The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

The need for add-back with gonadotrophin-releasing hormone agonist therapy.

The usefulness of the gonadotrophin-releasing hormone (GnRH) agonists in treating benign chronic gynaecological disorders, such as endometriosis and uterine fibroids, or pre-menstrual syndrome (PMS), is limited by their hypo-oestrogenic side effects, including bone demineralisation and vasomotor symptoms. Studies in patients receiving GnRH agonists and hormone replacement therapy (HRT) show that whilst the efficacy of GnRH agonist monotherapy in treating endometriosis and fibroids is maintained, the concomitant add-back HRT can prevent the bone loss and reduce the incidence and severity of vasomotor symptoms. However, in a study of add-back HRT (an oestrogenic plus a progestogenic agent) in severe PMS, although the efficacy of Zoladex (goserelin acetate) against oestrogen-responsive symptoms, such as mood, was still evident, progestogenic side effects still occurred. It is likely that add-back HRT may need to be tailored to individual indications.

HRT and long-term compliance: the efficacy and safety of Menorest.

Hormone replacement therapy (HRT) is perhaps the most important development in preventive medicine in the Western world for half a century, yet long-term compliance is notoriously poor. Up to 75% of women who start on HRT are reported to drop out within the first 6 months. Poor compliance may arise from a lack of awareness of the benefits of HRT, or from a number of common misconceptions, particularly the idea that HRT is ¿unnatural', and will cause weight gain, cancer, or unpleasant side effects. While side effects (usually progestogenic) may of course occur on HRT, they can usually be managed by a change in the regimen. Studies of the efficacy and safety of Menorest, an adhesive matrix transdermal system, used in combination with dydrogesterone for 12 days in each cycle, show it to be effective in relieving menopausal symptoms and increasing lumbar and spinal bone mass. Menorest was as effective and well-tolerated as a reference oral treatment (conjugated estrogens), and its twice weekly application may be considered to promote compliance.

Increase in bone mass of older postmenopausal women with low mineral bone density after one year of percutaneous oestradiol implants.

OBJECTIVE: To evaluate the effect of 75 mg oestradiol implants on the bone mass of older postmenopausal women with osteoporosis. DESIGN: One year prospective-controlled study. SUBJECTS: Thirty-two postmenopausal women over 60 years of age and more than five years postmenopausal with low bone density were recruited. Thirty women completed treatment for one year with 75 mg oestradiol implants. The changes in bone density were compared with a control group of 14 women. The side effects with treatment were documented. MAIN OUTCOME MEASURES: Dual energy X-ray absorptiometry of the lumbar spine and proximal femur using Hologic 1000 QDR before treatment and at one year. Plasma oestradiol assays were performed before and after one year. RESULTS: The median percentage changes in the treated group after one year was 12.6% at the lumbar spine and 5.22% at the total hip. The increase in vertebral bone density was greatest in women with low initial bone density (r = -0.35, P < 0.05) and those with highest treatment plasma oestradiol levels (r = 0.47, P < 0.01). Side effects were common but most were transient and mild in nature. CONCLUSION: 75 mg oestradiol implants significantly increase the bone mineral density at the spine and hip of older postmenopausal women with established osteoporosis.

The dose-response of percutaneous oestradiol implants on the skeletons of postmenopausal women.

OBJECTIVE: To determine whether there is a dose-response effect of percutaneous oestradiol implants on the skeletons of postmenopausal women using a range of doses available in clinical practice. DESIGN: One year randomised study. SUBJECTS: Forty-five postmenopausal women who requested oestrogen replacement therapy were randomised to receive 25 mg, 50 mg, or 75 mg oestradiol implants. The bone mineral density changes were compared with a control group of 15 untreated women. MAIN OUTCOME MEASURES: Dual energy X-ray absorptiometry using Hologic 1000 QDR before treatment and after one year of treatment. Plasma oestradiol and follicle stimulating hormone levels before treatment and after one year. RESULTS: There were significant correlations between the plasma oestradiol levels and the percentage increase in bone density at the lumbar spine, the total hip, the femoral neck, and the trochanter. The median (range) plasma oestradiol level was 327 pmol/l (114-853) in the 25 mg group, 358 pmol/l (220-957) in the 50 mg group and 518 pmol/l (167-828) in the 75 mg group. Three women who lost a significant amount of bone from the clinically relevant sites in the 25 mg oestradiol group all had plasma oestradiol levels below 300 pmol/l. None of the women in either the 50 mg or 75 mg oestradiol groups lost bone from these sites. CONCLUSIONS: Oestradiol implants resulted in a wide range of circulating oestradiol levels with each of the doses used. There was a significant relation between plasma oestradiol levels and the increases in bone density at both the lumbar spine and the proximal femur. None of the women lost bone density at the clinically important sites of the spine and femoral neck if their plasma oestradiol levels were above 300 pmol/l.

