Administration Of Hormone Replacement Therapy Research Articles

Effects of norethisterone acetate addition to estradiol in long term HRT

Objective: The aim of this study was to evaluate the efficacy and tolerability of hormone replacement therapy (HRT) among postmenopausal women living in the Lund area of Southern Sweden and to analyze treatment effects in different types or routes of HRT administration, as well as to compare with unopposed estrogen therapy. Method: in an ongoing, large population-based, prospective cohort study, this interim analysis included 3900 women. Of them, 693 postmenopausal women were eligible in the present analyses as they continued to use one of the four commercial HRT products for at least 2–3 years, i.e. continuous oral estradiol (E 2) 2 mg+norethisterone acetate (NETA) 1 mg (CON-O), sequential oral estradiol 2 mg+norethisterone acetate 1 mg (CYC-O), sequential transdermal estradiol 50 μg+norethisterone acetate 250 μg (CYC-TRANS) and estradiol monotherapy. These women completed one generic questionnaire and one specific ‘hormonal’ questionnaire, as well as a personal interview pertaining to sociodemographics, detailed status of HRT use, and therapeutic efficacy and untoward side-effects by HRT. Results: comparing the three combined E 2+NETA groups with E 2 monotherapy, the beneficial effects on sexual desire and emotional well-being were significantly less in the combined groups than in E 2 monotherapy group. There was no significant difference regarding the negative side-effects between the groups. No significant difference was found between CON-O and CYC-O groups either in positive effects or in negative side-effects. A higher prevalence of positive effects was found in CYC-TRANS group than that in CYC-O group, especially in amelioration of sleep and urinary symptoms. Higher odd ratios of negative effects by HRT, such as irregular bleeds, weight gain, food craving and skin disorders were also found in CYC-TRANS group. Conclusion: in long-term HRT administration, the addition of a progestogen in HRT could compromize the beneficial effects of estradiol, particularly, the effects on women's emotional well being and psychosexual functioning. Administration of NETA continuously and sequentially had similar therapeutic efficacy and tolerability. More marked positive effects, such as improving of sleep and urinary symptoms, as well as nuisance side-effects, i.e. irregular bleeds, weight gain, food craving and skin disorders were encountered by the women using sequential transdermal regimen

Cardioprotective effects of ovarian hormones and the HERS in perspective

The increased population of women in menopause living in the industrialized countries is associated with an increase of diseases which are dependent or facilitated by a state of estrogen deficiency such as cardiovascular and cerebrovascular diseases. Several studies have shown that estrogen replacement therapy reduces the occurence of coronary and may be of cerebrovascular disease by nearly 50% in treated women compared to non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls as well as a direct effect on the vessel wall. Progestins may, in some cases, counteract the beneficial effect of estrogens upon cardiovascular functions. More androgenic progestins may have a detrimental effect upon vascular reactivity while less androgenic progestins seem not to reduce the beneficial effect of estrogens. Of interest, continuous combined administration of hormone replacement therapy seem to be preferable for women with coronary artery disease or for those with increased cardiovascular risk. Case-control and cohort studies have shown that estrogen progestin therapy is associated with a significant reduction of cardiovascular mortality and morbidity. The HERS study has added critical data regarding the cardioprotective effect of hormone replacement therapy in elderly women with proven coronary artery disease. Because of the several methodological and statistical flaws of the HERS study, further studies are warranted to evaluate the effect of hormone replacement therapy on cardiovascular prognosis. Large scale randomized studies will evaluate the effect of estrogen and estrogen–progestin replacement therapy upon cardiovascular events in menopausal women. Until completion of these studies hormone replacement therapy in women with increased cardiovascular risk should be seen with no enthusiasm but also with no fear.

