Premature ovarian failure from current perspective

Premature ovarian failure (POF) is a syndrome characterised by amenorrhoea, hypoestrogenism and hypergonadotropinism before the age of 40. It is a disorder affecting approximately 1% of women?<40 years, 1/1,000 women by the age of 30 and 1/10,000 women by the age of 20. POF is not merely an early menopause. Up to 50% of the patients with POF will have intermittent and unpredictable ovarian function which may persist for some years. Heterogeneity of POF is also reflected by the variety of possible causes, including autoimmunity, toxics, drugs, radiation, infectious as well as genetic defects. HRT remains the cornerstone of treatment and the only proven method of achieving pregnancy in these patients is by ovum donation.     

Premature ovarian failure: which approaches?

Premature ovarian failure (POF) occurs in one case of 10,000 in women below the age of 20, one case of 1000 below 30 and 1% in women before the age of 40. In 80% of POF cases, the etiology is unknown, except for Turner syndrome. Spontaneous fertility is very weak, only 3 to 10% of the patients will have natural conception. If the diagnosis is confirmed, ovarian stimulation usually fails. When fertility is desired, the alternative treatments are oocyte and/or embryo donation or adoption and "learn to be happy just in couple". Psychological management is always necessary.     

„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.     

Genetic aspects of premature ovarian failure: a literature review

Background  

The diagnosis of premature ovarian failure (POF) is based on the finding of amenorrhea before the age of 40 years associated with follicle-stimulating hormone levels in the menopausal range. It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 years and 1:1,000 women by age 30 years. POF is generally characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea).     

Premature ovarian failure: etiology and prospects.

A search of past and current articles on ovarian physiology and premature ovarian failure (POF) using MEDLINE was performed in order to present an overview of clinical manifestations, necessary laboratory investigations, possible etiologies and treatments for POF. POF is defined as gonadal failure before the age of 40 years. Initially, POF was thought to be permanent, but it is now believed that spontaneous remissions and even pregnancies are possible in affected women. In most cases, the etiology of POF remains elusive, but several rare specific causes have been identified. Although the etiology of POF is heterogenic, the treatment principles are the same. Hormone replacement therapy (HRT) is still the cornerstone of treatment. The only proven method of obtaining a pregnancy in patients with POF is fertilization of a donor oocyte. Cryopreservation of oocytes has worked well in animals but awaits refinement before it can be applied routinely to humans with prodromal POF, or to patients before chemotherapy or irradiation in order to save their oocytes for future fertilization. New alternatives to traditional HRT and methods of fertility preservation are under development, but understanding of the basic pathophysiology of POF is necessary for the development and use of innovative treatments.     

卵巢早衰98例临床特征分析

目的 了解卵巢早衰（premature ovarian failure，POF）患者的临床特征及治疗现状，以指导临床对POF的诊治。方法 回顾性分析2001-08—2004-03北京大学第三医院98例POF患者的临床特征，对98例POF患者和25例正常对照患者的临床数据进行比较，并对POF组中有无家族史者进行临床特征比较。结果 21例POF患者有家族史，占21．4％。83例（84．7％）患者阴道超声可探及至少一侧卵巢，20例（20．4％）患者有卵泡样回声，8例有排卵。POF组初潮年龄与对照组无差别，POF组BMI大于对照组（P〈0．05）。POF组子宫体积和卵巢体积较对照组明显减小（P〈0．01）。POF组抗核抗体阳性率高，但无统计学意义（P〉0．05）。家族性POF和散发性POF的临床特征无明显差别。28．6％的患者缺乏规范化的激素替代治疗（hormone replacement treatment，HRT）。结论 遗传因素和自身免疫因素在POF的发病中占一定地位，但大部分POF为特发性不明原因．POF患者应进行长期的HRT治疗，预防并发症，而赠卵胚胎移植是POF患者获得妊娠的最有效的治疗。     

Spontaneous pregnancies and premature menopause

Hypoestrogenic hypergonadotrophic amenorrhea occurring before the age of 40 years is generally considered irreversible. The term "premature menopause" used to define this condition seems a misnomer, and "premature ovarian failure" (POF) is preferred on both a psychological and a physiological basis. POF is not uncommon considering the incidence rate of 1-2% of women during their theoretically reproductive life. These circumstances are particularly painful when a child is desired. However, since a long time the notion of permanent cessation of ovarian function is challenged and intermittent and transient return of ovarian function has been described with 5-10% chance of pregnancy often more than 12 months after the beginning of the amenorrheic status. A multicentric retrospective study conducted by the GEDO reports 27 pregnancies out of 518 patients waiting for an in vitro fertilization with oocyte donation because of POF or occult ovarian insufficiency. Considering this work and a literature review, we try to propose part of understanding of the basic POF physiopathology, and to examine the factors which could act on the prognosis and the clinical management.     

