pregnant women, with statistically significant differences for the left eye whole field latency (P < 0.05) and the left eye right and left half field latencies (P < 0.005 and P < 0.05, respectively) and the right eye right half field latency (P < 0.05). The latencies in women in the pregnant group showed a negative correlation with gestation, which reached statistical significance for the REWF (r = -0.55, P < 0.05). These observed differences in PRVEP latencies in pregnant and non-pregnant women and the association between latency and gestation are likely to be due to differences in circulating sex steroids, and this effect may be the principal reason for latency differences between the sexes.

The practicalities of hormone replacement therapy.

An appropriate regimen of HRT using oestrogen with or without progestogen can be found for the majority of patients. In many cases this will be the first or second therapy that is chosen and for most women will be one of the combination packs that are commercially available. In a significant number of patients, however, these formulations will either not control symptoms or bleeding or will cause unacceptable progestogenic side-effects. Separate prescribing of oestrogen and progestogen will then be required. We suspect that the reported low compliance of women taking HRT in the general population may be related to the deficiencies of the available combination packs and reluctance of physicians to separately prescribe the oestrogen and progestogen components of HRT. The latter is understandable as the literature contains so few guidelines concerning prescribing. It is hoped that progestogens that have less side-effects than the C-19 steroids (currently universally used in combination packs of HRT) will be incorporated into new formulations. The option of prescribing oestrogens to non-hysterectomized women in the form of continuous combined therapy is not available to many physicians because the necessary endometrial sampling every 12-18 months cannot be arranged; the current outpatient methods of sampling require experience of manipulation of instruments within the uterine cavity that is usually only acquired during gynaecological training. There are still many uncertainties about the appropriate combination of oestrogen and progestogen that should be incorporated into a continuous combined regimen to avoid the troublesome bleeding that occurs in a significant proportion of women when starting this therapy. Many previous studies were seriously flawed and further research, carefully designed and conducted, is urgently needed.

Uterine artery blood flow parameters in women with dysfunctional uterine bleeding and uterine fibroids: the effects of tranexamic acid.

The objective of this study was to investigate the effects of tranexamic acid on uterine vascular resistance in women with dysfunctional uterine bleeding and in women with menorrhagia associated with fibroids. A longitudinal, prospective study was carried out in premenopausal women referred to a gynecological outpatient department with a complaint of menorrhagia. We studied 24 women with dysfunctional uterine bleeding (mean age 38.8 years; normal ultrasound examination, hysteroscopy and endometrial biopsy) and 12 women (mean age 42.8 years) with at least one fibroid greater than 2.0 cm on ultrasound examination. None were on any form of oral contraception or other medication which could influence uterine vascular resistance. All women had normal coagulation and thyroid function tests. Transvaginal scanning was performed using an Aloka SSD 650 machine with a 5-MHz probe and pulsed Doppler. Pulsatility index (PI) and resistance index (RI) were measured from the left and right uterine arteries before and during the second month of treatment with tranexamic acid (1 g orally three times a day). Menstrual blood loss was assessed using a validated pictorial blood chart. In women with dysfunctional uterine bleeding, the mean PI and RI fell significantly with treatment (PI 2.20-1.94, p = 0.0001; RI 0.81-0.77, p = 0.003). There was a reduction of approximately 30% in menstrual blood loss with treatment (210.0-137.6 ml, p = 0.0001). In women with uterine fibroids, there was no significant change in either the PI or the RI with treatment and there was no significant reduction in menstrual blood loss. We conclude that tranexamic acid significantly reduces uterine artery vascular resistance in women with dysfunctional uterine bleeding. This effect is unlikely to be a mechanism for the action of tranexamic acid in reducing menstrual blood loss but may have important implications for women taking this treatment in the long term.

Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss.

Transdermal hormone replacement therapy (HRT) is now an accepted form of treatment, but the long-term skeletal effects have not been assessed. Sixty-six early postmenopausal women were randomized to receive either transdermal HRT (continuous 17 beta-oestradiol 0.05 mg/day, with 0.25 mg/day of norethisterone acetate added for 14 days of each 28-day cycle) or oral HRT (continuous conjugated equine oestrogens 0.625 mg/day, with 0.15 mg/day dl-norgestrel added for 12 days of each 28-day cycle). Treatment was given for 3 years and 30 matched untreated women were studied concurrently as a control group. Bone density was measured in the lumbar spine and proximal femur by dual-photon absorptiometry at 6-monthly intervals. Bone turnover was assessed by measurement of biochemical markers. At 3 years bone density had declined by 4% in the lumbar spine and by more than 5% in the femoral neck in the untreated group. By comparison bone density increased in both treatment groups at both sites (p < 0.001 vs. untreated) and biochemical measurements indicated a significant reduction in bone turnover. There were no significant differences between the treatment groups. Twelve per cent of women on transdermal or oral treatments lost a significant amount of bone from the femoral neck by 3 years despite adequate compliance. Women taking therapy primarily for hip fracture prevention may require a follow-up bone density measurement to establish the efficacy of treatment.

Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis.

In a randomized, double-blind, placebo-controlled trial, we have studied the effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and biochemical markers of bone turnover over a period of 2 years. Our study comprised 117 Caucasian postmenopausal women, otherwise healthy apart from reduced bone density. They received either intranasal synthetic SCT (200 IU either three times weekly or daily) or placebo. Compared with placebo, daily intranasal calcitonin resulted in no significant bone loss in the lumbar spine, as assessed by dual photon absorptiometry, over the 2-year study period (P < 0.02). In this group, women more than 5 years postmenopause, with the lowest baseline bone mass, showed the greatest response to this treatment, with a total increase placebo in lumbar spine BMD of 3.1%. Significant spinal bone loss (P < 0.005) occurred in women receiving either placebo or thrice-weekly calcitonin. Although the rates of bone loss in the proximal femur were not significantly different in the three groups, there were differences over time. Whereas bone loss in the daily calcitonin group was insignificant, women who received placebo or thrice-weekly calcitonin experienced significant bone loss (P < 0. 001). No significant changes in biochemical markers were observed in any group. Therapy was well tolerated and there were no significant treatment-related adverse events. We conclude that intranasal SCT 200 IU daily is effective and safe for the prevention of bone loss in postmenopausal women with reduced bone mass.