Personal view: Hormones and depression in women.

Depression is more common in women, occurring at times of hormonal fluctuations as premenstrual depression, postnatal depression and perimenopausal depression. These are all related to changes in hormone levels and constitute the diagnosis of reproductive depression. There is a risk that severe premenstrual depression can be misdiagnosed as bipolar disorder and that women will be started on inappropriate antidepressants or mood-stabilizing therapy. The most effective treatment for severe premenstrual syndrome is by suppression of ovulation and suppression of the cyclical hormonal changes by transdermal estrogens or by GnRH analogs. Postnatal depression is more common in women with a history of premenstrual depression and also responds to transdermal estrogens. Transdermal testosterone gel can be also used in women who suffer loss of energy and loss of libido which may be due to the inappropriate prescription of antidepressants. There is also a role for the Mirena IUS and laparoscopic hysterectomy and oophorectomy in women who are progestogen-intolerant. The hormonal causation of certain common types of depression in women and the successful treatment by estrogens should be understood by psychiatrists and gynecologists.

The sonopartogram: a novel method for recording progress of labor by ultrasound.

OBJECTIVES: Progress of labor has hitherto been assessed by digital vaginal examination (VE). We introduce the concept of a non-intrusive ultrasound (US)-based assessment of labor progress (the 'sonopartogram') and investigate its feasibility for assessing cervical dilatation and fetal head descent and rotation. METHODS: This was a prospective study performed in 20 women in the first stage of labor in two European maternity units. Almost simultaneous assessment of cervical dilatation and fetal head descent and rotation were made by US and digital VE. RESULTS: The total number of paired US and digital VE assessments was 52, with a median of three per woman. Overall, 5% of sonopartogram parameters were not obtained compared with 18% of conventional digital VE parameters (P < 0.001). Assessment of cervical dilatation was possible in 86.5% of US examinations and 100% of digital VEs (P = 0.02), and dilatation was assessed as being greater by digital VE than by US (mean difference, 1.16 (95% limits of agreement, -0.76, 3.08) cm, r(2) = 0.68, P = 0.01). Fetal head descent was measured in all 52 cases by both methods (r(2) = 0.33, P < 0.001), but correlation between the two was only moderate. Head rotation was obtainable in 98% of US examinations and 46% of digital VEs (P < 0.001), with a mean difference of -3.9° (95% limits of agreement, -144.1°, 136.3°). CONCLUSION: In this proof-of-concept study, the acquisition of data regarding progress of labor was more successful for the sonopartogram than the conventional partogram. The agreement between digital VE and US was good for cervical dilatation and head rotation but less so for head descent. US assessment of the progress of labor is feasible in most cases.

'PROFOX'--the post HRT nightmare.

The recent report of a two-fold increase in esophageal cancer in women taking oral bisphosphonates is yet another reason to question current relegation of hormone replacement therapy (HRT) to a minor role in the correction of many problems occurring in the younger postmenopausal woman. Women under the age of 60 years with low bone density, flushes, sweats, vaginal dryness, loss of libido and climacteric depression would be treated with estrogens by gynecologists and most general practitioners. It is regrettable that bone physicians use bisphosphonates as first-line therapy in this age group, in spite of the growing number of serious complications reported. Similarly, psychiatrists have little experience in the use of estrogens for the reproductive depression syndrome of postnatal depression, premenstrual depression and perimenopausal depression, but use antidepressants. The adverse effects reported in the 2002 Women's Health Initiative study are given as justification for not using estrogens, although serious complications did not occur in women starting HRT before the age of 60 years. But, in reality, the objection to estrogens from psychiatrists and bone physicians preceded this study by decades and was a result of their unfamiliarity with this treatment. Regrettably, PROFOX (PROzac + FOsomaX) will become an established treatment for women who really need estrogens.

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.

Therapeutic options for postmenopausal female sexual dysfunction.

