A guide to the treatment of depression in women by estrogens.

Premenstrual depression, postnatal depression and climacteric depression are related to changes in ovarian hormone levels and can be effectively treated by hormones. It is unfortunate that psychiatrists have not accepted this form of treatment and this paper is an attempt to simplify this treatment, which should include transdermal estrogens, possibly testosterone and, if the woman has a uterus, also progestogen. A balance is often necessary between these three hormones. Transdermal estrogens in the appropriate dose will suppress ovulation and suppress the cyclical hormonal changes that produce premenstrual depression. Estrogens also have a mood-enhancing effect in postnatal depression and the depression in the transitional phase of the menopause. It is possible to add transdermal testosterone which will improve mood, energy and libido. The problem is the progestogen as these women are often progestogen-intolerant. Progestogen should be used in the lowest dose and for the shortest duration necessary to prevent endometrial hyperplasia or the return of premenstrual syndrome-type symptoms if the women are progestogen-intolerant. The use of estrogens for depression in these women does not exclude the use of antidepressants. Hormone-responsive depression cannot be diagnosed by measuring hormone levels but can only be diagnosed by a careful history relating depression to the menstrual cycle, pregnancies and the perimenopausal years. These appropriate questions should prevent the endocrine condition of premenstrual depression being misdiagnosed as bipolar disorder and the woman given inappropriate treatment.

Reduced bone mineral density in HIV-positive individuals.

A total of 105 HIV-positive patients underwent dual-energy X-ray absorbtiometry (DEXA) scan to assess bone mineral density (BMD). The prevalence of reduced BMD was found to be 71% and was higher in patients who had ever been treated with protease inhibitors (PI). Our results suggest a possible association between PI and reduced BMD, and further complicate the debate regarding when to commence treatment of HIV and with what agents to start.

Premenstrual syndrome and the use of alternative therapies.

Premenstrual syndrome is a collection of symptoms that may be encountered by up to 95% of the population, although it is estimated to affect 5% of women severely. The use of complementary and alternative therapies is high among this group, but does not seem to compromise conventional treatment. It has been established that complementary therapies are used by a large proportion of the developed world, but their efficacy and safety are not always proven. This is partly due to the difficulty of studying alternative practices and the cost, but also with respect to premenstrual syndrome, problems with defining the condition and specifying end points are encountered. The difficulties in evaluating unorthodox therapies are elucidated and the evidence base for nonprescribed treatments for premenstrual syndrome is presented. Overall these women are a neglected group for whom the evidence for conventional therapy is sparse and controversial. Since the majority of women self-diagnose and self-medicate, it is important that physicians have an understanding of the variety of interventions tried and their worth.

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.

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.

Skin collagen changes in postmenopausal women receiving different regimens of estrogen therapy.

Collagen is a widespread body constituent that is affected by estrogen status in women. Its decrease after menopause can be prevented and/or restored by estrogen treatment. We explored the effect of four different hormonal replacement regimens on total skin collagen content by measuring hydroxyproline in skin biopsy specimens taken from postmenopausal women. All regimens showed increases in skin collagen levels proportionate to the levels at the start of the treatment. Estrogen replacement therapy is shown to be prophylactic in women who have higher skin collagen levels and both prophylactic and therapeutic in women with lower skin collagen levels.

Response of skin thickness and metacarpal index to estradiol therapy in postmenopausal women.

A radiologic method for measuring skin thickness and metacarpal index was used to investigate 41 postmenopausal women treated with estradiol (100-mg) subcutaneous implants (Organon, UK). All the women completed the first six months of the study, and 33 completed one year. Both skin thickness and metacarpal index increased to a statistically significant degree over the one-year period, with most of the increase occurring in the first six months of therapy. Skin thickness showed the largest increases, from a mean of 0.86 mm at the start of the study to 0.97 mm at six months and 1 mm at one year. The metacarpal index increased from a mean of 0.77 at the start of the study to a mean of 0.799 and 0.8 at six months and one year, respectively.

A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman.

The skin collagen content, skin thickness, metacarpal index, and forearm bone mineral content in postmenopausal women showed a similar decline of between 1-2% per year after the menopause. All four parameters showed a decline that was significant when compared with the years from the menopause. Significant correlations between all four parameters suggest that a similar pathology causes the decrease in bone mass and skin thickness--a decline in the connective tissue element that is common to both bone and skin.

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.

Bone loss after hysterectomy with ovarian conservation.