Serum level of vascular endothelial growth factor is decreased by hormone replacement therapy in postmenopausal women without hypercholesterolemia

The administration of hormone replacement therapy (HRT) to postmenopausal women (PMW) reportedly has beneficial effects on their levels of lipid and lipoproteins. Estrogen retards the development of atherosclerosis induced by a high-fat diet in animals. Although vascular endothelial growth factor (VEGF) may be involved in the development of atherosclerosis in humans, there is no information on effect of estrogen administration on VEGF level and lipid metabolism. We evaluated 64 healthy normotensive or hypertensive PMW before and during the administration of HRT (0.625 mg conjugated equine estrogen combined with 2.5 mg medroxyprogesterone acetate orally) daily for 6 months. All hypertensive PMW were well-controlled on antihypertensive drug therapy. According to their total cholesterol level at baseline, we divided the PMW with HRT ( n=54) into a normocholesterolemic group (NC, total cholesterol <220 mg/dl, n=35) and a hypercholesterolemic group (HC, total cholesterol ≥220 mg/dl, n=19). We evaluated the serum levels of VEGF at baseline, and again at 3 and 6 months after starting HRT. HRT significantly ( P<0.01) reduced the mean VEGF level from 31.5±4.3 pg/ml at baseline to 18.2±2.3 pg/ml after 6 months in the NC group. However, the VEGF levels in the HC group and the control group exhibited no significant change at either 3 or 6 months after starting HRT. In summary, HRT, using a combination of conjugated equine estrogen and medroxyprogesterone acetate, reduced the level of VEGF in normocholesterolemic PMW more effectively than in those with hypercholesterolemia.

Hormone replacement therapy in postmenopausal women with essential hypertension increases circulating plasma levels of bradykinin

Hormone replacement therapy (HRT) reduces the incidence of cardiovascular disease (CVD) in postmenopausal women (PMW). Recently, it has been reported that HRT declines angiotensin converting enzyme (ACE) activity, which may be one of the factors protecting against CVD. We measured the plasma levels of bradykinin, which would be expected to increase because the bradykinin-degrading enzyme (kinase II) is the same as ACE. Treatment with conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/day) was given for 3 months as HRT to 19 hypertensive and 19 normotensive PMW. Plasma bradykinin and ACE activity levels were measured at baseline and after 3 months of HRT. The plasma levels of ACE activity in both the hypertensive and normotensive PMW were significantly reduced by HRT. The plasma levels of bradykinin in the hypertensive PMW were significantly increased by HRT, whereas the administration of HRT tended to increase plasma levels of bradykinin in the normotensive PMW. The increased bradykinin levels with a concomitant decrease of plasma ACE activity by HRT in hypertensive PMW seem to be beneficial for reducing the risk of CVD.

Prospective, randomized, controlled study of the effect of hormone replacement therapy on peripheral blood flow velocity in postmenopausal women

Objective: To investigate the effect of different types and methods of delivery of hormone replacement therapy (HRT) on peripheral vascular flow velocity in postmenopausal women. Design: A prospective, randomized, operator-blinded, controlled study. Setting: A hormone replacement clinic in a university teaching hospital. Patient(s): Sixty-eight women who had undergone surgical menopause. Intervention(s): No treatment, oral estrogen, continuous combined estrogen and progestogen, or percutaneous estrogen. Main Outcome Measure(s): The pulsatility indices of the brachial, dorsalis pedis, popliteal, and radial arteries were measured under standardized conditions before the commencement of HRT and after 2 and 6 months of treatment. Serum E 2 levels were measured at each visit. Result(s): There was an inverse correlation between the serum E 2 levels and the pulsatility indices. There was a significant reduction in the pulsatility index in at least one of the four arteries after 2 months of HRT in all the treatment groups but not in the control group. The effect of HRT on the pulsatility index persisted until the completion of the study in all the treatment groups. Conclusion(s): These results confirm that the administration of HRT is associated with a reduction of the pulsatility index, and hence an increase in blood flow in the peripheral arteries; this change in the pulsatility index is related directly to serum E 2 levels. The percutaneous route of administration of estrogen was at least as effective as oral treatment in improving peripheral vascular flow velocity. The beneficial effect of estrogen was not affected by the addition of a progestogen.

