Search

Objective: To determine the effects of tibolone or oestradiol (E(2) )/norethisterone acetate (NETA) hormone replacement therapy on glucose and insulin metabolism in postmenopausal women., Design: Single-centre double-blind placebo-controlled randomized clinical trial., Subjects/methods: We randomized 105 healthy postmenopausal women to tibolone 2·5 mg daily, continuous combined oral E(2) 2 mg/NETA 1 mg daily or placebo over a 2-year study. We performed intravenous glucose tolerance tests (IVGTT) with measurements of plasma glucose, insulin and C-peptide concentrations and the IVGTT glucose elimination rate, k. Mathematical modelling was performed to determine measures of insulin sensitivity, S(i) , pancreatic insulin secretion and hepatic and plasma insulin elimination., Results: Tibolone decreased S(i) to 53-63% and k to 72-79% of baseline values but increased IVGTT phase 2 C-peptide concentrations 1·6-1·8-fold and pancreatic insulin secretion 2·2-2·4-fold, so overall IVGTT glucose concentrations were unaffected. Similar, but for k, significantly smaller changes in insulin and C-peptide secretion were seen with E(2) /NETA, also with no effect on overall IVGTT glucose concentrations., Conclusions: Tibolone reduces insulin sensitivity. Healthy postmenopausal women seem able to compensate for this and maintain normal postload glucose concentrations, but it may not be advisable to prescribe tibolone to women with, or at increased risk for, diabetes., (© 2012 Blackwell Publishing Ltd.)

Whether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40-65 years, entered a prospective, double-blind, randomized, placebo-controlled clinical trial; 55 women completed the 6-month study. Women received either transdermal oestradiol 17beta 0.05 mg and norethisterone acetate 0.125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E-selectin (P < 0.01), and angiotensin-converting-enzyme (ACE; P = 0.05). Cholesterol (P < 0.05), low-density lipoproteins (LDL; P < 0.05), high-density lipoprotein3 (HDL3; P < 0.05) and apolipoproteins AII (P < 0.05) and B (P < 0.05), and fasting insulin (P < 0.05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0.01) and plasminogen activator inhibitor-1 and fibrin D-dimer increased (P < 0.05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0.05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)-2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.

Few studies have examined the effects of 17beta-estradiol on parameters of insulin and glucose metabolism. We studied 42 healthy, untreated postmenopausal women seeking relief from menopausal symptoms. They were randomized to receive either oral 17beta-estradiol 2 mg daily combined with sequential oral norethindrone acetate (NETA) 1 mg daily from days 12 to 22, or transdermal 17beta-estradiol 0.05 mg daily combined with sequential oral NETA 1 mg daily from days 17 to 28. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and after 46 weeks (estrogen-alone phase) and 48 weeks (combined phase) of completed therapy. Mathematical modeling analysis of plasma glucose, insulin, and C-peptide concentration profiles provided measures of insulin resistance, secretion, and elimination. Both types of therapy were associated with a decrease in fasting insulin and glucose levels. Insulin sensitivity was increased by oral estradiol during the estrogen-alone phase but was reversed by the addition of NETA. Transdermal estradiol did not affect insulin sensitivity. Hepatic insulin uptake and insulin secretion were increased with both types of treatment. The oral regimen of estradiol therapy was favorable to both insulin elimination and sensitivity. Transdermal estradiol therapy had relatively few effects on insulin metabolism.

Objectives: This study was designed to assess the incidence of amenorrhea with continuous combined therapy by using two different progestogens and to determine whether early bleeding predicts subsequent bleeding and endometrial response., Study Design: Seventy-nine postmenopausal women on sequential estrogen-progestogen treatment were switched to continuous combined estrogen-progestogen therapy comprising conjugated equine estrogens 0.625 mg daily with either norethindrone acetate 0.35 mg twice daily or medroxyprogesterone acetate 2.5 mg twice daily added continuously for 78 weeks. All bleeding was recorded, and endometrial biopsies were performed at 26 and 78 weeks., Results: Only one third of the women who starting the study had amenorrhea by week 78, but 46 (62%) of these women had withdrawn, mainly because of chronic irregular bleeding. Endometrial atrophy was observed in the majority of biopsy specimens. The two progestogens had similar effects. Bleeding patterns were useful predictors of subsequent bleeding, but not of endometrial response., Conclusions: Persistent irregular bleeding is common with continuous combined estrogen-progestogen therapy. Women with persistent early bleeding should probably revert to sequential treatment. Regular endometrial sampling is advised.

