Piperazine oestrone sulphate and interrupted norethisterone in postmenopausal women: effects on bone mass, lipoprotein metabolism, climacteric symptoms, and adverse effects


Correspondence: Dr P. Alexandersen, Center for Clinical and Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark.


Objective To compare the effects of two doses of piperazine oestrone sulphate combined with interrupted norethisterone, with that of oestradiol continuously combined with norethisterone acetate, and with placebo, in postmenopausal women.

Design A prospective randomised trial.

Participants Two hundred postmenopausal women.

Setting Monocentre study with expertise in osteoporosis.

Methods The participants were randomly assigned to two years of treatment with alternating three-day cycles of 1.5 mg of piperazine oestrone sulphate plus 0.7 mg of norethisterone (highEP), or alternating three-day cycles of 0.75 mg of piperaine oestrone sulphate plus 0.35 mg of norethisterone (lowEP), or 2 mg of 17β-oestradiol continuously combined with 1 mg of norethisterone acetate (E2+NETA), or placebo.

Main outcome measures Change in bone mineral density, lipoprotein metabolism, climacteric symptoms, and adverse effects.

Results One hundred and twenty-one women completed the study. Spinal bone mineral density was increased about 9% over two years by E2+NETA, about 6% by highEP, 4% by lowEP, but remained unchanged in the placebo group. The same pattern was seen in the hip and forearm. All hormone regimens decreased markers of bone turnover and alleviated climacteric symptoms. Serum lipoproteins decreased by about 10% in all hormone groups.

Conclusions All hormone regimens studied prevented bone loss completely and lowered serum lipids.


Oestrogens are known to alleviate climacteric symptoms, prevent postmenopausal bone loss and reduce the risk of cardiovascular disease. The effect of combined oestrogen-progestogen replacement on these conditions in postmenopausal women seems to depend on the hormonal type, doses, and route of administration. As the adverse effects of hormone replacement therapy (HRT) are strongly related to the dose, development has focused on treatment regimens with doses of both components as low as possible. For women with an intact uterus a combined oestrogen-progestogen therapy is recommended to avoid an increased risk of endometrial cancer1. Sequential addition of a progestogen usually induces regular bleeding episodes which many women consider inconvenient. This may lead to problems with compliance. With the purpose of avoiding regular withdrawal bleeding, the continuously combined oestrogen-progestogen regimen was introduced2,3. The scientific rationale behind this type of HRT is that continuous administration of a progestogen suppresses DNA synthesis and the formation of oestrogen receptors. As a result, the endometrium is kept atrophic and amenorrhoea usually results2. However, in a continuously combined HRT, the woman is exposed to a relatively high amount of the progestogen which, at least for some types of progestogens, is not beneficial for cardiovascular risk factors, such as high density lipoprotein cholesterol4,5. In order to address both the bleeding problem and the potential loss of cardiovascular protection, the low dose oestrogen and interrupted progestogen type of HRT was introduced6. This regimen is a modification of the continuously combined therapy in which the oestrogen is given continuously, and the progestogen is given in five interrupted periods of three days for a total of 15 days out of a 30-day cycle. In this way, the total dose of progestogen is halved.

The aim of the present study was to characterise the efficacy and safety of two doses of piperazine oestrone sulphate and interrupted progestogen replacement therapy for prevention of bone loss as assessed by measurement of the changes in the spine, the hip, and the nondominant forearm, respectively. Furthermore, the influence on serum lipid and lipoprotein metabolism and alleviation of climacteric symptoms were evaluated, and adverse effects were recorded.


Participants and study design

Four hundred and seventy-one healthy postmenopausal Danish women, all contacted by a questionnaire, were invited to an information meeting about the study (protocol M92-053). Of those invited, 200 women (45–65 years old) were enrolled consecutively in the study, as they met the selection criteria. These criteria included amenorrhoea for at least 12 consecutive months, body mass index (i.e. the body weight [in kg] divided by the height [in m2]) < 35 kg/m2, blood pressure ≤ 160/95 mmHg, and no medication known to affect bone or serum lipid metabolism for at least six months before the study. All participants gave their written informed consent to participate. The study was approved by the local ethics committee and performed according to the Helsinki Declaration II. All procedures complied with the guidelines for clinical studies.

