Premature Ovarian Failure: a Review

By Nippita, T A; Baber, R J

Key words: PREMATURE OVARIAN FAILURE, PREMATURE MENOPAUSE, HORMONE REPLACEMENT

ABSTRACT

Objectives To present an updated review on the etiology, consequences and management of premature ovarian failure.

Design A search of the English language literature using the Cochrane Library database and Medline 1966-2006, with a hand search of the references.

Conclusion Premature ovarian failure is defined as the occurrence of amenorrhea, hypergonadotropinemia and estrogen deficiency in women under the age of 40 years, with the prevalence being 0.9- 1.2%. In the majority of cases, the etiology is unknown, but known causes include chemotherapy, radiotherapy, surgery, genetic disorders, particularly involving the X chromosome, associations with autoimmune diseases, infections, smoking and other toxins. The three critical issues of management in these women are the effect of the diagnosis on the psychological health of the patient, the consequent infertility and the long- and short-term effects of estrogen deficiency arising from ovarian decline. Promising methods of screening for premature ovarian failure are being developed.

INTRODUCTION

Premature ovarian failure (POF) is defined as the occurrence of amenorrhea, hypergonadotropinemia, and estrogen deficiency in women under the age of 40 years1,2. Another term used to describe POF is premature menopause; however, in women with POF, ovarian failure may not mean complete cessation of function and up to 50% of those so diagnosed will have intermittent and unpredictable ovarian function which may persist for some years . This review focuses on the etiology, consequences and management of this relatively common and poorly understood condition.

METHODS

We conducted a search of the English language literature using The Cochrane Library database and Medline (US National Library of Medicine) from 1966 to 2006, using the key words premature ovarian failure and premature menopause. A hand search of the references of these articles was also performed.

EPIDEMIOLOGY

The prevalence of POF is 0.9-1.2% in women 40 years or younger2,4,5. There are ethnic differences ranging from 1.4% in women of African-American and Hispanic descent to 1.0% in Caucasian, 0.5% in Chinese and 0.1% in Japanese women4. In women with primary amenorrhea, the prevalence of POF is 10-28%; in those with secondary amenorrhea, the prevalence is 4-18%6.

ETIOLOGY

POF arises from a genetically pre-determined reduced number of ovarian follicles at birth, accelerated follicular atresia, or follicular dysfunction’. Although, in 90% of cases, the etiology is unknown, the number of known causes and genetic factors continues to increase.

Chemotherapy and radiotherapy for treatment of malignant disease are the most common known causes of POF. Whilst improved chemotherapy and radiotherapy regimens for cancers in young people have led to increased long-term survival, one consequence has been a diminution in ovarian reserve and thus an increased incidence of premature ovarian failure. The risk of treatment leading to POF increases with age after puberty, with various high-dose chemotherapy regimens and with combined chemo- and radiation therapy7.

Chemotherapy depletes oocyte numbers and affects the structure and function of oocytes and granulosa cells, in a dose- and drug- dependent manner8. Combination chemotherapy and alkylating agents are most likely to cause POF. Induced POF can be temporary; however, the chance of spontaneous recovery of ovarian function decreases with increasing patient age. Some evidence exists that co-treatment with gonadotropin releasing hormone (GnRH) agonists may reduce the gonadotoxic effects of chemotherapy9,10.

Depending on the radiation field, radiotherapy may affect the ovaries. There is little risk of POF in women treated with radiation fields outside the pelvis”. Age and dosage of radiation are also significant factors for the risk of POF in women; prepubertal ovaries are relatively resistant to radiation12, whilst direct radiation doses of 9 Grays or higher render ovaries at high risk of failure, although there have been case reports of pregnancy even after this dosage13.

Several genetic disorders are associated with POF and there have been reports of familial POF, indicative of a genetic inheritable disorder14,15. Approximately 20-30% of women with POF have affected relatives, suggesting that the inherited predisposition to POF is common16. It is likely that POF is a heterogeneous disorder caused by mutations in multiple genes, with each mutation identified so far causing only a few cases of POF. The majority of genetic disorders are related to the X chromosome17, but there have also been autosomal recessive and autosomal dominant forms of the disease documented18.

Several X chromosomal abnormalities have been reported, including partial deletions, translocations, deficiencies and excesses.

