Long-term postmenopausal hormone replacement therapy effects on bone mass: differences between surgical and spontaneous patients.

BACKGROUND: Hormone Replacement Therapy (HRT) begun soon after spontaneous menopause or oophorectomy minimizes or even reverses the loss of bone that occurs normally during those years. The persistence of this HRT protective effect at long-term on bone density, however, is not well documented. AIM: to evaluate the effects of 5 years of HRT in postmenopausal women on bone mineral density of the lumbar spine. SUBJECTS AND METHODS: The 5-year prospective study enrolled 154 postmenopausal women, of them 136 completed the first year and were considered electible to continue the follow-up. These 136 postmenopausal women were allocated to two groups according their origin: surgical (n=68) and spontaneous (n=68). HRT was prescribed and bone mineral density (BMD) was measured at the lumbar spine prior to commencement of therapy, and then yearly for the duration of the study. All patients received a continuous therapy with standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or 50 microg/day of 17-beta-Estradiol in transdermal therapeutic systems (TTS). Subjects who experienced natural menopause also received 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Treated groups were compared with two non-treated control groups (surgical n=77; spontaneous n=53). RESULTS: Our data showed that HRT increased the BMD of women who had experienced spontaneous menopause. Comparison with a control group revealed that HRT also protected against bone loss in women who had undergone surgical menopause. CONCLUSION: Long term hormone replacement therapy increases bone mineral density in women who have experienced natural menopause, and protects against bone loss in surgically postmenopausal women.     

Pharmacokinetics of raloxifene and its clinical application.

Hormone replacement therapy (HRT) administered to postmenopausal women relieves climacteric symptoms, prevents loss of bone mass, and counteracts the development of coronary artery disease. However, whereas all the benefits associated with HRT are achieved only following long-term therapy, the long-term compliance to the regimen is poor. The most common reasons for discontinuance are uterine bleeding, breast pains, and a fear of breast cancer. Long-term HRT may be associated with an increased risk of breast cancer. Consequently, there is a need for an "ideal estrogen", designed to pinpoint desired target tissues for estrogen, such as the bone and liver, while acting as an antiestrogen in uterus and breast tissues. Raloxifene belongs to a new class of compounds, selective estrogen receptor modulators (SERMs). It binds to and interacts with estrogen receptors, acting as an estrogen agonist in bone and liver, but as an estrogen antagonist in breast and uterus. Therefore, raloxifene represents a potentially important alternative to HRT in postmenopausal women for the prevention and treatment of osteoporosis and cardiovascular disease. Clinical studies regarding the drug's long term benefits are still required.     

Etidronate and hormone replacement therapy (HRT) for postmenopausal women with osteoporosis despite HRT

Hormone replacement therapy (HRT) is effective treatment for postmenopausal bone loss and osteoporosis. However, postmenopausal women with low bone mass fail to respond after a few years of HRT and some postmenopausal women show no bone response to HRT. In these cases, additive therapy is necessary. Bisphosphonates are highly effective in postmenopausal osteoporosis. We investigated the effects of adding etidronate, a bisphosphonate, to HRT. The addition of etidronate to HRT improved bone density (4.40+/-1.12% increase per year) in patients showing no increase or even a decrease after at least 1 year of HRT (5.39+/-2.40% decrease per year).     

Bone Mass,Serum Lipids,and Lipoproteins during Three Years of Opposed Estrogen Replacement

The effects of three years of low dose or moderate dose hormone replacement on bone mass and serum cardiovascular risk factor were measure in post-menopausal women. After six months of calcium supplementation, women chose to add hormone replacement therapy (HRT) or to remain on calcium. Those choosing hormones were randomized either to a law dose or moderate dose group. The low dose regimen was 0.3 mg/d equine estrogen and 2.5 mg/d medroxyprogesterone for three years. The moderate dose group rook 0.625 mg/d equine estrogen (days 1-25) and 5 mg/d medroxyprogesoerone (days 16-25) for the first two years, after which the cyclical regimen was replaced with a continuous regimen of 0.625 mg/d dequine estrogen and 2.5 mg/d medroxyprogesterone.Low dose HRT prevented the loss of radius bone mass observed in subjects taking calcium only. Moderate dose HRT also protected radius bone mass, increased lumbar spine bone mass, and improved the ratio of serum high density to low density lipoproteins.     

