早发性卵巢功能不全激素补充治疗利弊评价

早发性卵巢功能不全（POI）指女性在40岁之前卵巢活动衰退的临床综合征,以月经紊乱伴高促性腺激素及低雌激素为特征。POI患者可出现潮热、出汗等绝经期症状,远期可发生骨质疏松、心血管疾病等问题。激素补充治疗（HRT）是POI患者的有效治疗方法。文章对POI患者应用HRT的获益及可能存在的风险进行综合分析与评价。     

早发性卵巢功能不全激素补充治疗利弊评价

早发性卵巢功能不全（POI）指女性在40岁之前卵巢活动衰退的临床综合征，以月经紊乱伴高促性腺激素及低雌激素为特征。POI患者可出现潮热、出汗等绝经期症状，远期可发生骨质疏松、心血管疾病等问题。激素补充治疗（HRT）是POI患者的有效治疗方法。文章对POI患者应用HRT的获益及可能存在的风险进行综合分析与评价。     

Management der prämaturen Ovarialinsuffizienz

The term “premature ovarian insufficiency” (POI) describes the premature loss of ovarian function before the age of 40 years. With POI comes a combination of hypogonadotropic hypogonadism and primary/secondary amenorrhea. POI not only has an adverse impact on a woman’s quality of life, psychological well-being and fertility, but is also associated with negative long-term effects on bone health, cardiovascular system and cognitive function. To prevent estrogen deficiency-related long-term consequences hormone replacements therapy at least until the average natural menopause age is recommended. The benefit-risk profile of HRT in naturally postmenopausal women cannot be unrestrictedly extrapolated to the cohort of patients with POI. In patients with POI, the benefits of HRT far outweigh the potential risks.     

早发性卵巢功能不全激素补充治疗

早发性卵巢功能不全（POI）是指女性40岁之前卵巢活动衰退,对患者健康造成严重不良影响的临床综合征。POI患者更需要激素补充治疗（HRT）,并且HRT风险更低,只要没有禁忌证,应积极推荐POI患者使用HRT以缓解症状并降低远期风险。POI患者建议应用系统性HRT,推荐序贯方案。所需雌激素剂量相对更高,孕激素剂量需根据雌激素的剂量相应调整。HRT用药期间应定期检查并评估利弊,建议长期应用,至少持续至正常绝经年龄。     

Individualisierte Hormontherapie in Peri- und Postmenopause

Initiation and surveillance of menopausal hormone therapy is important in the gynecological care of patients. Tailored therapy that meets the patient’s needs and simultaneously considers her individual risks is a major goal in proper counseling. The individual impairment of quality of life has to be weighed against the risks of hormone therapy. In addition to dominant symptoms, the patient’s risk profile and still existent follicular activity are crucial. In patients with vascular risk factors, estrogen should be administered transdermally. In women with an intact uterus, progestin administration is mandatory in addition to estrogen therapy and the delivered dose must be sufficient for transformation of the endometrium. When choosing an appropriate progestin, its hormonal potency to suppress the hipopituitary–ovarian axis and its partial effects on different steroid receptors should be considered.     

Estrogen and combined hormone therapy for women after genital malignancies: a review

This review summarizes information regarding estrogen therapy (ET) and hormone therapy (HT) for women with endometrial cancer as well as other gynecologic malignancies. The cumulative experience from 4 case-control studies consists of 537 affected women. Of the 228 patients who received estrogen therapy, 3.5% developed recurrences as opposed to 16.5% among the 309 women receiving no therapy. Administration of ET at an early stage of disease is therefore appropriate if a few conditions are fulfilled. The impact of estrogen on other gynecologic malignancies is not as evident. As to ovarian cancer, the information on hormone employment is scantier and derives mainly from statistical analysis of data on healthy users of estrogen alone or combined with progestin. Several age-matched, case-control studies and 4 meta-analyses disclosed a higher rate, though not significant, of the later development of ovarian cancer among hormone users. Focusing on patients with disease, 2 trials conducted so far have failed to demonstrate any change in survival or mortality from ET or HT. It is agreed, however, that the histologic type of the tumor is an important factor to consider prior to the initiation of such therapy. The current literature permits ET in most cases of ovarian cancer, but further studies are needed to clearly delineate specific contraindications. Utilizing estrogen compounds has no bearing on risks of later developing squamous cell carcinoma of the cervix, or tubal, vulvar or vaginal cancer. Those conditions do not seem to contraindicate later employment of ET or HT. A previous history of cervical adenocarcinoma, however, definitely prohibits the use of these hormonal regimens.     