The women participating in the study were assigned consecutively to one of the following two-year treatments by means of simple randomisation: double-blind treatment with sealed sequential and identical boxes containing either placebo (n= 50) or highEP (n= 50): i.e. alternating three-day cycles of oral piperazine oestrone sulphate 1.5 mg daily plus oral norethisterone 0.7 mg daily or lowEP (n= 50): i.e. a similar alternating three-day regimen of oral piperazine oestrone sulphate 0.75 mg daily plus oral norethisterone 0.35 mg daily; or single-blind treatment with E2+NETA (n= 50): i.e. oral 17β-oestradiol 2 mg daily continuously combined with oral norethisterone acetate 1 mg daily. The E2+NETA treatment group was single-blind because the tablets differed in appearance from the others groups. Each participant had the same chance of receiving one of these four treatments.

Treatment codes were sealed and kept at the Center for Clinical and Basic Research throughout the study and were not broken until the completion of the study by all participants. The treatments and the boxes containing the treatments were prepared by the sponsor and the contents were known neither to the participants nor the investigator until after completion of the study. The women were examined every three months during the study, and climacteric symptoms were assessed by the Kuppermann index. This index was determined for each women every three months, based on a weighted function of the severity scores of 11 menopausal symptoms (e.g. vasomotor symptoms, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia and myalgia, headache, palpitation, formication) for each woman on a daily basis. The severity of the Kuppermann index scores were as follows: 0 (none); 1 (slight); 2 (moderate); or 3 (marked). Furthermore, all the women completed a diary card to indicate tablet intake, uterine bleeding and, if present, the severity, and hot flushes (graduated). Adverse events were recorded every three months throughout the study period.

The effect of the treatment regimens on the endometrium was investigated thoroughly as to bleeding pattern, histological and biochemical assessment of endometrial biopsies, and endometrial thickness measured by ultrasonography, as described in detail elsewhere7.

With an expected mean percentage decrease in bone mineral density of 4% in the placebo group and 0% in the hormone groups, and assuming a standard deviation of 6% in each group, 120 women were required in the whole trial (α= 0.05; 1-β= 0.74).

The two oral doses of piperazine oestrone sulphate were chosen because administration of 0.6 mg of piperazine oestrone sulphate has been shown to produce slightly lower blood levels of oestrone and oestradiol than those achieved with 0.6 mg of conjugated equine oestrogens8. Therefore, the dose of piperazine oestrone sulphate expected to be equivalent to 0.625 mg of conjugated equine oestrogens (which is the lowest dose affording protection against postmenopausal osteoporosis9) is about 0.75 mg. The dose of 0.35 mg norethisterone was decided after a phase II study10 demonstrated that a regimen identical to the lowEP regimen of the present study prevented oestrogen-induced endometrial hyperplasia in this group of women. Furthermore, 0.35 mg of norethisterone appears to be approximately equivalent to 5 mg of medroxyprogesterone acetate. As 5 mg of medroxyprogesterone acetate does not completely protect the endometrium against hyperplasia when combined with 1.25 mg of conjugated equine oestrogens11, it was decided to add 0.70 mg of norethisterone to the regimen with 1.5 mg of piperazine oestrone sulphate. The continuously combined E2/NETA group was included as a positive control group receiving one of the most widely used regimens of this type of HRT.