Influence of estrogen replacement therapy on endogenous calcitonin production rates.

Calcitonin is now a well-accepted therapy for inhibition of bone loss, both in the first years of menopause and in established osteoporosis. However, its exact role in the pathogenesis of that disease as well as the interactions between calcitonin production and estrogen metabolism remain unsolved. In order to clarify the influence of estrogen replacement therapy (ERT) on calcitonin secretory capacity, we measured whole plasma immunoreactive calcitonin basal levels, metabolic clearance rates and production rates in a group of postmenopausal women, before and after a daily intake for 28 days of 0.625 mg/day of conjugated equine estrogens, and again 4 weeks after the withdrawal of that estrogen replacement therapy. No significant changes appeared in immunoreactive calcitonin or immunoreactive calcitonin metabolic clearance rate but the production rate significantly increased over the 28 days (mean +/- SEM, from 21.3 +/- 5.1 pg/ml to 25.2 +/- 5.9 pg/ml, p less than 0.05), and then decreased 4 weeks after therapy was withdrawn to the initial level (17.9 +/- 3.6 pg/ml). We concluded that estrogen replacement therapy significantly increases calcitonin secretory capacity. This confirms the interactions between calcitonin production and estrogen metabolism, and may provide an explanation concerning the mode of action of estrogen replacement therapy in prevention of postmenopausal bone loss.     

Prevention of postmenopausal osteoporosis

Prevention of osteoporosis is clearly the preferred approach, since treatment of the established disorder is less than satisfactory. However, accurate identification of those at risk for fractures is impossible at present. By judicious use of risk assessment and the addition of bone mass measurements in the postmenopausal patient, the physician can define a group of patients who will be at some increased likelihood of subsequent osteoporosis. Since estrogen therapy is the most effective single agent for prevention of bone loss, estrogens can be recommended for this group of patients, if otherwise not contraindicated. The addition of a progestogen to the regimen may add to the effect of estrogen by stimulating bone formation. Estrogen therapy may have other effects in the postmenopausal patient population that must be considered when deciding about the introduction of therapy.     

Hormone replacement therapy or SERMS in the long term treatment of osteoporosis

Replacement therapy with estrogen and progestogen (HT) or estrogen alone (ET) and selective estrogen receptor modulators (SERMS) still constitute valuable additions to the range of osteoporosis treatments available. Due to the diverse action on a wide variety of organs, HT/ET has the capacity to improve quality of life in most postmenopausal women,- more than other more specific osteoporosis treatments. The initial optimism associated with HRT 20-30 years ago was reduced considerably after the HT arm of WHI was stopped prematurely due to safety concerns. Later analyses of the WHI study have, however, tempered the negative messages emerging from the first publication in 2002. HT/ET still constitutes a first line choice for prevention of bone loss and fracture in the early postmenopausal period for a period of 5 years. However, in women with low risk of adverse events classically associated with HT/ET newer analyses show that treatment can be continued with an acceptable risk benefit ratio. These analyses have also highlighted the negative impact of progestogens on breast cancer risk an adverse effects on the cardiovascular system. Newer guidelines therefore suggest that a combination of a progestogen IUD and transdermal estrogen seems to be the best alternative for long term treatment. This combination minimizes cardiovascular safety concerns by avoiding the negative impact of first pass metabolism in the liver seen with oral compounds and minimizes exposure to progestogens. SERMS are valuable alternatives, particularly in osteopenic women (t-score -1,0 to -2,5) at increased risk of breast cancer, but their general lack of anti fracture efficacy towards non vertebral fractures limits their use in women at high risk of osteoporotic fracture.     

Serum osteocalcin and urinary crosslaps are suitable markers of bone turnover in response to short-term hormone replacement therapy.