The genetic basis of premature ovarian failure

Premature ovarian failure (POF) is a common condition, affecting approximately 1:100 women. It is characterised by amenorrhea, hypoestrogenism, and elevated gonadotrophin levels in women under the age of 40. It is often an unexpected and distressing diagnosis, which coincides with infertility and menopausal symptoms. There is a well recognised genetic basis to the development of POF. Our laboratory has identified several candidate genes associated with POF.     

Hormone replacement therapy at women with fertility problems and proofs of hypergonadotropic hypoovarism

The premature ovarian failure (POF), is the main precondition for the origin and the progress of the hypergonadotropic hypoovarism in part of the women with infertility. The significant decrease of the ovarian reserve, makes the treatment of these patients very difficult and problematic, still pregnancy is observed at 5-10% of them. Objective of the research: To study the effect of the Hormone Replacement Therapy (HRT) on the values of FSH before and after the treatment of women with POF, as well as its effect on the percentage of effective pregnancy. 47 infertile women with high values of FSH were included in the study and they followed a 2-4 month treatment with Trisequens tabl. The results of the ART were reported after the reduction of the FSH levels to the normal values. At the end of the treatment followed, the values of the FSH of 41 from 47 patients (87,23%), were reduced to normal range and necessary reproductive procedures were performed. Dividing the patients in 5 groups by age, it was found that the results depend to the greatest extend on this factor. In the group of women up to 30, pregnancy occurred in 25%, between 30 and 35 years this percentage decreased to 22,2%; in the group 35-40 years it sharply decreased to 10% and over 40 years the percentage was 0%. The total percentage of conceived patients for the whole last contingent is 13,4%. The patients with POF and high levels of FSH are worth to follow a Hormone Replacement Therapy before undertaking the oocyte donation.     

卵巢功能早衰的免疫学发病机制及免疫治疗的研究进展

卵巢功能早衰（POF）是指女性在40岁以前发生自然绝经,发病率呈逐年升高的趋势,且有低龄化倾向,可导致不孕不育,雌激素水平低下,对骨骼、心血管系统等也会造成一定影响。POF病因复杂、机制不明,除了部分遗传因素、自身免疫性因素、感染因素、酶缺陷及医源性因素等可明确病因以外,大部分无明确病因可循（即特发性POF）,是临床治疗的一个难题。近期研究表明,自身免疫是POF的重要发病机制之一。自身抗体的产生及细胞免疫功能异常均参与POF的发生。目前的治疗方法疗效均不理想,阐明POF的分子免疫学发病机制及与神经内分泌间的内在联系,将是寻求预防、治疗POF有效方法的关键。     

Twin gestation two years after the diagnosis of premature ovarian failure in a woman on hormone replacement therapy. A case report

BACKGROUND: Premature ovarian failure (POF) is a condition causing amenorrhea, hypoestrogenism and elevated gonadotropins before the age of 40 years and affects around 10% of patients seeking evaluation for secondary amenorrhea. Although it is a rare event, pregnancy has occurred in this group of patients. CASE: A successful twin pregnancy occurred in a 30-year-old woman two years after the diagnosis of POF. Cyclic hormone replacement therapy was initiated after the diagnosis. Twenty-one months later, ultrasound revealed an 8-week twin pregnancy. Two healthy infants, a boy and a girl, were delivered at 36 gestational weeks. CONCLUSION: There are no clinical or laboratory features that unequivocally establish the diagnosis of POF. Neither high levels of gonadotropins nor an ovarian biopsy with rare follicles excludes the possibility of pregnancy. Even though pregnancy in patients with POF is very unlikely, patients should be informed of this possibility, and a contraceptive method should be considered if pregnancy is not desired.     