BACKGROUND: Female sexual dysfunction (FSD) is a multidimensional problem combining biological, psychological and interpersonal elements of multiple etiologies. Menopause-related sexual dysfunction may not be reversible without therapy. Hormonal deficiency does not usually decrease in severity over time. Many options are available for the successful treatment of postmenopausal FSD. OBJECTIVE: To review the pharmacological and non-pharmacological therapies available for postmenopausal FSD, focusing on practical recommendations for managing postmenopausal women with sexual complaints, through a literature review of the most relevant publications in this field. PSYCHOSOCIAL THERAPY: This type of therapy (basic counselling, physiotherapy and psychosexual intervention) is considered an adaptable step-by-step approach for diagnostic and therapeutic strategies, normally combined with biomedical interventions to provide optimal outcomes. PHARMACOLOGICAL THERAPY: For postmenopausal FSD, many interventional options are now available, including hormonal therapies such as estrogens, testosterone, combined estrogen/testosterone, tibolone and dehydroepiandrosterone. CONCLUSIONS: Menopause and its transition represent significant risk factors for the development of sexual dysfunction. FSD impacts greatly on a patient's quality of life. Consequently, it is receiving more attention thanks to the development of effective treatments. Non-pharmacological approaches should be used first, focusing on lifestyle and psychosexual therapy. If required, proven effective hormonal and non-hormonal therapeutic options are available.

Estrogens as first-choice therapy for osteoporosis prevention and treatment in women under 60.

A case is made for estrogens to be the first-choice therapy for the prevention and treatment of osteoporosis in women below the age of 60 years. Estrogens produce a dose-related increase in bone density and also, by their effect on collagen, have a beneficial effect not only on the bone matrix but the intravertebral disc. Bisphosphonates do not have that effect upon the disc. Estrogens are also associated with other beneficial effects upon mood, vasomotor symptoms, pelvic atrophy, sexuality and quality of life. The data from the Women's Health Initiative (WHI) study are used as a justification for not using estrogens but the neglect of estrogen therapy by physicians antedated this and other studies by many years. Subsequent publications from the WHI study show that hormone replacement therapy, particularly estrogens alone, is not associated with the excess side-effects found in the older population. The substantial but non-significant decrease in heart attacks, breast cancer and mortality in women under the age of 60 taking estrogens alone should persuade the advisory bodies to revise their judgment on the benefits and safety of hormone replacement therapy in this population.

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.

Anabolic effect of estrogen replacement on bone in postmenopausal women with osteoporosis: histomorphometric evidence in a longitudinal study.

It is well recognized that estrogen (E(2)) prevents postmenopausal bone loss by suppressing bone resorption. Despite evidence that E(2) may also stimulate bone formation in animals, an anabolic effect in humans is still controversial. To investigate this, we studied 22 older postmenopausal females, with a mean age of 65.4 yr and mean interval of 16.9 yr since menopause and low bone mineral density. Transcortical iliac bone biopsies were performed before and 6 yr after E(2) replacement therapy (ERT) [75 mg percutaneous E(2) replaced 6-monthly plus oral medroxy progesterone acetate (5 mg daily) for 10 days each calendar month]. The mean serum E(2) level after 6 yr of treatment was 1077 (range, 180-2568) pmol/L. Bone mineral density improved in every patient, with a median increase of 31.4% at the lumbar spine and 15.1% at the proximal femur. Bone histomorphometry showed an increase in cancellous bone volume from 10.75% to 17.31% (P < 0.001). The wall thickness after 6 yr of E(2) treatment was 38.30 micrometer compared with 31.20 micrometer before commencement of ERT (P < 0.0005), indicating net bone gain. This is the first report showing histological evidence for an increase in cancellous bone volume, together with an increase in wall thickness, in a longitudinal follow-up study of ERT in older postmenopausal women. Our results show that E(2) is capable of exerting an anabolic effect in women with osteoporosis, even when started well into the menopause.

Exogenous androgens in postmenopausal women.

There is an increasing awareness that androgens are of therapeutic value in postmenopausal women. Evidence is emerging demonstrating the role of testosterone in both female embryologic development and normal sexual behavior and mood. Women who are androgen depleted develop physical and behavioral symptoms referred to as female androgen deficiency syndrome. To a lesser degree, women who undergo an oophorectomy are deprived of endogenous ovarian androgens and have consistently been shown to have impairment of sexual functioning, loss of energy, depression, and headaches. Testosterone seems to act synergistically with estrogen in the treatment of these symptoms. The combination of estradiol and testosterone has been shown to have a beneficial effect on the skeleton, although not significantly better than estradiol therapy alone. Cosmetic side effects are rare if supraphysiologic doses are avoided. The potential metabolic complications have not been consistently demonstrated in studies to date. Androgen replacement therapy is a neglected area of medical practice and further research is needed to identify all women who will benefit from it since studies in menopausal women have shown parenteral administration to be well tolerated and safe. Such therapy is underused and very much underresearched. While testosterone implants work adequately, it would be more desirable and convenient to use a testosterone patch and safer, more effective oral androgens, if these products were available.