Relationship between apolipoprotein E polymorphism, menopausal symptoms, and serum lipids during hormone replacement therapy

Objective: Menopausal women receive hormone replacement therapy (HRT) to relieve symptoms and to help prevent osteoporosis or atherosclerotic disease. We investigated the association of apolipoprotein (apo) E polymorphism with menopausal symptoms, body fat mass and lipid profile in 236 women, together with the lipid changes accompanying HRT administration in 172 women from this population who were postmenopausal. Study design: The subjects were divided into three groups according to apo E phenotype: group E2, apo E2/2 and 2/3; group E3, apo E3/3; group E4, apo E4/3 and 4/4. Typical menopausal symptoms were classified into four degrees of severity; body fat mass, lipid profile, and serum lipid levels were measured before and 6 months after oral HRT. Results: There were no significant differences between the symptoms of the three groups. The serum levels of apo E were the highest in group E2 and lowest in group E4. Analogous tendencies were seen in the mean levels of, and apo B, with group E4 having total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) the highest levels and group E2 the lowest. Triglyceride levels (TG) were the highest in group E2, but the difference was not significant. These parameters suggest that group E4 had the highest risk of cardiovascular disease. The LDL-C/high density lipoprotein cholesterol (HDL-C) ratio was improved from 2.18 before HRT to 1.52 after HRT in group E2; from 2.26 to 1.92 in group E3; and from 2.57 to 2.10 in group E4. Conclusion: The apo E phenotype was not associated with any difference in menopausal symptoms. Group E4 had the highest risk for cardiovascular disease, and group E2 the lowest. Oral HRT could be recommended for the women in group E4.

Sex-hormone binding globulin as an indicator of the hepatic impacts of continuous combined hormone replacement regimens

Objectives: Nonoral administration of hormone replacement therapy avoids the first pass metabolism of steroids in the liver. We wanted to determine to what extent it has an effect on the serum concentrations of sex-hormone binding globulin and the free testosterone index. Methods: Postmenopausal women received 50 μg per day transdermal estradiol associated with the use of a levonorgestrel-releasing intrauterine device (20 women) or a daily oral dose of 2 mg of estradiol and 1 mg of norethisterone acetate (20 women) for 1 year. Eight women, five in the nonoral and three in the oral therapy group discontinued the study. Results: Although serum sex-hormone binding globulin concentrations decreased in women receiving transdermal estradiol in combination with a levonorgestrel-releasing intrauterine device, the free testosterone index did not change significantly. In the continuous oral regimen, no significant changes in serum sex-hormone binding globulin or free testosterone index were observed. The free testosterone index, however, was significantly higher in the nonoral therapy group after 6 and 12 months of treatment than in the oral therapy group. Conclusions: Continuous progestin combined with continuous estrogen in oral and nonoral replacement therapy does not lead to a substantial androgenic excess in postmenopausal women. The intrauterine administration of levonorgestrel appears to have some hepatic effect.

The effects of ovarian hormone deficiency on wound contraction in a rat model.

To demonstrate the effect of a deficiency of ovarian hormones on the process of wound contraction, using the oophorectomised rat model of the human menopause. A randomised controlled trial. Ninety-six adult Wistar rats were randomly allocated into either an oophorectomised group or a sham-oophorectomised control group. Having confirmed a significant reduction in plasma oestradiol levels in the oophorectomised rats, full-thickness excised lesions were made in the flank skin of the adult rats at either two weeks or four months after oophorectomy, so that the effects of two different durations of hormone deficiency could be assessed and compared with the sham-oophorectomised controls. Following wounding, the rats were left for 3, 5, 10 or 22 days; wound contraction was assessed from photographs of the wounds taken at these intervals after injury. In the rats wounded four months after oophorectomy there was a slower rate of wound contraction, resulting in larger wounds at days 3, 5, 10 and 22, compared with control rats. No significant difference was observed in rats wounded two weeks after oophorectomy, indicating that the effects of ovarian hormone deficiency on this process are delayed. Due to the pivotal role of wound contraction in the process of wound healing these findings may be of clinical relevance and could have an important impact on the administration of hormone replacement therapy.

Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels.

The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.

A preliminary study on the effect of hormone replacement therapy on peripheral flow velocity in postmenopausal women.

Apart from predisposing to the formation of atherosclerosis in the coronary and cerebrovascular circulation, the menopause is also associated with an increased risk of developing peripheral vascular disease. The aim of this observational study was to determine whether the administration of hormone replacement therapy (HRT) had any effect on peripheral flow velocity in postmenopausal women. Changes in peripheral resistance were recorded in 11 healthy postmenopausal women using Doppler ultrasound. The pulsatility index (PI) of the brachial, radial, dorsalis pedis and popliteal arteries was measured before treatment and every 2 months after the commencement of HRT for 6 months. There was a significant decrease in the PI of the radial and dorsalis pedis arteries after HRT, and there were also reductions in the PI of the brachial and popliteal arteries which were not statistically significant. These changes persisted over the complete study period. Our findings suggest that the administration of HRT will have a beneficial effect on peripheral flow velocity in postmenopausal woman. These changes require confirmation in a larger controlled trial.

Clinical Trials Report: Oncologic, Endocrine &amp; Metabolic: Clinical trials in progress with hormone replacement therapy

Hormone replacement therapy (HRT) has been heralded as a medical breakthrough for improving the quality of life experienced by post-menopausal women. HRT is most commonly used for the treatment of climacteric symptoms. In addition, complications arising from/exacerbated by oestrogen deficiency, such as oesteoporosis and hypercholesterolaemia, may be minimised by HRT administration. Earlier epidemiological studies have suggested that long-term HRT usage is associated with an increase in breast cancer risk. However, the results from these trials are conflicting and this may be due to differences in study design and population bias which affect study interpretation. Ongoing and future randomised, prospective trials in the UK and USA should shed more light on this important issue but oncology data will not be available for at least ten years. Furthermore, it is hoped that the question of whether HRT is of benefit as a secondary prevention agent in the treatment of established cardiovascular disease will be an...

The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation.

Long permanent remissions in malignant hematopoietic disorders can often be achieved by autologous bone marrow transplantation (ABMT) or by allogenic bone marrow transplantation (BMT). Previous studies have shown that such therapies may induce osteoporosis due to iatrogenic ovarian failure. The administration of hormone replacement therapy (HRT) in these women could prevent the adverse effects of long-term ovarian failure without remarkable side effects. The aim of this study was to evaluate how the bone mass is affected by HRT in patients undergoing ABMT or BMT adjusting the results for age, weight, and height. Thirteen women with previous ABMT/BMT were treated with a standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or with 50 micrograms/day of 17-beta-estradiol in transdermal therapeutic systems (TTS) plus 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Bone mass was measured prior to and 12 months following HRT. Blood samples were collected before therapy and during the 6th and 12th treatment months. The mean time elapsed between bone transplantation and HRT initiation was 13.0 months (range 3-26 months). Before treatment nine patients were osteopenic and after HRT bone mass increased in all cases. Following ABMT/BMT, hepatic hyperenzymemia was detected in three patients. After 6 and 12 months of treatment no significant changes were observed in hepatic enzymes. Although hepatic hyperenzymemia is commonly considered as a contraindication for HRT, our results suggest that HRT is safe for these patients and that such therapy should be initiated after transplantation in women to prevent adverse effects of long-term ovarian failure.