Monitoring of ovulation induction with HMG-HCG therapy by plasma estrogen and progesterone

Seventeen patients with anovulation or luteal deficiency were tested with HMG-HCG for 40 cycles. Follicular development was monitored daily by measurement of immunoreactive plasma estrogen. Ovulation was evaluated by determination of plasma progesterone. Ovulation was induced in 16 patients and 37 of 40 cycles (93%). Fourteen pregnancies occurred in 13 patients. Plasma estrogen measurements in ovulatory cycles at the time of HCG injection ranged from 315 to 1,482 pg/ml (mean 764 pg/ml). Mild hyperstimulation occurred in two cycles with preovulatory estrogen values of 720 pg/ml and 784 pg/ml. The highest preovulatory estrogen level which was followed by anovulation was 493 pg/ml. The preovulatory estrogen peak in one triplet pregnancy measured 1,356 pg/ml. Determinants of treatment failure included inadequate follicular stimulation, interruption of HMG therapy for more than 1 day, previous ovarian wedge resection, and congenital anomaly of the uterus. Increase in body weight required higher doses of drug therapy in one case. We conclude that optimal estrogen levels prior to HCG injection range from 500 to 700 pg/ml. The risks for ovarian hyperstimulation and multiple pregnancy may be reduced and ovulation accomplished by daily administration of HMG until the defined estrogen level is reached.     

早发性卵巢功能不全对心血管疾病影响

早发性卵巢功能不全患者与同龄个体相比心血管疾病风险较高。目前仍缺乏有效筛查早发性卵巢功能不全女性心血管疾病风险的工具。内源性雌激素对心血管有保护作用,及时适量进行激素补充治疗可延缓心血管疾病的发生。     

Endometrial "sarcomas" complicating ovarian thecoma, polycystic ovarian disease and estrogen therapy

Unopposed endogenous and exogenous estrogenic stimulation has been considered by most investigators to have a role in the pathogenesis of carcinoma of the endometrium. Although a few cases of "sarcomas" of the endometrium that had developed in an estrogenic setting have been reported, a clear-cut association between estrogenic stimulation and these forms of endometrial cancer has not been established. We report six cases of endometrial sarcomas complicating ovarian thecomas, polycystic ovarian disease, or prolonged estrogen therapy. Three ovarian thecomas, which are considered to be estrogenic tumors, were associated with endometrial malignant mullerian mixed tumor, mullerian adenosarcoma, and low-grade stromal sarcoma in postmenopausal women. Polycystic ovarian disease, a condition characterized by unopposed estrinism due to the peripheral conversion of excessive androstenedione to estrone, was found in a 27-year-old infertile woman with an endometrial malignant mullerian mixed tumor. A pure osteogenic sarcoma of endometrial stromal origin developed in a 28-year-old woman with gonadal dysgenesis (Turner's syndrome) who had received estrogens for 18 years. The sixth woman, with an empty sella turcica after radiation therapy of a pituitary adenoma, had an endometrial mullerian adenosarcoma at the age of 40 years after 16 years of estrogen therapy. None of these patients had had pelvic radiation therapy. The evidence from this series of cases and from six additional cases identified in the literature suggests that the risk of endometrial sarcomas may be increased by estrogen therapy or endogenous disorders that lead to unopposed estrogenic stimulation of the uterus.     