Bone densitometry was performed at baseline (on entrance) and every six months thereafter. Bone mass of the lumbar spine (BMDspine) and proximal nondominant femur (BMDhip) were determined by dual energy X-ray absorptiometry with the QDR-2000 (Hologic Inc, Waltham, Massachusetts, USA). The bone mineral density of the nondominant forearm (BMDarm) was assessed by single energy X-ray absorptiometry with the DTX-100 (Osteometer MediTech A/S, Denmark). The long term in vivo precision for dual energy X-ray absorptiometry was 1%–3%12 and for single energy X-ray absorptiometry 1%–2%13.

Samples of blood and urine were taken at baseline and at 3, 6, 12, 18 and 24 months. Blood and urine samples were collected in the morning after an overnight fast and tobacco abstinence. All the samples were stored immediately after collection at −20°C.

Serum osteocalcin was measured using ELISA, which detects the n-terminal mid-segment of the osteocalcin molecule (N-mid osteocalcin, Osteometer BioTech A/S, Denmark)14. The inter-assay and intra-assay variations were 6.5% and 6%, respectively14. Serum bone-specific alkaline phosphatase was measured by a two-sided IRMA (Tandem-R, Ostase, Hybritech, CA) with an inter-assay and an intra-assay variation of 7%–8% and 4%–7%, respectively15.

Urinary C-terminal telopeptide fragments of type I (collagen were measured by the CrossLaps ELISA (Osteometer BioTech A/S, Denmark) (12). Values of urinary CrossLaps were adjusted for the urinary concentration of creatinine (CrossLaps/Cr). The inter-assay and intra-assay variation of CrossLaps were 6.6% and 5.3%, respectively16.

Total serum cholesterol and serum triglycerides were measured enzymatically by the Cobas Mira Plus (Roche Diagnostic Systems, F. Hoffmann-La Roche, Basel, Switzerland) according to the manufacturer's instructions. High density lipoprotein cholesterol was measured after precipitation with phosphotungstate magnesium chloride of apolipoprotein B-containing lipoproteins17. Low density lipoprotein cholesterol was calculated according to the formula of Friedewald et al.18.

Statistical analysis

Baseline values were used to compare the characteristics of the four groups. One-way analysis of variance (ANOVA) was used for the comparison among groups. If ANOVA revealed a statistical significance, an unpaired t test was performed. The biochemical markers were transformed logarithmically before calculation to achieve normally distributed and homogeneous data. Only the data of the women who completed all 24 months of therapy are used in the statistical analyses of efficacy parameters, but we also undertook an intention-to-treat analysis. This was also used to evaluate adverse events. All analyses were performed with the statistical analysis system (SAS) with a 5% level of significance19. For calculation of response during the study, all baseline values were set at 100% and subsequent values were expressed as a percent of baseline. The changes in the Kuppermann index from baseline to months 3, 6, 12, 18, and follow up (i.e. within 10 days of the last dose of trial medication) found between all groups and between the hormone groups were analysed by ANOVA. The bone mineral density changes per year were calculated by linear regression analysis for each individual from a total of the five bone measurements during the two-year study period. The total averaged responses in the biochemical markers were calculated as the mean of the individual average change in per cent during the study period. The individual changes in serum lipids and lipoproteins during the two-year study period was calculated.


Table 1 gives the baseline characteristics, showing the comparability of the four treatment groups. There was no significant difference between the groups for any of the parameters measured. The baseline values of the women who completed the study did not differ from those of the entire population at entry (data not shown).