OBJECTIVE: To examine the long-term effects of hysterectomy with conservation of the ovaries on bone density of the lumbar spine and proximal femur. METHODS: A cross-sectional study of the bone density of 40 postmenopausal women who had undergone hysterectomy with ovarian conservation before menopause compared with a matched group of 40 women who had not had hysterectomy. The 40 women who had undergone hysterectomy were also compared with a control population, using multiple linear regression analysis. Bone density of the femoral neck and lumbar spine was measured by quantitative digital radiography. RESULTS: Bone density in the hysterectomy group was significantly reduced at the spine (P < .05) and at the femoral neck (P < .05) compared with the matched group. Comparisons of the hysterectomy group with the reference group demonstrated that in addition to significant reductions in bone density at the spine (P < .05) and hip (P < .05), bone density at the femoral neck (P < .05), trochanter (P < .05), Ward's triangle (P < .05), and the second (P < .05) and fourth (P < .05) lumbar vertebrae was also significantly less in the hysterectomy group. CONCLUSION: Premenopausal women who have hysterectomy will have significantly lower bone density than controls, despite conservation of both ovaries at the time of surgery.

Amenorrhea and endometrial atrophy with continuous oral estrogen and progestogen therapy in postmenopausal women.

An oral regimen of continuous conjugated equine estrogens (Premarin 0.625 or 1.25 mg daily) and low-dose progestogen (Norethisterone 0.35 to 2.1 mg daily) have been used to treat 95 nonhysterectomized postmenopausal women for up to 2.5 years. This method of hormone replacements was undertaken in an attempt to avoid the withdrawal bleeding and progestogenic side effects associated with conventional cyclical therapy with estrogen and progestogen, while simultaneously protecting the endometrium from estrogenic over-stimulation. With the lower dose of estrogen, amenorrhea was achieved immediately in 30 of 46 patients (65%), and after adjustments to the dose of the progestogen in all ten patients observed for at least one year (maximum 2.5 years). With the higher dose of estrogen, irregular spotting during the first three months resulted in the cessation of treatment by six of the 49 patients (12%), but 23 (47%) women had no bleeding during that time; by 15 months, all 13 patients who had remained in treatment had become amenorrheic (maximum 2.25 years). Endometrial biopsy specimens after six months of combined treatment in 56% of patients revealed atrophic histology regardless of the dose of the estrogen.

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.

Comparative clinical trial of fenticonazole ovule (600 mg) versus clotrimazole vaginal tablet (500 mg) in the treatment of symptomatic vaginal candidiasis.

A multi-centre, randomized, single-blind, parallel-group clinical trial was undertaken in 50 patients (26 fenticonazole, 24 clotrimazole) with symptomatic vaginal candidiasis to compare the antifungal efficacy and tolerability of single-dose intra-vaginal treatment with a fenticonazole ovule (600 mg) or a clotrimazole vaginal tablet (500 mg). Assessment was by laboratory mycological investigation and symptomatic assessments for a period of 3 weeks from the day of treatment. Of the 50 patients, 43 (23 fenticonazole, 20 clotrimazole) returned for assessment 1 week after drug administration and 32 (17 fenticonazole, 15 clotrimazole) were re-assessed 3 weeks after drug administration. Both treatments resulted in very similar and highly significant improvements in symptoms, associated with disappearance of detectable Candida in approximately 70% of patients. There were no significant differences between treatments and no appreciable incidence of relapse during the 3-week period of observation. At the end of this period, 10 (59%) of 17 fenticonazole patients were totally disease-free, as compared with 10 (67%) of 15 patients after clotrimazole treatment. The cure rate observed was somewhat less than that previously seen when intra-vaginal cream formulations of the same two drugs were given on a multiple-dose basis. Both drugs were very well tolerated, with no reports of appreciable local or systemic adverse reactions to either drug.

The symptomatology of progestogen intolerance.

It is common for women receiving oestrogen replacement therapy to experience adverse symptoms whilst taking cyclical progestogen. This study highlights the similarity of these symptoms to those experienced in pre-menstrual syndrome and confirms that the Moos Menstrual Distress Questionnaire is an appropriate tool for future research. The data also indicate that progestogens vary in the type of symptoms they cause. Norethisterone is more likely to cause symptoms from the Moos pain symptom cluster than either medroxyprogesterone or dydrogesterone, but is less likely to cause negative affect symptom cluster symptoms. The relative levels of oestrogen and progestogen may influence the severity of progestogenic symptoms.

A first study to compare two dosages of dydrogesterone in opposing the 50 mg oestradiol implant.

Thirty post-menopausal, non-hysterectomised women received a 50 mg oestradiol implant subcutaneously and either 10 mg or 20 mg dydrogesterone daily for 14 days every 28 days for 6 months. Endometrial biopsies were taken during the initial oestrogen-only phase and again during the final progestogen phase. Of the ten initial samples which were adequate for histological diagnosis, nine showed proliferative and one non-secretory endometrium. Of the 28 samples obtained at the end of the study during the progestogen phase, all except one showed satisfactory conversion, irrespective of dose. Acceptable bleeding patterns were seen in both dosage groups. Tolerance was good and no patient discontinued treatment. This study has shown that both 10 mg and 20 mg dydrogesterone for 14 days are potent enough to oppose the proliferative effects of the 50 mg oestradiol implant. In view of the wide inter-patient variation in endometrial response to progestogens, it appears appropriate to choose the dosage of dydrogesterone on the basis of cycle control and tolerability, whilst being able to maintain confidence in endometrial protection.