Turner syndrome is due to mosaicism or complete monosomy of the X chromosome. It is characterized by ovarian failure, growth restriction and other physical abnormalities. For oogenesis to be complete, it is essential for both X chromosomes to be present and hence in Turner syndrome ovarian function is defective14. The loci for ovarian failure have been difficult to identify, but there has been some evidence that one of the critical regions may be on the region of XpI 1.2-p22.119.

Trisomy X syndrome (47,XXX) is caused by non-disjunction of the X chromosome during maternal meiosis. The association of POF and trisomy X has been reported, but the prevalence of POF in this group of women is unknown20,21.

Fragile X syndrome is an X-linked genetic disorder with incomplete penetrance. The incidence of POF in women carrying the fragile X syndrome premutations (FMRl gene) has been reported to be as high as 20%22,23. However, the incidence seems to be partly dependent on whether the FMRl gene is paternally or maternally acquired; in one study, 28% of patients with the paternally acquired fragile X premutation had POF compared to only 3.7% of women with maternally acquired fragile X premutation”.

Deletions in either the short or long arm of the X chromosome have resulted in primary and secondary amenorrhea with elevated gonadotropin levels24, with identification of two independent loci Xq26-q28 (POFl) and Xql3.3-q22 (POF2)24.

Balanced X chromosome translocations have been shown to be associated with POF through cytogenetic mapping. However, in this group of rearrangements of the X chromosome, POF seems to be independent of the presence of the X-linked genes and more likely a result of the X chromosome reorganization that occurs during oogenesis and hence may affect the expression of non-linked X genes in the oocyte, leading to ovarian failure18.

The other X-linked gene for ovarian failure is the bone morphogenetic protein 75 (BMPlS) gene. BMPlS was reported to carry mutations in two sisters who had primary amenorrhea, inherited from their father25. No other mutations have been reported and the prevalence in POF is unknown18.

Galactosemia is a rare autosomal disorder due to a defect in galactose 1-phosphate uridyltransferase (GALT) metabolism. Despite good dietary control, the prevalence of POF in women with galactosemia is 70-80%26. Possible mechanisms include the toxic effect of galactose or its metabolite on follicular structures during fetal life, galactose-induced reductions in the initial number of oogonia, and the glycosylation of gonadotropin subunits leading to biological inactivity26.

17α-Hydroxylase deficiency is a rare enzymatic defect characterized by primary amenorrhea, sexual infantilism, hypergonadotropism, hypokalemia and hypertension. Development of ovarian failure is due to defective ovarian steroid synthesis and ovarian biopsies have shown disorderly follicular maturation27. There has been a case report documenting the retrievability of a fertilizable oocyte despite undetectable levels of estradiol28.

There are many other genes identified as being associated in the causation of POF. These include mutations of the follicle stimulating hormone (FSH) receptor24, luteinizing hormone (LH) receptor30,31, inhibin gene16 and FOXL2 gene16 associated with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).

POF has a close association with many autoimmune diseases. It is estimated that 20% of patients with POF have an associated autoimmune disease32, most commonly diabetes mellitus, thyroid and adrenal disease33. Ovarian failure may occur as part of the autoimmune polyglandular syndrome types I and II. Type I is characterized by hypoparathyroidism, adrenal insufficiency, chronic mucocutaneous candidiasis, POF and hypothyroidism. Type II is characterized by adrenal insufficiency, autoimmune thyroid disease, type I diabetes mellitus and POF.

There has been an association of POF with myasthenia gravis, Sjogren’s syndrome, Crohn’s disease, vitiligo, pernicious anemia, rheumatoid arthritis, and systemic lupus erythematosis3.

Antibodies to the ovarian enzymes or tissue components could also cause clinical autoimmune POF. Decades of research have investigated ovarian autoantibodies and their association with POF. Unfortunately, the results are conflicting due to different methods of detection, and thus neither the specificity nor clinical significance of ovarian autoantibodies has been established34. Autoantibodies to the \zona pellucida also have been described as a cause of follicular dysfunction35.

Smoking has consistently been shown to be associated with earlier menopause36,37. The suggested pathophysiology is that tobacco smoke contains polycyclic hydrocarbons which are toxic to germ cells, leading to follicular exhaustion38.