In this study we evaluated the effect of short-term hormone replacement therapy (HRT) on bone formation (serum osteocalcin) and resorption markers (urinary type I collagen peptides (crosslaps), urinary total free pyridinoline (TPYRI) and urinary free deoxypyridinoline (DPYRI)) as well as female sex hormones (serum estradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH)) in a group of early postmenopausal women with severe estrogen deficiency. The 46 healthy postmenopausal women with serum estradiol levels < 10 ng/l were subsequently divided into two groups, according to their compliance with HRT. In the group taking HRT significant changes from baseline values could be observed in estradiol, FSH, urinary crosslaps and serum osteocalcin levels after 6 months, whereas no changes could be observed in LH, TPYRI and DPYRI from baseline values. In the group which refused HRT all values were increased relative to baseline values, indicating increased bone turnover. Serum osteocalcin and urinary crosslaps were significantly decreased in women taking HRT in comparison to the group refusing HRT. After 6 months the treated patients showed a decrease in urinary crosslaps of 42% (SD 12%) and in serum osteocalcin of 24% (SD 6%) in comparison with baseline values. In patients who refused HRT, urinary crosslaps were increased by 43% (SD 20%) and serum osteocalcin levels decreased by 2% (SD 9%) compared to baseline values. In postmenopausal women suffering from severe estrogen deficiency (estradiol < 10 ng/l) serum osteocalcin and urinary crosslaps are significantly increased, indicating a clear correlation between estrogen deficiency and an increase in bone resorption as well as bone formation. The recommended HRT dose was sufficient to reduce the rate of bone turnover to premenopausal values. Serum osteocalcin and urinary crosslaps are suitable candidates not only for the assessment of a high postmenopausal bone turnover, but also for monitoring the response to and for verifying the actual intake of HRT or other antiresorptive treatment.     

The menopause in Europe

Most women in developed countries will live a third of their lives after the menopause. Vasomotor symptoms (hot flushes, night sweats, irritability, sleep disturbances, mood swings), and urogenital complications (atrophic vaginal irritation and dryness, dyspareunia) occur frequently during this period of life, but their severity and duration may vary widely between individuals. The menopause also induces accelerated bone loss and is the principal risk factor for osteoporosis. Hormone replacement therapy (HRT; estrogen or estrogen plus progestogen) alleviates these symptoms and can be administered orally, transdermally, topically, intranasally, or as subcutaneous implants. HRT is also effective for prevention and treatment of postmenosausal osteoporosis throughout the time that it is used. It is not surprising that HRT use has increased substantially during the past decade. Nevertheless, there are still considerable variations in use between different countries within the European community. This presentation will analyze: the frequency of menopausal symptoms among women in different European countries and the factors that influence them; the frequency of other postmenopausal women's health issues in Europe; the use of HRT in Europe as well as the type of HRT and its evolution during the last decade; and possible reasons explaining heterogeneity between countries.     

Use of progestogens in postmenopausal women

Estrogen therapy for postmenopausal women has received adverse publicity since the mid-1970s because several reports linked estrogens with an increased risk of endometrial cancer. Other studies indicated that the risk of endometrial malignancy is reduced when a progestogen is added to the estrogen replacement. Not all postmenopausal women need estrogen replacement. Because some continue to produce significant amounts of endogenous estrogens, many need progestogen replacement to reduce the risk for endometrial hyperplasia and adenocarcinoma. It has been well demonstrated that estrogen replacement therapy does not increase the risk for breast cancer. However, added progestogen may actually reduce the risk for this malignancy in some women. Where estrogen therapy retards the development of and helps to prevent osteoporosis, added progestogen may restore bone which has been lost by promoting new bone formation. The greatest benefit to accrue to postmenopausal estrogen users is prevention of cardiovascular disease. Concern has been expressed that added progestogen may negate this benefit by adverse effects on lipids. Side effects of added progestogen occur, but these may be managed by changing to another progestogen or adding a mild diuretic.     

Monitoring of hormone replacement therapy in postmenopausal women by transvaginal sonography and color flow doppler: study in different phases of sequential therapy