Table 1.  Baseline characteristics of the treatment groups. Values are given as mean (SD) or geometric mean [mean − SD to mean +SD]. HighEP = piperazine oestrone sulphate 1.5 mg + interrupted norethisterone 0.7 mg daily; LowEP = piperazine oestrone sulphate 0.75 mg + interrupted norethisterone 0.35 mg daily; E2+NETA = continuous 17β-oestradiol 2 mg + norethisterone acetat 1 mg daily; YSM = years since menopause (as stated by the participants); BMI = body mass index; BMD = bone mineral density; sOC N-mid = serum osteocalcin (N-mid); sB-AP = serum bone specific alkaline phosphatase; uCrossLapdCr = urinary CrossLaps adjusted for urinary creatinine; TC = serum total cholesterol; TG = triglycerides; HDL C = high-density lipoprotein cholesterol; LDL C = low-density lipoprotein cholesterol.
 HighEP (n= 50)LowEP (n= 50)E2+NETA (n= 50)Placebo (n= 50)
Age (years)59.2 (2.9)59.5 (2.8)58.7 (3.2)59.293.5)
YSM (years)9.0 (2.6)9.0 (3.6)9.5 (3.6)9.7 (3.7)
BMI (kg/m2)24.8 (4.0)26.0 (3.6)25.4 (3.3)25.6(4.3)
BMDspine (g/cm2)0.896 (0.12)0.911 (0.12)0.853 (0.14)0.867 (0.13)
BMDneck (g/cm2)0.703 (0.01)0.699 (0.09)0.665 (0.11)0.678 (0.08)
BMDarm (g/cm2)0.402 (0.06)0.408 (0.06)0.396 (0.05)0.388 (0.06)
sOC N-mid (ng/L)31.5 [24640.3]31.4 [23 & 41.7]31.5[22.843.4]31.8 [23.9–42.5]
sB-AP(μg/L)8.8 [6.2–12.5]9.4 [6.6–13.4]10.1 [7.3–13.9]9.5 [6.6–13.8]
uCrossLapdCr (μg/mol)280.9 [142.8–552–5]310.8 [208.7462.7]309.0 [201.8473.0]330.2 [215.6–505.9]
TC (mmol/L)6.69 [5.90–7.59]6.85 [6.01–7.82]6.61 [5.64–7.75]6.63 [5.63–7.81]
TG (mmol/L)1.06 [0.73–1.52]1.11 [0.7 & 1.63]1.19 [0.72–1.97]1.02 [0.69–1.50]
HDL C (mmol/L)1.91 [1.48–2.45]1.68 [1.28–2.22]1.40 [1.21–2.35]1.68 [1.36–2.38]
LDL C (mmol/L)4.20 [3.50–5.04]4.53[3.67–5.59]4.23 [3.30–5.42]4.25 [3.39–5.33]

One hundred and twenty-one women (60.5%) completed the two year study period (n= 26 in the highEP group, n= 35 in the lowEP group, n= 30 in both the E2+NETA, and the placebo groups). The reasons for dropping out are shown in Table 2.

Table 2.  Principal reasons for dropping-out divided according to treatment group. Values are given as n. Key as for Table 1.
  1. *Includes hip pain, myocardial infarction (one in the HighEP group at 18 months), breast cancer (one in the placebo group at 9 months, and one in the E2+NETA group at 2 years), ovarian cancer (one in the placebo group at 2 years), malignant melanoma (one in the LowEP group at 6 months), facial paresis (one in the LowEP group at 9 months) and rheumatic polymyalgia (one in the placebo group at 3 months).

Breast tenderness, mood change, headache, oedema, weight gain, nausea3763
Unrelated to treatment*98815
Lost to follow up1012

Figure 1 (top) shows the time-related changes in BMDspine and BMDhip. At these sites there was a gradual increase in the bone mineral density of all hormone groups over time. The highEP group produced a mean (SEM) increase in BMDspine of +6.2% (0.6) over two years, the lowEP group +4.2% (0.6), and the E2+NETA group +9.3% (0.8), compared with placebo [0.0% (0.6)] (ANOVA, P < 0.0001). BMDhip showed corresponding average increases of +3.6% (0.6) (the highEP group), +1.8% (0.4) (the lowEP group), +5.4% (0.8) (the E2+NETA group), and −1.4% (0.6) (placebo) (ANOVA, P < 0.0001). Figure 1 (bottom) shows the integrated treatment response in the forearm and femoral neck. The response to hormones in both regions was smaller than in the spine, but the pattern was similar. This was also the case for other regions of interest (e.g. Ward's triangle, and the intertrochanteric region) (data not shown). For the primary efficacy comparison (i.e. each of the hormone regimens vs placebo), there is sufficient power to detect between the regimens a clinically important difference in mean percent changes in the bone mineral density from baseline to two years.