Review of Hormone Replacement Therapy in Girls and Adolescents with Hypogonadism

Girls with either hypo- or hypergonadotropic hypogonadism need treatment with estrogens to initiate puberty and maintain a normal hormonal milieu. The focus of this review is hormone replacement treatment in girls with hypogonadism, to initiate and progress through puberty, and to maintain a healthy hormonal milieu in women. It also addresses what is known in the literature regarding estrogen levels in girls and women, instructive cases, practical tables for reference and application, and thoughts on future directions in this area. It represents a thorough literature review with author opinions and recommendations. Girls with normal ovarian function begin puberty on average at 10.5 years old, although there is variation according to ethnicity and degree of excess weight gain. The aim of estrogen therapy to initiate puberty is to mimic normal onset and rate of progression. On the basis of the currently available literature, when a diagnosis of hypogonadism is established, we recommend initiating treatment between age 11 and 12 years of age, with dose increases approximately every 6 months until adult levels are reached. In some situations, treatment may be delayed to allow time for diagnosis or permit more time for linear growth, or address unique risks found in girls treated for various cancers or blood disorders. When adult dosing is reached, progestins are also used to protect uterine health. This can be combined sequentially, allowing regular menstruation, or combined continuously when menstrual bleeding is not preferred. Treatment is continued until the average age of menopause, again with various considerations for longer or shorter duration on the basis of risk-benefit ratios. Transdermal estrogens are considered the most physiologic replacement and theoretically might have fewer associated risks. We review what is known about risks and outcomes and areas for future research.     

„Premature ovarian insufficiency/failure syndrome“ (POI/POF)

The average age of women at menopause is 50-52 years. Approximately 1?% of women are affected by an earlier onset of ovarian insufficiency before the age of 40 years which is known as premature ovarian insufficiency/premature ovarian failure syndrome (POI/POF). Affected women suffer from estrogen deficiency syndromes identical to the symptoms of older menopausal women. There are multifactorial causes of POI/POF including various autoimmune, iatrogenic, genetic, infectious and idiopathic reasons. In cases of suspected POI/POF syndrome a systematic diagnostic procedure and counseling are required. Association with various autoimmune diseases is relevant and testing for Addison’s disease is required. A karyogram is useful to detect gonadal dysgenesis. For genetic reasons testing for a premutation of the FMR1- (fragile X mental retardation 1) gene is recommended. The probability of spontaneous conception of approximately 5?% is also important to make adjustments to the hormone therapy (HT). Such a HT is useful to improve symptoms of estrogen deficiency and is probably also osteoprotective and cardioprotective. An HT should be continued until the normal age of menopause. Chemotherapy and/or radiotherapy are iatrogenic reasons for POI/POF; therefore, women should be counseled about fertility preservation methods before starting adjuvant therapy for malignant diseases.     

Postmenopausal endometriosis

The frequency of postmenopausal endometriosis (ovarian endometriosis and adenomyosis) was 2.2%. The mean of the menopausal ages in 11 patients with ovarian endometriosis was 50.3 yr and the average time elapsed since menopause, 7.3 yr. The corresponding values in 8 patients with adenomyosis were 52.1 and 8.8 yr. Carcinoma was a common associated finding in patients with ovarian endometriosis. Increased estrogen activity was observed more frequently in patients with adenomyosis than in those with ovarian endometriosis. Only one of the patients had received estrogen therapy. Hormone-producing tumors in the ovaries or adrenal glands were not confirmed. 70% of the patients were obese and the signs of increased estrogen activity could be explained by extraglandular estrogen formation.     