Amongst viral infections, mumps oophoritis may cause POF and an incidence of 3-7% has been reported in patients who contracted mumps during an epidemic 9. There have also been case reports of cytomegalovirus (CMV)-related oophoritis in immunocompromised patients40.

Pelvic surgery has the potential to compromise blood supply to the ovaries and may cause inflammation. Recurrent surgery for benign ovarian conditions leads to follicular depletion and premature ovarian failure; for example, the rate of post-surgical premature ovarian failure after laparoscopic excision of bilateral endometriomas is 2.4%41. Bilateral oophorectomy will obviously precipitate a surgical menopause and hysterectomy may also compromise the ovarian blood supply, leading to an early menopause42.

DIAGNOSIS

Most women with spontaneous POF present with menstrual disturbances. Often, there is a delay in diagnosis. In one survey, the mean time from presentation to diagnosis was 2 years, with 25% of women not being diagnosed until 5 years after presentation43. Some women present with vasomotor symptoms, vaginal dryness and dyspareunia as a result of estrogen deficiency, whilst others present after failed attempts at ovulation induction for infertility.

The diagnosis should always be considered in young women presenting with secondary amenorrhea. A detailed history should include questioning regarding prior ovarian surgery, chemotherapy, radiotherapy, and autoimmune diseases. A family history of autoimmune diseases, POF, fragile X, other X chromosome defects and developmental delay is also significant.

After excluding pregnancy, the core diagnostic criteria are more than 4 months of amenorrhea and two serum FSH values of >40 mIU/ml more than 1 month apart in a woman less than 40 years old6.

On clinical examination, most women with POF will have no abnormalities, but subtle signs may be present.

Phenotypic features of Turner syndrome, the most common abnormal karyotype found in women with POF, include short stature, webbed neck, high arched palate, shield chest with widely spaced nipples, wide carrying angle and short fourth and fifth metacarpals.

Signs of associated autoimmune disease may be present. Sparse axillary and pubic hair, orthostatic hypotension, increased pigmentation in the skin creases and vitiligo are features of adrenal insufficiency. Other signs of autoimmune disease include butterfly malar rash, joint tenderness and vitiligo in systemic lupus erythematosis; dry eyes and mouth in Sjogren’s syndrome, whilst myxedema, proximal myopathy, a ‘hung up’ reflex, and alopecia may be present in hypothyroidism.

Pelvic examination may reveal signs of atrophie vaginitis, and rarely ovaries may be palpable due to lymphocytic oophoritis or a steroidogenic enzyme defect44.

INVESTIGATIONS

Laboratory baseline investigations should include β-human chorionic gonadotropin (β-hCG), LH, FSH, prolactin and estradiol. There is no place for a progesterone withdrawal test, which is inaccurate and may delay diagnosis’39,45.

Consideration should be given to karyotyping. All women who experience POF before the age of 30 years, and have a positive family history of POF, developmental delay, ataxia or dementia should have karyotyping and FMRl testing. The presence of an inactive Y chromosome in phenotypic women is associated with a substantial risk of cancer of the gonads and these women should have their gonadal tissue removed.

Screening for associated autoimmune diseases has been recommended, in particular screening for hypothyroidism and diabetes mellitus46. Adrenal autoantibodies are used to identify women with POF who have associated steroidogenic cell autoimmunity and who are at risk of developing adrenal insufficiency47,48 and adrenal crisis3.

Pelvic ultrasound, ovarian biopsy and antiovarian antibodies have no proven clinical benefit in the work-up of these patients. Pregnancies have been documented in women found to have no follicles, suggestive of sampling errors49. Anti-ovarian antibodies do not correlate with the severity or presence of oophoritis and do not predict whether POF will occur6.

MANAGEMENT

A diagnosis of POF brings with it three critical issues: the effect of the diagnosis on the psychological health of the patient, the consequent infertility, and the long- and short-term effects of estrogen deficiency arising from ovarian decline.

Psychological health

A diagnosis of POF can affect the mental, spiritual and social health of a woman. Patients may experience a sense of helplessness, anger, sadness and guilt following the diagnosis, which may also give rise to a negative impact on body image and perception of femininity3,50. Women who wish to have children find the diagnosis of POF particularly traumatic, and the symptoms triggered by this diagnosis are similar to the grief reaction. The loss of reproductive capacity may trigger feelings of loss, grief and shame and may lead to a loss of self-esteem and relationship difficulties.