Figure 1.

Time-related changes (upper panel) in the bone mineral density (BMD) of the spine (upper, left), total hip (upper, right), nondominant forearm (lower, left), and femoral neck (lower, right) in relation to treatment. Values are mean (SEM). ***P < 0.001, compared with placebo. ▪ daily piperazine oestrone sulphate 1.5 mg combined with interrupted norethisterone 0.7 mg (highEP); ▴ daily piperazine oestrone sulphate 0.75 mg combined with interrupted norethisterone 0.35 mg (lowEP); • daily 17β-oestradiol 2 mg continuously combined with norethisterone acetate 1 mg (E2+NETA); ○ placebo.

When calculated as the intention-to-treat, the results were virtually identical for the changes in bone density at all time points for all treatment groups, for the biochemical markers of bone turnover, and for the serum lipoproteins (data not shown). This indicates that the women who completed the study were representative of the study population at any given time.

The response to treatment in markers of bone turnover is illustrated in Fig. 2. For serum bone-specific alkaline phosphatase (Fig. 2, top), there was a statistically significant decrease with all hormone therapies (P < 0.001, compared with placebo), with the largest decrease in the E2+NETA group [−41.7% (2.6) calculated as the total averaged response to treatment, but this marker stabilised at about 50% after the first year of treatment], followed by the two hormone regimens with interrupted progestogen [-28.4% (3.6) for the highEP group and −22.7% (3.0) for the lowEP group, which both stabilised at about 65% after a year], and no net change occurred in the response of this marker to placebo [-3.1% (5.0)]. The pattern was similar for serum N-mid osteocalcin (Fig. 2, centre), with decreases (total averaged response to treatment) in the E2+NETA group, followed by the highEP and lowEP groups, respectively [-41.6% (2.7); −36.8% (3.5); and −32.3% (2.5)]. These values stabilised at about 55%–60% after a year and were statistically significant compared with those of the placebo group [-9.4% (4.2)] (P < 0.05 for all comparisons). The marker of bone resorption (Urinary CrossLaps/Cr) (Fig. 2, bottom) also showed a significant decrease in all hormone groups (P < 0.001 compared with placebo), with the largest decrease (calculated as the total averaged response to treatment) given in percent in the E2+NETA group [-72.2% (2.4), stabilising at about 20% after the first six months], and followed by the highEP group [-60.2% (3.8), the lowEP group [-55.2% (3.6), both of which stabilising at about 40% after six months], and the placebo group [-13.6% (3.7), stabilising at about 85%].

Figure 2.

Time-related changes in biochemical markers of bone formation (i.e. serum bone alkaline phosphatase (top) and serum N-mid osteocalcin (centre)) and of bone resorption (i.e. urinary CrossLaps adjusted for urinary creatinine levels (bottom)). Values are mean (SEM). Symbols as in Fig. 1. ***P < 0.001, compared with placebo.

Serum total cholesterol decreased significantly by about 10% in the highEP and the E2+NETA groups, and about 6% in the lowEP group, whereas it tended to increase in the placebo group (P < 0.001 between placebo and each of the hormone groups) (Fig. 3). A similar difference, and of equal magnitude, was found between the groups for low density and high density lipoprotein cholesterol, which both decreased significantly by about 10% in all hormone groups, compared with placebo. There were no net changes in serum triglycerides, although the serum concentration tended to increase in the placebo group. No significant differences were found between the hormone regimens with respect to any of the lipids and lipoproteins.

Figure 3.