The randomized world is not without its imperfections: reflections on the Women's Health Initiative Study

In May 2002, the Women's Heath Initiative (WHI) clinical trial, designed to clarify the risks and benefits of combination hormone replacement therapy, came to a premature halt. An interim safety review after an average follow-up of 5.2 years found that a combination of estrogen and progestin often prescribed to postmenopausal women increased the risk of invasive breast cancer, heart disease, stroke, and pulmonary embolism. The combination hormone therapy reduced bone fractures and colorectal cancer, but not enough to outweigh the other risks. The WHI trial presents a challenge for patients, physicians, and epidemiologists, since many observational studies have shown cardiovascular benefits of long-term hormone replacement therapy (HRT). At the same time, a companion paper in the same journal reported an epidemiologic study with a 13.4-year mean follow-up suggesting that estrogen replacement therapy, when used alone for 10 years or more, increases the risk of ovarian cancer. The medical community is still recovering from these twin shocks and trying to digest the results of both of these studies. The WHI study calls into question the long-term use of HRT in healthy women. The benefit of the temporary use of estrogen in controlling disruptive symptoms of the menopause is not being contested. Absent from many news releases are the hedging and equivocation typical of other reported clinical trials. There are still some "hanging chads" out there, and this commentary is designed to examine the uncertainties that remain after the WHI report. It is also intended to suggest development of alternative strategies to control symptoms of the menopausal transition that will reduce risks of HRT. The evidence from the WHI study will need to be incorporated into medical decision making, but clinical decisions, like most human decisions, are complex and in the final analysis must be based on information from many sources.     

Case report. Successive pregnancies in a patient with premature ovarian failure

A woman, age 28 yr, visited the gynecological endocrine clinic for oligomenorrhea and primary infertility. Serum FSH and LH levels were high and estrogen concentrations were subnormal. In spite of the presence of high and sustained gonadotropin concentrations, resumption of ovarian function with evident ovulation resulted in the first pregnancy after clomiphene therapy. Four years later the patient did not respond to clomiphene but intramuscular progesterone was effective in induction of ovulation, followed by the second pregnancy. The effect of progesterone on hypergonadotropic ovarian failure is discussed.     

Doubts about oestrogen therapy in postmenopausal women

In postmenopausal women, the predominate steroid is estrone, and data have indicated that conversion of androgen to estrone is 2-3 times greater in women with endometrial cancer than in others. 2 studies of exogenous estrogens in postmenopausal women are summarized. In the 1st, 317 patients with adenocarcinoma were compared with matched controls with cervical, ovarian, and vulval neoplasms. 152 patients had estrogen therapy as compared with 54 controls, and calculations revealed the cancer risk as 4.5 times greater among patients than controls. The 2nd study concerned the use of conjugated estrogens. 94 patients with endometrial cancer and double that number of matched controls were examined. Conjugated estrogens had been used by 57% of patients and only 15% of controls. The data revealed an increased risk of 5.6 times in patients using estrogen for between 1 and 5 years, rising to 13.9 times greater risk after 7 or more years; and this relationship could not be explained by factors such as age, parity, obesity, or menopausal age. The chance of endometrial cancer in postmenopausal women not using estrogens is 1/100,000/year. In estrogen users, the level increases to between 4 and 8/100,000/year. More information is needed on effects of estrogens; they are valuable in relieving psychological symptoms, vasomotor instability, and, perhaps, mortality, osteoporosis, fractures, and vascular diseases after oophorectomy. These advantages have to be weighed against thromboembolism, coronary diease, strokes, and possible cancer; the benefits and risks are not easily calculated.     

Reproductive hormones and cancer: ovarian and colon cancer

Evidence continues to accumulate that oral contraceptive use provides substantial protection against ovarian cancer. Less clear is whether the benefit affects women with genetic predisposition or women in the perimenopausal age range. The role of hormone replacement therapy in the occurrence of ovarian cancer is unclear. Available evidence suggests that if there is any potential risk, it involves women who use estrogen alone. Few women if any entering the menopause are at risk. There is some evidence that oral contraceptives have a favorable impact on the risk of colorectal cancer. Available data are limited. Finally, there is growing evidence that hormone replacement therapy reduces risk of colorectal cancer, a benefit that accrues to perimenopausal women.     