Histomorphometric changes in the skeleton of postmenopausal women with low bone mineral density treated with percutaneous estradiol implants.

OBJECTIVE: To identify the effects of percutaneous estradiol (E2) implants on bone histology and bone mass of postmenopausal women with low bone mineral density. METHODS: Sixteen postmenopausal women with low bone mineral density were treated with 75-mg E2 implants. Each had iliac crest bone biopsies performed, following double-tetracycline labeling, before treatment and 1 year later. Dual energy x-ray absorptiometry of the lumbar spine and proximal hip was also performed before and after 1 year of therapy. Serum E2 and FSH were measured after 1 year. RESULTS: There were significant reductions in the osteoid volume, osteoid surface, eroded surface, and activation frequency following treatment. There was a statistically insignificant increase in the median bone volume from 11.3 to 15.8%. The median percentage increase in bone density at the lumbar spine was 14.4% and at the total hip 5.3%. The median post-treatment serum E2 level was 570 pmol/L. CONCLUSIONS: Estradiol implants reduce bone turnover in the iliac crest without significantly increasing trabecular bone volume after 1 year. The increases in bone density at the spine and hip may be explained by increased mineralization within the existing trabecular bone. However, the iliac crest may not represent the effect of estrogen at sites susceptible to osteoporotic fracture. If resorption is suppressed more than formation, then new bone would be deposited to account for the increase in bone density.

Changes in collagen composition and cross-links in bone and skin of osteoporotic postmenopausal women treated with percutaneous estradiol implants.

OBJECTIVE: To determine the effects of percutaneous estradiol (E2) implants on the collagen composition and maturity in the bone and skin of osteoporotic postmenopausal women. METHODS: Sixteen postmenopausal women with low bone mineral density were treated for 1 year with 75-mg E2 implants. Iliac crest bone and skin biopsies were analyzed for collagen content and collagen cross-links before treatment and at 1 year. Dual energy x-ray absorptiometry of the lumbar spine and proximal femur was also performed before and after 1 year of therapy. RESULTS: The cortical bone showed a significant increase in the mature cross-links of both hydroxylysylpyridinoline (P < .01) and lysylpyridinoline (P < .01), with a significant reduction in the percentage of collagen (P < .001). The pattern was similar in trabecular bone, with lysylpyridinoline increasing significantly (P < .05). The skin exhibited a significant reduction in the immature cross-link hydroxylysinonorleucine (P < .01), but no significant change in the percentage of collagen content or the mature cross-link histidinohydroxylysinonorleucine. The median increases in bone density were 11.5% at the spine and 4.34% at the total hip. The median post-treatment serum E2 level was 639 pmol/L. CONCLUSIONS: Bone mineral density increased at all the sites measured in the spine and proximal hip. The quality of the collagen within the transiliac biopsies had matured in that the concentration of the mature collagen cross-links had increased. These findings support a reduction in the turnover of bone collagen following estrogen replacement therapy. More important, the formation of a more mature collagen fiber should help to reduce the risk of future bone fracture.

The effect of 25-mg percutaneous estradiol implants on the bone mass of postmenopausal women.