Hysterectomy, ovarian failure, and depression.

The incidence of depressed mood is high in women before hysterectomy. This finding is usually the effect of prolonged heavy periods, chronic pelvic pain, and severe premenstrual syndrome that warrant the surgical treatment. The therapeutic effects of hysterectomy thus include both the cure of physical symptoms and improvement of mood. However, in women with preexisting psychiatric illness or predisposing personality problems, depressed mood may persist or occur with the stress of hysterectomy. Hysterectomy is commonly performed in the perimenopausal age but also results in a premature ovarian failure. Thus, ovarian hormone deficiency following hysterectomy may be responsible for the negative effect on mood. The cyclical nature of such hormone-related depressed states often remains unrecognized in the absence of menstruation; without routine endocrinologic monitoring the need for estrogen replacement following hysterectomy is often missed. Associated bilateral oophorectomy results in the depletion of endogenous androgens, which also has a significant effect on mood. Estrogen plus testosterone replacement following hysterectomy with or without bilateral oophorectomy has been shown to reduce the incidence of depressed state. The compliance with hormone replacement following hysterectomy is high in the absence of withdrawal bleeding and the depressant effect of progestins on mood. Therefore, a practice of regular endocrinologic monitoring following hysterectomy to detect the need for estrogen replacement and a near-routine replacement of combined estrogen and testosterone following bilateral oophorectomy should be adopted to reduce the incidence of posthysterectomy depression.

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.

A cross-sectional study of the effects of long-term percutaneous hormone replacement therapy on bone density.

The effect of hormone implants on the bone density of postmenopausal women was studied in 110 patients (mean age 54.7 years; mean menopausal age 8.6 years, range 2-30) who had received hormone replacement in the form of estradiol (50-75 mg) and testosterone (100 mg) pellets at 6-month intervals for 2-24 years (mean 5.2). They were compared with 254 untreated women (mean age 55.0 years; mean menopausal age 6.8 years, range 1-37). The bone density at the spine, measured by quantitative digital radiography, was 1.123 grams hydroxyapatite (gHa)/cm2 in the treated group and 0.951 gHa/cm2 in the controls (P less than .0001). The total bone density at the proximal femur was 1.002 gHa/cm2 in the treated group, compared with 0.914 gHa/cm2 in the controls (P less than .0001). There were significant differences in the density of the trochanteric, intertrochanteric, and neck areas of the proximal femur as well as the Ward triangle (all P less than .0001). These differences became significant from the age of 55 at the neck of the femur, Ward triangle, and lumbar spine, and from age 60 for all other values. Subcutaneous estradiol and testosterone prevent postmenopausal osteoporosis and maintain normal bone density for as long as treatment is continued.

The effects of plasma estradiol levels on increases in vertebral and femoral bone density following therapy with estradiol and estradiol with testosterone implants.

Percutaneous estradiol (E2) implants effectively preserve bone density in postmenopausal women. However, these implants are often given with testosterone, which may itself have an anabolic effect on bone. To determine whether testosterone confers any additional bone-sparing effect, we studied 50 postmenopausal women randomly allocated to receive E2 (75 mg) alone or with testosterone (100 mg) every 6 months for 1 year. Women with an intact uterus received cyclic norethindrone (5 mg) for 10 days of each calendar month. Twenty-five untreated women were recruited to act as a reference group. Bone density was measured at the lumbar spine and proximal femur by dual x-ray densitometry. By 1 year, bone density at the lumbar spine had fallen by 1.8% in the reference group. In the women treated with E2 alone, it increased significantly by 7.8% (P less than .0001) and in those receiving E2 with testosterone, it increased by 6.3% (P less than .0001). At the femoral neck, bone density decreased by 3% in the controls and increased by approximately 4% in both treated groups (P less than .0001). The increase in bone density at these sites was unrelated to the woman's chronological age, menopausal age, or initial bone density. However, it correlated significantly with the serum E2 levels attained after 1 year of therapy. In no treated patients did bone density decrease significantly. These data show that testosterone confers no additional bone-sparing effect in postmenopausal women.

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.