Lasting response to ovariectomy in severe intractable premenstrual syndrome

A total of 14 women with severe premenstrual syndrome unresponsive to conservative medical therapy were treated with danazol in doses sufficient to suppress cyclic ovarian steroidogenesis. In each case medical ovarian suppression resulted in complete relief from symptoms. For ongoing symptom relief, each woman elected to undergo bilateral ovariectomy and concomitant hysterectomy. Both medical ovarian suppression and ovariectomy with low-dose conjugated estrogen therapy afforded lasting relief from cyclic symptoms of premenstrual syndrome and a corresponding improvement in overall quality of life. We conclude that cyclic ovarian steroidogenesis is a powerful determinant for the expression of premenstrual symptomatology. Ovariectomy with low-dose estrogen replacement is an effective alternative for the woman with debilitating premenstrual syndrome who does not respond to conventional interventions.     

Assisted reproduction and breast cancer

Breast cancer is the most frequent cancer in reproductive age women. Although well known causal link between estrogen and breast cancer, the impact of ovulation induction on the risk of breast cancer still remains to be clarified. One of the recently recognized long term adverse effects of adjuvant cytotoxic chemotherapy given for breast cancer is premature ovarian failure and infertility, both of which significantly compromise the quality of life of a cancer survivor. Thanks to significant developments in assisted reproductive technologies these patients may benefit from a wide range of fertility preservation options. The most established technique is embryo cryopreservation; oocyte cryopreservation can be considered in single women; both of which require at least 2 weeks of ovarian stimulation beginning with the onset of the patient's menstrual cycle. Novel ovarian stimulation protocols using tamoxifen and letrozole can be used to increase the margin of safety in estrogen sensitive breast tumors. When there is no time available for ovulation induction, ovarian tissue can be cryopreserved for future transplantation without delay in cancer therapy. The benefit of ovarian protection by gonadotropin-releasing hormone analogues is unproven and unlikely, and thus this treatment should not be recommended as the sole method of fertility preservation.     

Estrogens and epithelial ovarian cancer

OBJECTIVE: Molecular mechanisms involved in ovarian carcinogenesis are still unclear, but there is growing evidence that estrogens promote tumor progression in an epithelial ovarian cancer (EOC) subgroup. METHODS: We reviewed current knowledge on the effects of estrogens in ovarian carcinogenesis and new potential research focuses concerning hormonal therapy of EOC. RESULTS: Experimentally, estrogen stimulates the growth of ovarian tumor cell lines expressing estrogen receptors (ER). We and other authors have demonstrated differential expression of ERalpha or beta during ovarian carcinogenesis, with overexpression of ERalpha as compared to ERbeta in cancer. This differential expression in ER suggests that estrogen-induced proteins may act as ovarian tumor-promoting agents. Among these proteins, c-myc, fibulin-1, cathepsin-D, or several kallikreins may play a role, since high expression levels have been found in EOC. Consistently, recent prospective epidemiological studies have indicated that estrogen replacement therapy in postmenopausal women may increase ovarian cancer incidence and mortality. CONCLUSION: Questions on the estrogen-sensitivity and potential benefits of new hormone therapies in an EOC subgroup should be readdressed in the light of recent experimental and clinical data.     

Turbulent times for hormone replacement therapy: is there a way out?

The long-awaited results of the large Women's Health Initiative (WHI) trial on the effects of combined estrogen-progestin hormone replacement therapy (HRT) in postmenopausal women show that the overall benefits are smaller than the risks. Herein I argue that many of the findings could be predicted from earlier observational studies. Although the WHI trial will rightly reverse the soaring HRT use of the last decades, there is unquestionably a future for HRT. A consensus is growing that postmenopausal women may be treated with HRT only when seeking help for disturbing symptoms of the ovarian hormone insufficiency syndrome, rather than be treated for menopause per se. The ovarian hormone insufficiency syndrome comprises conditions of estrogen and/or androgen insufficiency; at this time, the diagnosis of these clinical entities is based largely on symptomatology. Future research should disclose why the deprivation of ovarian hormones has a variable impact on women's functioning, and further trials ought to reveal effective and safe treatments for women suffering from this syndrome.