OBJECTIVE: To assess uterine artery blood flow and endometrial thickness in postmenopausal patients receiving sequential hormone replacement therapy (HRT) at different phases of the treatment. DESIGN: Prospective controlled study. SETTING: Ultrasound and menopause units of the obstetrics and gynecology department of the University of Tor Vergata, Rome, Italy. PATIENT(S): Forty postmenopausal women were treated with cyclic sequential HRT (transdermal E2, 50 microg/d, days 1-21; and dydrogesterone, 10 mg/d, days 12-24). INTERVENTION(S): All patients underwent transvaginal color Doppler sonography in the estrogen (phase E) and progestogen (phase E/P) phases and after uterine bleeding when no hormone was administered (phase 0). MAIN OUTCOME MEASURE(S): Endometrial thickness; systolic, diastolic, and mean velocities; and pulsatility and resistance indices of the uterine arteries. RESULT(S): No statistically significant difference in endometrial thickness between phase E (6.5+/-1.6 mm) and phase E/P (6.0+/-1.7 mm) was observed. In phase 0, compared with phases E and E/P, a statistically significant decrease in endometrial thickness was found (4.1+/-1.2 mm). Doppler flow impedance parameters of uterine arteries during the different phases of the HRT cycle showed no differences between the phases considered. CONCLUSION(S): The decrease in endometrial thickness in phase 0 suggests a protective effect of our cyclic sequential regimen on the endometrium. Dydrogesterone does not interfere markedly with the vasodilatory effect of estrogen on uterine arteries.     

Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000

OBJECTIVE: To establish reference estimates of the effects of different hormone replacement therapy (HRT) regimens on lipid and lipoprotein levels. DESIGN: Review and pooled analysis of prospective studies published up until the year 2000. SETTING: Clinical trials centers, hospitals, menopause clinics. PATIENT(S): Healthy postmenopausal women. INTERVENTION(S): Estrogen alone, estrogen plus progestogen, tibolone, or raloxifene in the treatment of menopausal symptoms. MAIN OUTCOME MEASURE(S): Serum high- and low-density lipoprotein (HDL and LDL) cholesterol, total cholesterol, triglycerides, and lipoprotein (a). RESULT(S): Two-hundred forty-eight studies provided information on the effects of 42 different HRT regimens. All estrogen alone regimens raised HDL cholesterol and lowered LDL and total cholesterol. Oral estrogens raised triglycerides. Transdermal estradiol 17-beta lowered triglycerides. Progestogens had little effect on estrogen-induced reductions in LDL and total cholesterol. Estrogen-induced increases in HDL and triglycerides were opposed according to type of progestogen, in the order from least to greatest effect: dydrogesterone and medrogestone, progesterone, cyproterone acetate, medroxyprogesterone acetate, transdermal norethindrone acetate, norgestrel, and oral norethindrone acetate. Tibolone decreased HDL cholesterol and triglyceride levels. Raloxifene reduced LDL cholesterol levels. In 41 studies of 20 different formulations, HRT generally lowered lipoprotein (a). CONCLUSION(S): Route of estrogen administration and type of progestogen determined differential effects of HRT on lipid and lipoprotein levels. Future work will focus on the interpretation of the clinical significance of these changes.     

中老年女性骨质疏松症的其他治疗方法

激素补充治疗（hormone replacement therapy,HRT）是预防和治疗绝经后女性骨质疏松症（osteoporosis, OP）的一线治疗方案,但是中国女性HRT接受率仅1%~2%,主要原因是担心其不良反应的发生。因此,对于不愿意接受HRT或者有HRT禁忌证的绝经后骨质疏松症女性患者,可以用非激素类药物如选择性雌激素受体调节剂、双膦酸盐、降钙素、甲状旁腺激素、锶盐 、维生素K等。     

Ossein-hydroxyapatite compounds for preventing postmenopausal bone loss. Coadjuvant use with hormone replacement therapy

OBJECTIVE: To evaluate whether the addition of an ossein-hydroxyapatite compound (OHC) may improve the effect of hormone replacement therapy (HRT) on postmenopausal bone loss. STUDY DESIGN: Of the 118 recent surgically postmenopausal women initially selected for this open study, 96 completed one-year follow-up. Patients were allocated into four groups. The first group received 50 micrograms/d of transdermal 17-beta estradiol continuously (group E, n = 23), the second received 3.32 g/d of an OHC every day (group OHC, n = 23), the third received 50 micrograms/d of transdermal 17-beta estradiol continuously plus 3.32 g/d of the OHC every day (group E-OHC, n = 26), and an additional 24 women were used as untreated controls (group C). Bone mass, assessed by dual x-ray absorptiometry, was measured prior to and at the end of treatment. Samples, including serum calcium, phosphate and osteocalcine level, were collected before therapy and during the 6th and 12th treatment months. RESULTS: All treatment groups showed an increase in bone mineral content. This increase was higher in the E-OHC group (4.7%, P < .01). Concomitant biochemical effects at 6 and 12 months were compatible with the observed effects on bone mineral. CONCLUSION: The combined regimen of OHC and HRT increased vertebral bone mass in postmenopausal women to a greater extent than did OHC or HRT alone, suggesting that this drug combination may be useful in the management of postmenopausal bone loss.     