Alzubaidi43 found that many young women perceived a lack of quality of care regarding the diagnosis of this condition43. Spending more time with patients, expressing appropriate concern and establishing exactly how much the patient knows and wants to know are important parts of the counseling process50. An offer of referral to other sources of information and support groups such as the International Premature Ovarian Failure Association (http:// pofsupport.org/), the Daisy Network (http://www.daisynetwork.org.uk/ ) and The Jean Hailes Foundation (http://www.jean hailes.org.au) are invaluable for these women50.

In some cases, evaluation by a psychologist or psychiatrist is necessary to evaluate levels of depression, anxiety and coping mechanisms, and group or medical therapy may be required.

Infertility

The combined data of observational, uncontrolled and controlled studies suggest that women with POF have a 5-10% chance of natural conception at some time after diagnosis51. The rate of pregnancy loss is similar to that of the normal population, with approximately 80% of pregnancies resulting in the birth of a healthy child.

Only donor egg in vitro fertilization and embryo transfer using donor oocytes have demonstrated high success rates in women with spontaneous POF, and this should be considered the fertility treatment of choice3,26,32. Many women will seek egg donation from a family member and it is essential that the family is fully counseled regarding the risk of a possible donation of an ovum with genetic abnormalities, including the predisposition for POF, that are unable to be tested for to date.

Such randomized trials that have been done on other therapies for infertility, including gonadotropin therapy, estrogen, oral contraceptives, steroids, and clomiphene therapy, have failed to show a significant improvement in ovulation or pregnancy52,53

Cryopreservation of ovarian tissue prior to gonodotoxic treatments such as chemotherapy and radiation therapy is currently being investigated as an alternative to embryo freezing in the hope of restoring future fertility54. The advantage is that a large number of gametes are able to be stored without delaying oncology treatment. There have been several reports of pregnancy and birth following autotransplantation of cryopreserved ovarian tissue in women who have suffered chemotherapy-induced POF55″57. Thus ovarian transplantation may soon be a fertility option for women with chemotherapy-induced POF. However, there is a risk of transplantation of metastatic cancer cells during orthotopic transplantation, particularly for blood-borne malignancies58.

In the future, ovarian biopsy may be of use for treatment of infertility, given the first case report of success of in vitro oocyte maturation in humans with reduced ovarian reserve resulting in a live healthy infant . In vitro maturation of oocytes was initially for women with high risk of ovarian hyperstimulation syndrome, but may be useful for a population with reduced follicular reserve.

Estrogen deficiency

Women with POF often have symptoms of estrogen deficiency including vasomotor symptoms, atrophie vaginitis and dyspareunia. They are also at significant risk of osteoporosis and cardiovascular disease. Hormone therapy should be initiated in these women, not merely for symptom control but also to maintain long-term health, thus fulfilling the criteria of true hormone replacement therapy (HRT). Some women may need HRT before amenorrhea is established because of troublesome symptoms.

No randomized trials have been conducted to determine the ideal dose, regimen or delivery system for women with POF receiving HRT. Estrogens and progestins may be administered orally or transdermally, sequentially to induce a regular withdrawal bleed or in a continuous combined manner to achieve amenorrhea. Regulatory authorities and professional bodies worldwide all advise initiating treatment with a low dose and increasing as required until symptom control is achieved60’6′. Some young women will require twice the standard dose of estrogen to achieve symptom relief1. Women with an intact uterus should receive a progestin either cyclically or continuously although, because of the possibility of spontaneous endogenous ovarian activity, breakthrough bleeding is more common amongst women receiving continuous progestins’2. Progesterone should be given at least monthly, as less frequent administration may be associated with an increased incidence of endometrial hyperplasia62.

HRT does not provide contraception and, in women who desire reliable protection from pregnancy, the use of the oral co\ntraceptive pill is appropriate.

Osteoporosis is a major contributor to morbidity and mortality in today’s society. An osteoporotic hip fracture is associated with an increase in mortality of 12% in the first year63. Bone mass after the age of 30 years is dependent on the maximal bone mass achieved and the annual bone loss rate, which is strongly dependent on age and ovarian function64’65. Some studies suggest that reduced bone density and osteoporotic fractures under the age of 65 years are significantly related to premature menopause65-68, whilst other studies suggest that early menopause is statistically significantly associated with increased fractures during a lifetime69. HRT in the doses discussed above will maintain age-appropriate bone density, and randomized trials in older women have also demonstrated that such doses of HRT will significantly reduce fracture incidence70. Women with POF should also be given appropriate general health advice regarding calcium intake, daily weight-bearing exercise, vitamin D intake and cessation of smoking. Response to therapy should be followed on a regular basis using bone mineral density measurements.