Changes in serum total cholesterol (TC) during the study period (top). Values are mean ± SEM. Symbols as in Fig. 1. The individual responses to two-year treatment in serum triglycerides (TG), high density lipoprotein cholesterol (HDL C), and low density lipoprotein cholesterol (LDL C) are given at the bottom. Horizontal bars indicate mean and 95% CI of the mean. *P < 0.05; **P < 0.01; ***P < 0.001, compared with placebo.

Figure 4 shows a reduction of 25%–45% after three months of hormone treatment in the climacteric symptoms, expressed as percent change from baseline in the Kuppermann index (after correction for placebo). This reduction became significantly different from placebo for all hormone groups at six months of treatment (Fig. 4). However, the placebo group tended to have diminishing climacteric symptoms during the two-year study period, and the difference between the placebo group and the hormone groups was no longer statistically significant at 12 and 18 months of treatment. At no time point was there any difference between the three hormone groups in alleviating climacteric symptoms.

Figure 4.

The percent change in the mean Kuppermann index from baseline (set at 100%) during the study and at follow up (which was between 0 and 10 days after the last intake of study medication). There was no difference in the mean (SD) Kuppermann index at baseline (highEP: 8.5 (3.9); lowEP: 8.4 (4.6); E2+NETA: 9.3 (5.9); Placebo: 8.3 (4.0). Symbols as in Fig. 1. ANOVA (analysis of variance) for all groups: P < 0.05; ANOVA for hormone treatments was not statistically significant.

Table 3 shows the frequency and type of adverse events reported during the study with respect to the four treatment groups. The incidence for each organ system was virtually the same in all treatment groups, although higher incidences of expected adverse events occurred in the hormone than in the placebo group. During the two years of treatment, two cases of malignant breast neoplasms were diagnosed (one in the placebo group at nine months and one in the E2+NETA group at 24 months), one case of malignant ovarian neoplasm was detected in the placebo group (at 24 months), and one case of malignant melanoma in the lowEP group (at six months). In addition, there was one participant in the highEP group suffered a myocardial infarction (at 18 months). None of the neoplasms or the myocardial infarction was considered related to the study drug.

Table 3.  Number of adverse events occurring during the 2 years according to treatment groups (values in parentheses are the corresponding number of women). Key as for Table 1.
 HighEP (n= 47)LowEP (n= 48)E2+NETA (n= 48)Placebo (n= 46)
  1. *Also includes vaginal itching.

  2. **Adverse events other than those listed under ‘expected adverse events’.

  3. i.e. flu, common cold, malaise.

Expected adverse events    
Endometrial bleeding9 (9)3 (3)4 (4)0 (–)
Breast tenderness14 (14)7 (7)23 (23)2 (2)
Vaginal discharge*9 (8)7 (7)9 (8)1 (1)
Uterine contractions5 (5)3 (3)3 (3)1 (1)
Lower abdominal pain4 (4)3 (3)6 (6)0 (–)
Nausea3 (3)2 (2)3 (3)1 (1)
Headache and migraine8 (7)9 (9)10 (10)4 (4)
Oedema (local and generalised)5 (5)7 (7)9 (9)5 (5)
Unexpected adverse events    
Central nervous system and head13 (12)26 (19)9 (7)14 (11)
Cardiopulmonal events16 (10)12 (9)23 (17)19 (16)
Gastrointestinal events**14 (11)18 (13)14 (12)13 (10)
Urogenital events**4 (4)5 (4)5 (4)7 (7)
Musculoskeletal events9 (7)33 (21)31 (19)23 (21)
Metabolic/endocrine events2 (1)0 (–)5 (5)4 (4)
Generalised events14 (12)20 (17)31 (21)16 (13)
TOTAL129 (41)155 (43)185 (44)110 (40)


This prospective, randomised placebo-controlled study showed that even the regimen with the lowest dose of piperazine oestrone sulphate and interrupted norethisterone fully prevented bone loss by decreasing bone resorption and by increasing bone formation.