66 early postmenopausal women were randomised to 28-day cycles of either transdermal hormone replacement therapy--continuous oestradiol 17-beta 0.05 mg daily, with norethisterone acetate 0.25 mg daily for 14 of each 28 days--or oral therapy--continuous conjugated equine oestrogens 0.625 mg daily, with dl-norgestrel 0.15 mg daily for 12 of each 28 days. An untreated reference group of 30 women were studied concurrently. Bone density was measured in the lumbar spine and proximal femur by dual photon absorptiometry at 6-month intervals for 18 months. Skeletal turnover was assessed by serum measurements of calcium, phosphate, and alkaline phosphatase, and by urine estimations of hydroxyproline/creatinine and calcium/creatinine excretion. In both treatment groups by comparison with the untreated groups by comparison with the untreated group, bone density increased in the vertebrae and proximal femur and biochemical measurements indicated a significant reduction in bone turnover.

The effects of adding one of three doses (0.5, 0.75, or 1.0 mg/d) of norethindrone acetate for 12 days each month to continuous, transdermal estradiol (0.05 mg/d) have been determined in a prospective, randomized, multicenter study. Significant symptomatic and psychological improvements were observed and, with one exception, were not opposed by the added progestogen. Distinct redness at the site of last patch application was reported by 10% of patients and faint erythema by 30%. However, less than 5% of patients discontinued treatment because of skin problems. Breakthrough bleeding occurred infrequently and all three doses of norethindrone acetate induced a regular pattern of bleeding with secretory transformation in the endometrium. There was no hyperplasia or carcinoma.

The effects of an oestrogen/progestagen transdermal therapeutic system (TTS) were evaluated in sixteen oestrogen-deficient women. The patients applied conventional oestradiol-TTS for 14 days, then two combined norethisterone acetate/oestradiol patches for a further 14 days. The treatment was repeated for five cycles. Ten patients then underwent metabolic studies. One patient had amenorrhoea, but the rest experienced regular withdrawal bleeding which was seldom heavy. Fourteen endometrial biopsy samples were taken during the fifth treatment cycle; none showed proliferative or hyperplastic features. The effects of transdermal norethisterone acetate on symptoms, lipid metabolism, and psychological status were determined by comparing features in the oestrogen-only phase and in the combined phase; the effects were very mild. These preliminary findings show that transdermal progestagen can be successfully administered in hormone replacement therapy to prevent endometrial proliferation while minimising the adverse effects that may be seen with oral administration.

Nuclear oestrogen-receptor and soluble progesterone-receptor have been measured in postmenopausal endometria from women receiving either Premarin or Premarin plus norethisterone. Oestradiol dehydrogenase has been measured in some samples. It is concluded that the doses of Premarin currently in use have a potent oestrogenic effect on the endometrium. Norethisterone does not affect the amount of oestrogen entering the nucleus but it may temporarily suppress the biological activity of the oestrogen.

Although progestogens protect the endometrium against excessive oestrogen-induced stimulation, they can cause adverse symptomatic and psychological effects and may have undesirable metabolic consequences. Thus, the minimum progestogen dose which results in consistent endometrial transformation should be prescribed. To define this dose for norethisterone and dl-norgestrel, 197 endometrial samples obtained from postmenopausal women receiving conjugated equine oestrogens (0.625 mg or 1.25 mg daily) with one of six doses of norethisterone (or the acetate), or one of three doses of dl-norgestrel added for the first 12 days of each calendar month were examined with the light microscope; 109 samples were also assessed by transmission electron microscopy. There was an inverse relation between the percentage of samples showing proliferative features and the progestogen dose. However, proliferative endometrium was observed in 6% of samples with the highest dose of dl-norgestrel (500 micrograms) and in 3% of samples with 2.5 mg norethisterone. Conversely, complete secretory transformation was observed in 25% of samples with the lowest dose of norethisterone (0.1 mg) and in 40% of samples with 75 micrograms dl-norgestrel. Mild atypical hyperplasia was diagnosed in four samples. There was a wide inter-patient variation in response and none of the nine progestogen dose regimens induced secretory change in every patient.

The major hazard of postmenopausal cyclic estrogen therapy is endometrial hyperstimulation. The incidence of hyperplasia is dose dependent; the incidence of carcinoma is both dose and duration dependent. The risk of carcinoma is small. Invasive procedures such as endometrial biopsy to detect those patients with hyperplasia and carcinoma are unlikely to be cost-effective and have other disadvantages. With cyclic estrogens, biopsies should be performed at regular intervals irrespective of the bleeding pattern. The possible alterations to cyclic treatments to reduce the risk of endometrial hyperstimulation have been reviewed; only progestogen addition has been shown to be effective. Maximal effects are obtained when progestogens are added for 12 to 13 days each calendar month. To reduce the risk of side effects, the minimum dose of progestogen should be prescribed, and with the nor-testosterone derivatives, a small dose of norethindrone, approximately 1 mg daily, is as effective as 5 mg daily. The smaller doses cause minimal lipid changes. Interpatient variation in response to the 17-hydroxyprogesterone derivatives can occur, and at high doses, adverse lipid effects have been reported. With sequential estrogen/progestogen therapies, the endometrial histology appears to correlate with the bleeding pattern, thereby, perhaps, obviating the need for biopsy. The development of regimens to induce endometrial atrophy and amenorrhea is suboptimal, and further research is required.