There is a suggestion that women with POF may be at increased risk of cardiovascular disease and associated mortality71″’5. Hu and colleagues75 showed the relative risk for heart disease with each year of decrease in menopausal age was 1.03 (95% confidence interval (CI) 1.01-1.05) and that women who experienced menopause before age 40 were 53% more likely to suffer coronary heart disease compared with women whose menopause occurred after age 55 years. There is little known about the effect of POF and cardiovascular disease, but there is evidence showing that lack of estrogen in women with POF accelerates the process of endothelial dysfunction, a precursor of atherosclerosis76. An observational study demonstrated that endothelial dysfunction in women with POF was reversible after 6 months of cyclical HRT77.

Observational studies showed that HRT commenced hy symptomatic postmenopausal women in their fifties reduced the risk of cardiovascular events78, but large randomized controlled trials of largely asymptomatic postmenopausal women, on average 10 years older than those in observational studies, did not. The Heart and Estrogen/ progestin Replacement Study (HERS) showed that HRT did not reduce the rate of cardiovascular events in postmenopausal women with established cardiovascular disease , and the Women’s Health Initiative studies, investigating primary prevention of cardiovascular disease in healthy postmenopausal women, showed a small increase in the number of cardiovascular events in postmenopausal women receiving combined HRT but not estrogen-only therapy80.

It seems that, in relatively healthy blood vessels, estrogen prevents or slows development and progression of atherosclerosis, but, in the presence of established atherosclerosis, estrogen fails to reduce this progression and may actually trigger cardiovascular events by a proinflammatory or prothrombotic effect76. In animal models, estrogen inhibits plaque formation in oophorectomized monkeys when administered at the time of a surgical menopause, but not when delayed by 2 years from oophorectomy8”82. This suggests an age-dependent, or perhaps artery-dependent, response of the cardiovascular system to therapy with HRT. Such a proposition is supported by recent published data from several sources including the Nurses’ Health Study and the Women’s Health Initiative8′”85. Hence, in young women, estrogen may help to reduce the risk of plaque formation, but may not be useful for older postmenopausal women who have developed coronary artery disease irrespective of symptom status. It is unknown whether the addition of androgen therapy will confer any change in cardiovascular health for women with POF; in postmenopausal women already receiving HRT, transdermal testosterone has been shown to improve endothelial function86.

The findings of the Women’s Health Initiative studies70,80,82,87 of absolute increased risk of breast cancer, cerebrovascular and cardiovascular disease with HRT use in older postmenopausal women do not apply to young women with POF. Young women with POF have pathologically low levels of estradiol compared to their age- matched peers. Thus, estrogen administration replaces the estrogen which should have been produced by the ovaries and, in a manner similar to the treatment of hypothyroidism with thyroxine therapy, is true hormone replacement therapy.

The risk/benefit ratio for women with POF is different to that for women using HRT after reaching their menopause at the usual age of 51 years. Their baseline risk of breast cancer and cardiovascular disease is much lower, and the risk of osteoporosis during their lifetime is much higher than for the older women.

Whilst no randomized trials exist, or are likely ever to be conducted, logic suggests, and expert bodies have agreed60’61, that HRT for women with POF up to the normal age of the menopause will not only alleviate symptoms but also reduce the risk of chronic disease. Whilst oral HRT will increase the risk of thromboembolic disease88, the absolute risk is small and the overall message for women with POF commencing HRT should be positive and reassuring.

Androgen replacement

Women with POF have lower levels of free testosterone than age- matched normally ovulating controls3’89″91 and some authors have suggested that testosterone replacement be considered in these women, particularly those with Turner syndrome or those complaining of reduced libido and persistent fatigue despite adequate estrogen replacement’2’42. Inadequate testosterone has been suggested as a cause for reduced bone mineral density despite estrogen replacement in over two-thirds of women with POF9′”96, and studies are currently examining the effect of testosterone replacement on bone mineral density97. Evidence is available that androgens play a role in maintenance of bone turnover and bone mineral density in postmenopausal women, with those women on estrogen replacement and testosterone replacement showing greater increases in bone mineral density compared to women treated with estrogen alone98.