The administration of piperazine oestrone sulphate and interrupted norethisterone is a modification of the continuously combined therapy that attempts to make the progestogen administration more efficient by taking advantage of the steroid receptor dynamics. In the endometrium, progestogens down-regulate the oestrogen receptor (ER) and the progesterone receptor (PgR)20,21. Conversely, oestrogen up-regulates the ER and the PgR22. Withdrawal of progestogen for a time, while continuing with oestrogen, leads to increased levels of PgR. Reintroduction of a progestogen produces a greater biological effect. The three-day interval used in this study was based on in vitro and in vivo studies22,23. Thus, this regimen should protect the endometrium better than either the continuously combined HRT or sequential HRT, while using less progestogen.

All three hormone replacement therapies seemed to be effective in protecting against postmenopausal osteoporosis since they prevented bone loss during treatment. The continuously combined regimen with oestradiol and NETA has been shown to be very potent in increasing bone mass both in early and especially in late postmenopausal women24. Interestingly, the present data indicated a dose-response effect in bone mineral density of the spine and hip, whereas this effect was not apparent in the lower forearm. The explanation for this difference in bone response to the same hormone regimens may be the higher ratio of trabecular:cortical bone in the spine and hip than in the forearm. However, the power of the study was not high enough to suggest whether the difference in response to treatment between the hormone regimens is really dose-dependent or not. As for the biochemical markers of bone turnover, no dose-response effect was seen between the hormone regimens.

Some progestogens are known to affect serum lipids and lipoproteins in a way that may be interpreted negatively from a cardiovascular point of view. Numerous studies have shown that oestrogen given alone increases high density lipoprotein cholesterol and decreases low density lipoprotein cholesterol, whereas addition of a progestogen would seem to negate the positive effect4,5. In the present study all three hormone regimens decreased total serum cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol by about 10%–12%. The changes in serum total cholesterol and low density lipoprotein cholesterol are believed to have a beneficial influence on cardiovascular risk, but the concurrent change in high density lipoprotein cholesterol may seem somewhat unfavourable. Experimental animal studies indicate, however, that other nonlipid mediated mechanisms of sex hormones may play an important role in preventing atherogenesis25–27 and that some progestogens do not increase the accumulation of cholesterol in the aortic wall25,26, whereas others even seem to enhance the anti-atherogenic effect of oestrogen27. Clinical data also suggest a clear decrease in high density lipoprotein cholesterol during treatment with E2 and NETA28. On the other hand, it still seems preferable to have as low an effect on high density lipoprotein cholesterol as possible by adding a progestogen. Modification of the types and doses of both hormone elements in the interrupted progestogen regimen may be necessary to achieve a smaller or even a neutral effect on serum high density lipoprotein cholesterol.

All three hormone replacement therapies had virtually the same effect in alleviating climacteric symptoms by three months of treatment. However, this alleviation may have declined, since even the women in the placebo group experienced fewer symptoms with increasing age. Soon after discontinuation of the hormone therapies, there were no significant differences between the groups in climacteric symptoms.

In the present study none of the women in the placebo group, nor in the lowEP group left the study because of endometrial bleeding, whereas five in the E2+NETA and 11 in the highEP groups did. Although the decision to leave the study for this reason is the subjective judgement of the participant, these numbers reflect the ability of a regimen to control endometrial bleeding. This is supported by the data on bleeding from the women who completed the two-year study, as described elsewhere7.

In conclusion, the present study introduces an innovative way of administering HRT, which ensures prevention of bone loss at both cortical and trabecular sites, as well as alleviating climacteric symptoms and ensuring exposure to a relatively low dose of progestogen. The effect on the lipid metabolism seemed to be neutral in terms of cardiovascular risk factors, since the decrease in high density lipoprotein cholesterol corresponded to a similar decrease in serum total cholesterol and low density lipoprotein cholesterol, whereas serum triglycerides remained unchanged.


This study was supported by a grant from the R. W. Johnson Research Institute, Raritan, New Jersey, USA and Zürich, Switzerland.