Management of hormone replacement therapy: the Italian experience

Objectives: To review the characteristics of users and prescribers of hormone replacement therapy (HRT) in Italy, to attempt to explain the low uptake of this therapy. Methods: A review of the published literature and prescription data. Results: As in many other Western countries, gynaecologists are the main prescribers of HRT in terms of the number of prescriptions/physician/year. However, because general practitioners renew specialists' prescriptions several times a year, they are responsible for the greatest prescription volume. Overall GPs are responsible for 77.6% of HRT prescriptions while gynaecologists account for 20.7%. The attitude of gynaecologists and GPs to HRT is still equivocal and this may be a major factor in the low uptake. The percentage uptake is higher in northern and central Italy than in the south and it has been suggested that women in the hotter southern areas may suffer less from hot flushes. The evidence for this, however, is anecdotal. A recent study in Milan showed that the use of HRT was strongly correlated to social class and level of education. Women with 12 years of education or more were three times more likely to use HRT than those with less than 7 years education. There seemed to be no relationship between marital status and HRT use but fewer parous women used it and use decreased with an increasing number of children. In addition postmenopausal osteoporosis is not yet a registered indication for transdermal HRT, the major route of HRT administration in Italy. Conclusions: An increased uptake is expected in the future due to increased media interest and the greater availability and steady increase of transdermal HRT use over the last 5 years.

Antagonism of oestrogen-induced prolactin release by medroxyprogesterone acetate

Previous studies conducted at our clinic suggested that the administration of hormone replacement therapy (HRT) in postmenopausal women could result in the inhibition of oestrogen-induced prolactin (PRL) release. The aim of this study was to determine how the pituitary function is affected by the sequential addition of medroxyprogesterone acetate (MPA) to oestrogen replacement therapy. Twenty-one postmenopausal women receiving no other medication were treated with a standard dose (0.625 mg/day) of conjugated equine oestrogens (CEE) for a period of 24 days, plus 5 mg/day MPA added sequentially during the last 12 days of the oestrogen therapy. Blood samples were collected before treatment, during oestrogen and oestrogen-progestogen administration and after cessation of treatment. Folliclestimulating hormone (FSH), luteinizing hormone (LH), 17β-oestradiol (E 2) and PRL levels were studied. During treatment gonadotrophin concentrations decreased significantly, while after cessation of HRT the levels of FSH and LH increased. These gonadotrophin fluctuations indicated a sharp rise in E 2 levels during therapy and a significant decrease during the treatment-free period. PRL levels were found to be higher during CEE therapy, but they fell when patients received CEE in combination with MPA. These observations suggest that the role of progestogens in a variety of experimental and clinically relevant situations needs to be investigated not only as regards their direct action but also their modulation of the effect of oestrogen.

Hormone Replacement Therapy by the Transdermal Administration of Oestradiol and Norethisterone

Norman-Taylor, J. Q.; Crawford, F. E.; Jenkins, A. W.; Grudzinskas, J. G. Author Information

Hormone replacement therapy by the transdermal administration of oestradiol and norethisterone

The objective was to assess the efficacy and acceptability of a new transdermal norethisterone device as part of a hormone replacement therapy (HRT) regimen. The design was an open prospective clinical assessment for 6 months. The setting was the Academic Unit of Obstetrics and Gynaecology, Royal London Hospital, Whitechapel, London. Eighteen patients of confirmed menopausal status were recruited. Therapy consisted of continuous application of Estraderm TTS 50 (Ciba Laboratories) for a 28-day period, with the additional application of two norethisterone acetate patches in the last 12 days of this period. This schedule was repeated for six cycles. The main outcome measures were symptom and menstrual data —haematological indices, hepatic and renal function; lipid parameters; endometrial biopsy. The results showed a significant improvement in the patients' symptoms of hot flushes and sweating ( P = 0.03). Of the 15 women who completed at least 6 months of medication, withdrawal vaginal bleeding was established at regular intervals in 9. One patient had a local irritant reaction to the patch. There were no significant changes observed in haematological indices, hepatic and renal function. There was a slight but not statistically significant decrease in the HDL cholesterol fraction when the patient was in the norethisterone phase of the cycle, but no change was observed between the beginning and end of the study. Histological examination of the endometrial biopsies showed features of secretory activity in 56% of samples after 6 months. There was no evidence of hyperplasia, pre-malignant or malignant changes in the remaining biopsies. The conclusion was that combined transdermal administration of oestradiol and cyclical norethisterone is likely to be an effective mode of administration of HRT. No adverse biochemical or haematological changes were demonstrated, the clinical significance of the decrease in HDL cholesterol fraction is uncertain. Histological changes demonstrated were compatible with the menstrual data obtained.