Endometrial and menstrual response to subcutaneous oestradiol and testosterone implants and continuous oral progestogen therapy in post-menopausal women.

A regimen of subcutaneous implants of oestradiol and testosterone in combination with continuous oral norethisterone (0.35mg to 5mg daily) was used to treat 71 non-hysterectomised post-menopausal women for up to 30 mth in an attempt to avoid the withdrawal periods associated with conventional cyclical therapy, while at the same time protecting the endometrium from oestrogenic overstimulation. Amenorrhoea, defined as no vaginal bleeding for at least 3 mth, occurred immediately in 5.4-55.6% of women, the percentage depending on the daily dose of the progestogen. In those women who bled, the dose of norethisterone was adjusted at 3-mth intervals. Despite this protocol, only 51.0% of the patients were amenorrhoeic after 6 mth, and 63.2% after 1 yr. Although eight women did develop amenorrhoea for 12-27 mth, there was a high drop-out rate by the others, mainly because of unacceptable irregular bleeding. Irrespective of the bleeding pattern, endometrial biopsies 6 mth after treatment revealed endometrial atrophy. It is concluded that this form of therapy is inferior to oral continuous combined hormone replacement where amenorrhoea can almost invariably be achieved.

The long-term tolerability and efficacy of OESCLIM: results of a 1-year study.

OBJECTIVES: A 1-year, open-label, non-comparative study evaluated the long-term tolerability and acceptability of a new generation matrix patch in post menopausal women with estrogen deficiency. METHODS: Menopausal women (224) from 37 centres in five European countries received OESCLIM 50 microg/d (17-beta estradiol) for 3 months, titrated if necessary to either 25 or 100 microg/d for a further 9 months. Patients received either a continuous or discontinuous estradiol regimen with concomitant sequential progestogen (except hysterectomised patients). Skin tolerability was assessed by patient diaries and questionnaires. Global tolerability, efficacy, laboratory parameters and global acceptability were also monitored. RESULTS: Almost two-thirds of women did not experience any kind of skin reaction and only 4.3% of all applications (752/17,702) caused site reactions. Of these, the majority caused only slight or no discomfort (63.2%). Only 0.37% of total applications required patch removal; none required therapy. A low percentage of patients withdrew due to tolerability issues: 2.7% due to skin reactions; 7.5% due to hyperestrogenism. The mean number of hot flushes experienced by symptomatic women reduced by 91% from 4.0 at baseline to 0.4 after 2 months. Total cholesterol reduced by 3.9% and LDL cholesterol by 5.1%, with no increase in triglyceride levels. Investigators assessed treatment as effective in 96.8% of cases; well tolerated locally in 93.1% and well tolerated generally in 89.5%. At the end of this 1 year study, 79% of patients wished to continue therapy. CONCLUSION: OESCLIM is well tolerated locally and systemically in long-term therapy with a high proportion of patients wishing to continue therapy after 1 year.

Skin collagen changes in post-menopausal women receiving oestradiol gel.

Sixteen post-menopausal women who had never previously received any hormonal treatment applied Oestrogel cream 1.5 mg/day percutaneously for 1 yr. Skin biopsies were taken from the abdomen and from the lateral aspect of the thigh at 0, 3, 6 and 12 mth, and the changes in skin collagen content were noted. The abdominal skin collagen content increased significantly (P less than 0.001) over the 1-yr treatment period. The thigh skin collagen content also increased, but did not reach significant levels. There was a strong correlation between the change in skin collagen content (in both the abdomen and the thigh) and the original skin collagen content, indicating that the change in collagen content in response to oestrogen therapy is dependent on the original level. There is no further increase once an 'optimum' skin collagen level has been reached.

Efficacy and tolerance of Menorest compared to Premarin in the treatment of postmenopausal women. A randomised, multicentre, double-blind, double-dummy study.

Two-hundred and fourteen (214) menopausal women with moderate to severe vasomotor symptoms, aged 40-65 years, were randomised. After a 4-week treatment-free period, each women received a continuous regimen of Menorest 50 twice weekly or Premarin 0.625 mg daily, for 12 weeks. Didrogesterone 10 mg was also given to all women for 12 days of every 28-day cycle. The objectives were to compare the efficacy and safety profiles of Menorest and an oral estrogen. A statistically significant reduction in the mean number of hot flushes occurred in each group compared to baseline with a decrease from 7.1 at baseline to 0.9 at 12 weeks in the Menorest group, and from 6.7 to 0.5 in the oral estrogen group; there was no statistically significant difference between the two groups (P = 0.36). With each successive treatment cycle, there was a continuous improvement in the number of hot flushes. The incidence and severity of menopausal symptoms were reduced in the same manner in both groups. There were no statistically significant differences in the mean plasma estradiol and estrone concentrations between the two treatment groups after 10 weeks of therapy. The mean estradiol to estrone ratio was similar in both groups, as was the number of adverse events observed. In summary, Menorest was as effective as an oral estrogen in alleviating menopausal symptoms.