Ovarian conservation at the time of hysterectomy for benign disease

OBJECTIVE: Prophylactic oophorectomy is often recommended concurrent with hysterectomy for benign disease. The optimal age for this recommendation in women at average risk for ovarian cancer has not been determined. METHODS: Using published age-specific data for absolute and relative risk, both with and without oophorectomy, for ovarian cancer, coronary heart disease, hip fracture, breast cancer, and stroke, a Markov decision analysis model was used to estimate the optimal strategy for maximizing survival for women at average risk of ovarian cancer. For each 5-year age group from 40 to 80 years, 4 strategies were compared: ovarian conservation or oophorectomy, and use of estrogen therapy or nonuse. Outcomes, as proportion of women alive at age 80 years, were measured. Sensitivity analyses were performed, varying both relative and absolute risk estimates across the range of reported values. RESULTS: Ovarian conservation until age 65 benefits long-term survival for women undergoing hysterectomy for benign disease. Women with oophorectomy before age 55 have 8.58% excess mortality by age 80, and those with oophorectomy before age 59 have 3.92% excess mortality. There is sustained, but decreasing, benefit until the age of 75, when excess mortality for oophorectomy is less than 1%. These results were unchanged following multiple sensitivity analyses and were most sensitive to the risk of coronary heart disease. CONCLUSION: Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer when undergoing hysterectomy for benign disease.     

Premature ovarian failure. Clinical evaluation of 32 cases

AIM: Premature menopause, also termed premature ovarian failure (POF), is characterized by cessation of menstruation before the age of 40 years. Pathogenetic mechanisms are not so clear, particularly genetic implications of cellular apoptosis. Diagnostic approach is multifactorial and therapy depends on the pregnancy wish. METHODS: Eight hundred and thirty patients approached the Menopausal Center of the University Department of Gynaecological, Obstetrical and Reproductive Sciences of the Second University of Naples between October 1998 and October 2002. All patients were clinically investigated and selected on the basis of menopausal age, pregnancy wish and menopausal syndrome. RESULTS: Menopausal mean age was 48.31+/-4.62 years and 32 patients (4%) were affected by premature ovarian failure because of menopausal appearance before the age of 40. Three of these patients were treated to have a pregnancy; the remaining 29 required medical treatment to reduce menopausal symptoms. The osteoporosis risk for premature menopause patients was similar to the other women. The cardiovascular risk was increased because of an increase in risk factors in premature ovarian failure patients. No breast or endometrial pathology was revealed and therapy compliance was satisfactory without any drop-out. CONCLUSION: Premature ovarian failure has a varied etiology, pathogenetic aspects, clinical evolution and therapeutical approach. Adequate treatment of premature menopause women presents good compliance, resolution of infertility when required and a successful resolution of menopausal symptoms.     

Pregnancy in a patient with resistant ovary syndrome--a case report

Resistant ovary syndrome (ROS) and premature ovarian failure (POF) represent two forms of hypergonadotropic hypogonadism. Principal symptoms include primary or secondary amenorrhea (before the age of 40 years), low levels of estradiol and elevated FSH (above 40IU/ml) in serum. The main difference is the presence of follicles in ROS which is tantamount to the possibility of pregnancy. We present the case of pregnancy in a 31-year-old patient who was initially diagnosed with POF, which was the basis of the final diagnosis of ROS.     

Breast density in women with premature ovarian failure using hormone therapy.

BACKGROUND: Women with premature ovarian failure (POF) are treated with estrogen-progestin therapy; however, doubts remain regarding the effect of this therapy on the breasts of women with POF. OBJECTIVE: To evaluate the breast density of women with POF using estrogen-progestin therapy compared with normally menstruating women. METHODS: A cross-sectional study was performed in 31 women with POF using conjugated equine estrogens and medroxyprogesterone acetate and a control group of 31 normally menstruating women, paired by age. All underwent mammography, analyzed by digitization and Wolfe's classification, the latter defined as non-dense (N1 and P1) or dense (P2 and Dy). Parity, breastfeeding and body mass index were evaluated, as well as duration of hormone use and ovarian failure in the POF group. RESULTS: Digitization revealed no difference in mean breast density between the groups: 24.1+/-14.6% and 21.8+/-11.3% for POF and control groups, respectively. The Wolfe classification also failed to detect any significant difference between the groups, dense breasts being detected in 51.6% and 35.5% of cases in the POF and control groups, respectively. CONCLUSION: Periods of hypoestrogenism followed by hormone therapy resulted in no changes in breast density in women with POF, compared with normally menstruating women of the same age.     