At present, evidence is insufficient for testosterone therapy to be recommended as a standard treatment for young women with POF, but it should be considered in those with symptoms of androgen deficiency, bearing in mind that there are only limited data available on the long-term effects of androgen replacement therapy92.

Cognitive function

Several observational studies have suggested a decreased risk of dementia with HRT. Estrogen may be neuroprotective because of its promotion of cholinergic activity, its effects on the hippocampus and by increasing dendritic spine density .

There has been one small study investigating cognitive function in women with POF treated with HRT, comparing those with a normal karyotype with women with Turner syndrome and with normal female controls100, matched for age and verbal intelligence quota. After comprehensive neuropsychological assessment including evaluation of general cognition, verbal and nonverbal memory, executive abilities and motor function, there was no significant difference between controls and women with POF. However, the women with Turner syndrome had impaired performance on evaluation of nonverbal memory, spatial and constructional abilities, executive function and motor speed. It was concluded that replacement of estrogen in women with POF is sufficient to prevent cognitive defects that may have occurred due to estrogen depletion. However, the cognitive differences in women with Turner syndrome may be related to genetic differences and to changes in neural development. There has been no long-term evaluation of women with POF and their cognitive function. This study provides some reassurance for women with POF taking HRT, especially in light of the publication of the Women’s Health Initiative Memory Study (WHIMS)101,102.

WHIMS showed a doubling in risk of dementia for postmenopausal women taking estrogen plus progestins and almost doubling in risk of dementia in women taking estrogen alone. However, women enrolled in WHIMS (a subgroup of the WHI study), were aged 65 and older and results may not be applicable to younger women with POF. A ‘critical period hypothesis’ has been raised, similar to that for cardiovascular risk and hormone therapy, suggesting hormone therapy confers optimal cognitive benefits when initiated close in time to the menopausal transition103.

Screening and prevention

Currently, no screening is available for POF. There has been increasing interest in tests of ovarian reserve, initially developed to help predict successful outcome of assisted conception techniques. These may be potentially useful in patients who, although asymptomatic, are at risk of premature ovarian failure. Ovarian reserve tests aim to measure the remaining primordial follicular pool, since it has been suggested that a critical number of follicles determine menopause104. These tests may be useful in those women who have asymptomatic accelerated follicular decline. However, not all cases of premature ovarian failure are due to accelerated follicular decline.

Ovarian reserve tests include day 3 basal FSH levels, estradiol, inhibin B, antimullerian hormone (AMH), and antral follicular counts measured by transvaginal ultrasound105. Estradiol and inhibin B are produced by early antral follicles in response to FSH stimulation. With the reduction in the follicular pool, serum estradiol and inhibin B decrease with the concomitant increase in FSH106. However, these changes occur relatively late107. Antimullerian hormone is expressed in granulosa cells of growing ovarian follicles108. Expression is highest in pre-antral and small antral follicles and gradually diminishes in the subsequent stages of follicular development108\, thus reflecting the size of the primordial follicular pool. In a longitudinal observational study looking at young premenopausal women with normal menstrual cycles compared to postmenopausal women, de Vet and collegues109 measured early follicular phase hormones at a 3-year interval. They found that AMH levels declined significantly prior to changes in inhibin B and FSH levels, despite the presence of regular menstrual cycles. A strong correlation between AMH and antral follicular count was also found. Thus, this study suggests that AMH declines whilst women are asymptomatic and early in the events leading to ovarian failure.

The antral follicular count may also be a promising screening tool when used to estimate the remaining primordial follicular pool105. Antral follicular counts and serum antimullerian hormone seem to be the most sensitive noninvasive markers of ovarian reserve110 at present; however, further research is necessary to prospectively evaluate these markers and their clinical applicability.

FOLLOW-UP

Women with POF should be seen annually to monitor their response to hormone therapy, to address individual health issues and to review ongoing management in light of current research. If autoantibodies have been detected at the initial investigation, these, and thyroid and adrenal function, should be monitored annually. There is no evidence to recommend frequency of bone density screening, but we recommend that bone density should be monitored every 2 years initially to demonstrate skeletal protection and thereafter as clinically appropriate. A screening interval of less than 2 years is not warranted because the precision error of densitometry may be higher than the bone lost during this time111.