Effects of oophorectomy and hormone replacement therapy on pituitary-gonadal function

The purpose of this study was to determine how oophorectomy and different hormone replacement therapy (HRT) regimens using low doses of medroxyprogesterone acetate (MPA, 2.5 mg/day) influence the pituitary-gonadal axis function. Ninety (90) women, who had had regular menses prior to surgery, completed a I-year follow-up period. Patients were assigned to 5 groups. The first ( n = 16) received 0.625 mg/day conjugated equine oestrogens (CEE) cyclically, the second ( n = 20) 50 μday transdermal oestradiol (E 2) cyclically and the third ( n = 15) 0.625 mg/day CEE continuously. These 3 groups also received 2.5 mg MPA sequentially for the last 12 days of HRT administration. The fourth group ( n = 20) received 0.625 mg/day CEE and 2.5 mg/day of MPA continuously, while the fifth ( n = 19) constituted a control group. After oophorectomy all patients showed increases in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and decreases in those of E 2, oestrone (E 1), prolactin (PRL), sex-hormone-binding globulin (SHBG), androstenedione (ΔA 4) and testosterone (T). No changes were detected in dehydroepiandrosterone sulphate (DHEA-S) levels. After HRT, decreases′ in FSH, LH and PRL levels and increases in those of E 2, E 1 and SHBG were observed, but no changes were seen in T, ΔA 4 or DHEA-S plasma levels. As the differences that were found cannot be attributed to the presence of ovaries, it is reasonable to assume that they were perhaps due to the treatment. All these changes, with the exception of a decrease in PRL levels, are therefore to be expected after HRT.

Effects of oophorectomy and hormone replacement therapy on plasma lipids

The aim of this study was to determine the effects on plasma lipids and lipoproteins of oophorectomy and various hormone replacement therapy (HRT) delivery systems using low doses of medroxyprogesterone acetate (MPA, 2.5 mg/day). A total of 90 women completed the l-year follow-up period. Patients were randomly assigned to five groups. The first ( n = 16) received 0.625 mg/day conjugated equine oestrogens (CEE) cyclically, the second ( n = 20) 50 μg/day transdermal oestradiol cyclically and the third ( n = 15) 0.625 mg/day CEE continuously. These three groups also received 2.5 mg MPA sequentially for the last 12 days of HRT administration. The fourth group ( n = 20) received 0.625 mg/day CEE and 2.5 mg/day MPA continuously, while the fifth ( n = 19) constituted a treatment-free control group. After oophorectomy patients showed increases in low-density lipoprotein (LDL), apolipoprotein B and the atherogenic index, whereas after HRT patients exhibited falls in plasma LDL, apolipoprotein B and the atherogenic index and increases in high-density lipoprotein (HDL) and apolipoprotein A1. No significant changes in total cholesterol were observed after surgery or treatment and decreased levels of triglycerides were detected only in the transdermal treatment group.

The Value of Cervical Colposcopic Assessment in the Management of Genital Hormone Deficiency

ABSTRACT Twenty-nine female patients with symptoms of the climacteric were assessed by serum estradiol determinations, lateral vaginal wall cytology, and cervical colposcopic evaluation of the stigmata of hormone deficiency. The colposcopic assessment correlated with vaginal cytology and estradiol level and adoption of a scoring system allowed evaluation by the colposcope that was reproducible and amenable to quantitation. All assessments showed improvement with the administration of hormone replacement therapy, and the squamocolumnar junction became visible in patients in whom it was not previously visible. Colposcopic visualization of the cervix examines the end-organ response to both endogenous and exogenous hormones and may be used as an aid in the management of the climacteric.