A review of combination regimens for osteoporosis--prevention and treatment

Two long-used interventions for reducing the morbidity and mortality associated with osteoporosis are postmenopausal hormone replacement therapy (HRT) and treatment with antiresorptive agents. Postmenopausal HRT works through prevention of osteoporosis, whereas antiresorptive agents, such as the bisphosphonates, reverse low bone mass. Because of their different mechanisms, it has been thought that combining the two therapies would yield additive improvements in bone mineral density (BMD) and in fracture risk reduction. Results from several recent clinical trials in postmenopausal women with low bone mass support this idea, demonstrating clinically relevant additive improvements in BMD after treatment with HRT (or a selective estrogen receptor modulator) plus a bisphosphonate. Data regarding fracture rates after HRT and bisphosphonate combination therapy are unavailable, however. A newer osteoporosis treatment is subcutaneously injected parathyroid hormone (PTH). Treatment with PTH stimulates new bone formation, and recent studies have shown that PTH monotherapy reduces fracture rates. Initial data from studies of HRT and PTH combination therapy have shown impressive gains in BMD, but fracture rate data have not been published. Use of HRT for osteoporosis, either alone or in combination with a bisphosphonate or PTH, has become problematic since the recent report of a small number of serious adverse effects associated with HRT in the Women's Health Initiative.     

L-thyroxine prevents the bone-conserving effect of HRT in postmenopausal women with subclinical hypothyroidism.

Hypothyroidism, which is a common disorder among postmenopausal women, may be associated with higher than average bone mineral content. Contrarily, treatment with L-thyroxine may cause a significant bone loss. The aim of our study was to evaluate the effects of hormone-replacement therapy (HRT) on bone density in women with subclinical hypothyroidism treated with L-thyroxine. A total of 73 postmenopausal women with thyroid-stimulating hormone (TSH) levels > 5 mU/l and normal free thyroxine values, who never used HRT or L-thyroxine, were divided into three groups according to the treatment given during a 3-year follow-up period: 34 women received only HRT; 20 women received HRT and L-thyroxine, and the remaining 19 women received neither medications. A euthyroid control group included 41 postmenopausal women with TSH levels between 0.5 and 1.5 mU/l, who were using HRT since the initial visit. Lumbar spine bone density measurements were performed at baseline and study termination. Taken as a whole, the hypothyroid women had a non-significant higher baseline bone mineral density (BMD) as compared to the euthyroid controls (1.068 +/- 0.19 g/cm2 vs. 1.024 +/- 0.15). After 3 years, both the euthyroid and hypothyroid women on HRT only had an increase in BMD (0.032 +/- 0.04 g/cm2 and 0.028 +/- 0.05 g/cm2, respectively; p < 0.001 for both, compared to baseline). Hypothyroid women using no medication had a decrease of 0.034 +/- 0.07 g/cm2 in BMD, and those receiving both HRT and L-thyroxine lost the most: 0.04 +/- 0.08 g/cm2 (p < 0.05 for both, compared to baseline). The addition of L-thyroxine thus prevented the beneficial effect of HRT on BMD. Thyroid hormone replacement is recommended only when overt symptoms of hormone deficiency occur. In such cases, a single bone-conserving treatment with HRT may not suffice.     

Changes to the periodontium in postmenopausal women

Few up to date studies on the influence of hormonal replacement therapy (HRT) on periodontium has been conducted on small groups of patients and the conclusions made may require further investigation on a larger population. It has been widely accepted that decreased estrogen levels in postmenopausal women are associated with a gradual loss of a bone density and increased risk of a dental loss. Much less stress is put however on the fact that the same phenomenon, especially suboptimal levels of estradiol, may deteriorate periodontal tissue condition. The authors made a literature search on the influence of HRT on periodontium.     