X chromosome genes and premature ovarian failure

Premature ovarian failure (POF) is a disorder characterized by lack of ovulation and elevated levels of serum gonadotropins before the age of 40. The etiology of POF is not known but different environmental and genetic factors are involved, suggesting high heterogeneity of the disorder. The involvement of X-linked genes in the etiology of POF was hypothesized on the basis of its frequent association with chromosomal rearrangements and monosomies. In recent years a number of genes were described. Two genes, FRAXA and POF1B, have been formally demonstrated to be responsible for POF. Other genes have been proposed as candidates, but their role remains to be demonstrated.     

Ovarian function after radical hysterectomy for carcinoma of the cervix

We present a prospective observational study of ovarian function following Wertheim's hysterectomy and its relationship to age at hysterectomy. Serum gonadotrophin measurements were made annually on 55 women following Wertheim's hysterectomy with ovarian preservation.
  Within 1 year of surgery four women (4/54) had biochemical evidence of ovarian failure, three of whom were over the age of 40 at operation. At 2 years eight women (8/51) had ovarian failure, seven of these women were over the age of 40 at the time of surgery. After 4 years 11 women had ovarian failure (11/34), eight of these were over the age of 40 at operation.
  Ovarian function following Wertheim's hysterectomy is well maintained in women under the age of 40 at the time of their surgery, 87% of these women had normal gonadotrophin levels 4 years after their surgery. For women over the age of 40 ovarian function is poorly maintained, with only 27% with normal gonadotrophins 4 years following surgery. These data suggest that we should carefully consider recommending bilateral oophorectomy at Wertheim's hysterectomy in women over the age of 40.     

Does poor ovarian response to gonadotrophins predict early menopause? A retrospective cohort study with minimum of 10-year follow-up

One in 10 women reach menopause before they are 45 years of age, and 1 in 100 before 40. In most cases, poor ovarian response to gonadotrophins is a result of poor ovarian reserve. An early menopause is associated with long-term health risks. Identifying women at risk may allow appropriate measures to be instigated early. Women aged <40 years treated in the Aberdeen Fertility Centre between 1998 and 2002 were identified. Those with poor response to an age appropriate dose of gonadotrophins (obtaining ≤3 eggs or had cycle cancelled) after exclusion of hypothalamic insufficiency, or whose cycle was cancelled due to poor response were age matched with good responders (6–15 eggs). In this retrospective cohort study, women who have had IVF at least 10 years ago (157 poor responders and 314 good responders) were sent a postal questionnaire to determine age at menopause. A total of 219 women (64 poor responders, 155 good responders) returned their questionnaires. Poor responders were more likely to have premature menopause (3% vs. 0%; p?=?.024). A higher proportion of poor responders experienced early menopause (11% vs. 3%; p?=?.044). Despite being the first study with a 10-year follow-up, this study is limited to one centre and has a small number of women reaching premature menopause. Poor response to gonadotrophins in the context of IVF treatment is a marker of reduced ovarian reserve and is associated with early menopause. Results of this study underline the need for larger studies with long-term follow-up.     

Gynaecologic challenging issues in the management of BRCA mutation carriers: oral contraceptives,prophylactic salpingo-oophorectomy and hormone replacement therapy

BRCA1 and BRCA2 mutation carriers have a 54–85% and 45% lifetime risk of developing breast cancer, respectively, and a 18–60% and 11–27% lifetime risk of developing ovarian cancer, respectively. Oral contraceptives (OCs) significantly reduce the risk of ovarian cancer also in BRCA1/BRCA2 mutation carriers. The association between OC use and breast cancer risk in these women is controversial. Some studies showed a modestly increased risk especially among BRCA1 mutation carriers. The risk appears to be greater for women who took OCs for at least 5 years and who took OCs before the age of 30 years. Other studies reported that duration of use before first full-term pregnancy has a positive association with breast cancer risk. Salpingo-oophorectomy reduces the risk of coelomic epithelial cancer of 80–95% and the risk of breast cancer of approximately 50%. BRCA1 and BRCA2 mutation carriers should be encouraged to undergo prophylactic bilateral salpingo-oophorectomy at the age of 35–40 years or when childbearing is complete. Short-term use of hormone replacement therapy may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction obtained with salpingo-oophorectomy.