OBJECTIVE: To determine whether the lowest available dose of percutaneous implant, 25 mg estradiol (E2), is effective for the prevention of postmenopausal bone loss. METHODS: Eighteen healthy postmenopausal women were treated with 25-mg percutaneous E2 implants for 1 year. Dual energy x-ray absorptiometry was performed at the lumbar spine and proximal hip using a quantitative digital radiography densitometer before treatment and after 1 year. Estradiol and FSH were also measured before and after 1 year of treatment. The changes in bone mineral density were compared with a matched reference group of 18 women who did not wish treatment. RESULTS: The median percentage changes in the treated group after 1 year were 5.65% at the lumbar spine, 3.38% at the femoral neck, and 3.36% total hip. At 1 year, there was a significant increase in bone mineral density from baseline at all sites measured except Ward triangle. The median post-treatment E2 level was 320 pmol/L (range 114-813), and FSH was 28 IU/L (range 2-66). CONCLUSION: This study demonstrates that 25-mg percutaneous E2 implants significantly increase bone mineral density at the spine and hip in postmenopausal women. This dose is effective to prevent postmenopausal bone loss.

The prevention of bone loss in young women treated with GnRH analogues with "add-back" estrogen therapy.

OBJECTIVE: To determine whether the addition of a low dose of oral estrogen replacement therapy (ERT) taken daily can prevent the bone loss associated with continuous GnRH analogue use. METHODS: In a double-blind, placebo-controlled study, 60 women aged 21-45 years were randomized to one of three treatment groups: placebo implant every 4 weeks plus placebo ERT tablets daily, Zoladex (goserelin 3.6 mg) implant every 4 weeks plus placebo ERT tablets daily, or Zoladex (3.6 mg) implant every 4 weeks plus estradiol valerate, 2 mg/day, with norethisterone 5 mg from days 22-28. A dual x-ray bone density scan was performed before treatment and again after six treatment cycles. The percentage bone change with respect to the initial bone density was calculated. RESULTS: There was a significant loss of bone density at both the lumbar spine and proximal femur in the group receiving Zoladex plus placebo after 6 months compared with both pre-treatment values and with the group receiving placebo plus placebo. The addition of estrogen "add-back" therapy to GnRH analogue treatment (Zoladex plus ERT) resulted in no significant change in bone density compared with either pre-treatment values or the group receiving placebo plus placebo. The study had a dropout rate of 32%. CONCLUSION: The addition of "add-back" estrogen therapy to continuous GnRH analogue use can prevent bone loss.

Increase in bone mass after one year of percutaneous oestradiol and testosterone implants in post-menopausal women who have previously received long-term oral oestrogens.

OBJECTIVE: To determine the effect on the bone density of the skeleton after changing from oral oestrogen to subcutaneous oestradiol and testosterone replacement. DESIGN: Prospective non-randomized single centre study. SUBJECTS: Twenty women who were receiving long-term oral oestrogen replacement. Ten changed to oestradiol and testosterone implants; the remaining ten continued with oral oestrogens. MAIN OUTCOME MEASURES: Bone density was measured using dual photon absorptiometry at the lumbar spine and neck of femur at the start of the study and after one year. RESULTS: The bone density increased significantly by 5.7% at the spine and by 5.2% at the neck of femur in those women who changed to implant therapy but remained unchanged in those women who continued with oral therapy. CONCLUSION: Subcutaneous oestradiol and testosterone implants will result in an increase in bone mass even after many years of oral oestrogen replacement therapy.

Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women.

Continuous combined estrogen and progestogen preparations enable the postmenopausal woman to enjoy the benefits of estrogen replacement without the inconvenience of regular progestogen-induced withdrawal bleeding. The endometrium appears to be adequately protected in the short term, but no published data are available on the bleeding patterns or endometrial response after more than 18 months of therapy. Therefore, we reviewed 41 patients who continued on such preparations for up to 10 years (mean duration of use 8.0 years). Six women had experienced episodes of breakthrough bleeding after achieving amenorrhea, two of whom had benign endometrial polyps and two with adenocarcinoma of the endometrium. The remaining 35 women each had prolonged amenorrhea and were found to have an atrophic inactive endometrium. It is too early to comment on the long-term endometrial effects of these preparations because the numbers are too small; however, any breakthrough bleeding occurring after a period of prolonged amenorrhea must be investigated by means of endometrial biopsy.