New possibilities for diagnosis and treatment of osteoporosis

Postmenopausal osteoporosis is preventable and treatable. Women need not lose bone mineral density (BMD) after the menopause. Without intervention, all women lose bone after menopause, regardless of the amount of calcium, vitamin D, and exercise they undertake. Postmenopausal women need estrogen replacement, a selective estrogen receptor modulator (SERM), or a bisphosphonate to prevent bone loss. Alendronate, risedronate (bisphosphonates) and raloxifene (SERM) are approved for the prevention of bone loss. The diagnosis of at-risk postmenopausal women can best be accomplished by measuring BMD in all postmenopausal women age 65 years and older regardless of their risk profile and in all postmenopausal women under 65 years with one or more risk factors. Treatment guidelines direct physicians to treat postmenopausal women with T-scores lower than -2.0 SD regardless of their risk profile and postmenopausal women with T-scores lower than -1.5 SD with one or more risk factors. The lower the BMD, the greater the fracture risk, particularly in individuals with increased age, existing fragility fractures, or high bone turnover. The best intervention for a patient should be individually selected, based on careful clinical assessment. Although calcitonin is not approved for prevention, it is approved for treatment. The labeling of estrogens has been modified to state that they may be used to "manage" osteoporosis. The lack of efficacy of calcitonin to prevent bone loss during the first 5 years after menopause, and the lack of prospective fracture reduction data for estrogen, have resulted in these labeling restrictions. Alendronate, risedronate, and raloxifene are currently approved for the treatment of osteoporosis. Both of these compounds have been shown to increase BMD and decrease fracture risk. Monitoring of a patient's response to treatment may be accomplished using serial BMD testing and biomarkers of bone turnover.     

Effects on bone of surgical menopause and estrogen therapy with or without progesterone replacement in cynomolgus monkeys

The influence of estrogen replacement therapy on bone loss of surgically postmenopausal cynomolgus macaques was evaluated histomorphometrically using the first (L-1) lumbar vertebra and ex vivo dual photon absorptiometry of the third (L-3) lumbar vertebra. The animals were a subgroup of a larger study on the effects of estrogen replacement therapy on diet-induced coronary artery atherosclerosis. The three experimental conditions were as follows: untreated females with oophorectomy, females with oophorectomy treated with continuous estrogen replacement therapy plus cyclic progesterone, and females with oophorectomy treated with estrogen replacement therapy. Bone mineral density (grams per square centimeter) of L-3, when covaried for body mass index (body mass index, body weight/(trunk length/100)2), was significantly lower for the oophorectomy group compared with the group treated by estrogen replacement therapy plus progesterone and estrogen replacement therapy groups (p = 0.018). When covaried for body mass index, trabecular bone volume percentage of a midsagittal section of L-1 was not significantly different between groups, but the adjusted mean was greatest in the estrogen replacement therapy plus progesterone group, followed closely by the estrogen replacement therapy group, and was least in the oophorectomy group. When covaried for body mass index, trabecular plate number was significantly lower (p = 0.022) and mean trabecular plate separation was significantly higher (p = 0.033) in the oophorectomy group. Thus both estrogen replacement therapy and estrogen replacement therapy plus progesterone provided overall protection against surgical menopause--associated bone mass loss. Cynomolgus macaques are an extremely useful animal model for estrogen replacement therapy use in prevention of postmenopausal bone loss.     

Effects of hormone replacement therapy on plasma homocysteine and C-reactive protein levels.

In order to investigate the effect of hormone replacement therapy (HRT) on plasma homocysteine and C-reactive protein (CRP) levels 46 healthy postmenopausal women were prospectively enrolled. HRT, which was either 0.625 mg/day conjugated equine estrogen (CEE) plus 2.5 mg/day medroxyprogesterone acetate (MPA) or 0.625 mg/day CEE alone were administered. After 6 months, estrogen alone significantly increased serum CRP concentrations (p = 0.039), however, estrogen plus progesterone therapy did not significantly alter serum CRP levels. Both regimens significantly decreased plasma homocysteine levels (CEE group p = 0.034, CEE+MPA group p = 0.007). It was concluded that the reduction in plasma homocysteine levels with both regimens might contribute to the cardiovascular benefit of HRT and the CRP raising effect of estrogen might be partially prevented by the addition of progesterone.