CONCLUSIONS

Premature ovarian failure has a significant impact on the physical and psychological health of young women with the disorder. Effective management should involve early diagnosis, sensitive and sympathetic management and counseling of the individual and the use of hormone therapy to alleviate symptoms of estrogen deficiency and to reduce the burden of long-term disease such as osteoporosis.

There is no effective screening available for the diagnosis of premature ovarian failure, but there are promising new avenues of research investigating markers of ovarian reserve. Regular long- term follow-up and review are essential.

References

1. de Morales-Ruehsen M, Jones GS. Premature ovarian failure. Fertil Steril 1967; 18:440-61

2. Coulam CB, Adamson DC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol 1986;67:604

3. Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril 2005; 83:1327-32

4. Luhorsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multiethnic population study of the menopause transition. Hum Reprod 2002; 18:199-206

5. Cramer D, Xu H. Predicting age at menopause. Matuntas 1996;23:319-26

6. Anasti JN. Premature ovarian failure: an update. Fertil Steril 1998;70:1-15

7. Larsen EC, Muller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiationand chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88: 5307-14

8. Meirow D. Ovarian injury and modern options to preserve fertility in female cancer patients treated with high dose radio- chemotherapy for hemato-oncological neoplasias and other cancers. Lenk Lymphoma 1999;33: 65-76

9. Blumenfeld Z, Eckman A. Preservation of fertility and ovarian function and minimization of chemotherapy-induced gonadotoxicity in young women by GnRH-a. / Nail Cancer lnst Monogr 2005;34:40-3

10. Franke H, Smit W, Vermes I. Gonadal protection by a gonadotropin releasing hormone agonist depot in young women with Hodgkins disease undergoing chemotherapy. Gynecol Endocrinol 2005;20:274-8

11. Madsen BL, Giudice L, Donaldson SS. Radiation-induced premature menopause: a misconception, hit Radiat Oncol Biol Phys 1995;32:1461-4

12. Beerendonk CC, Braat DD. Present and future options for the preservation of fertility in female adolescents with cancer. Endocr Dei’ 2005;8:166-75

13. Spinelli S, Chiodi S, Bacigalupo A, et al. Ovarian recovery after total body irradiation and allogenic bone marrow transplantation: long term follow up of 79 females. Bone Marrow Transplant 1994;14:373-80

14. Vegetti W, Tibiletti MG, Testa G, et al. Inheritance in idiopathic premature ovarian failure: analysis of 71 cases. Hum Reprod 1998;13:1796-800

15. Conway GS. Premature ovarian failure. Cnrr Opin Obstet Gynecol 1997;9:202-6

16. Woad KJ, Watkins WJ, Prendcrgast D, Shelling AN. The genetic basis of premature ovarian failure. Anst NZJ Obstet Gynaecol 2006; 46:242-4

17. Shelling AN. X chromosome defects and premature ovarian failure. Aitst NZ/ Med 2000;30:5-7

18. Toniolo D. X linked premature ovarian failure: a complex disease. Cnrr Opin Genet Dev 2006;16:293-300

19. Zinn AR, Tonk VS, Chen Z, et al. Evidence for a Turner syndrome locus or loci at Xp 112p221. Am J Hum Genet 1998;63:1757- 66

20. Holland CM. 47XXX in an adolescent with premature ovarian failure and autoimmune disease. J Paediatr Adolcsc Gynecol 2001; 14: 77-80

21. Itu M, Neelam T, Ammini AC, Kucheria K. Primary amenorrhoea in a triple X female. Attst NZJ Obstet Gynaecol 1990;30:386-8

22. Hundscheid RDL, Sistermans EA, Thomas CMG, et al. Imprinting effect in premature ovarian failure confined to paternally inherited fragile X permutations. Am J Hum Genet 2000;66:413-18

23. Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective !published correction appears in Am J Hum Genet 2004;75:352]. Am J Hum Genet 2004;74: 805-16

24. Rebar RW. Mechanisms of premature menopause. Endocrinol Metab Clin N Am 2005;34: 923-33

25. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotrophic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004;75:159- 66

26. Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal E. Genetic disorders in premature ovarian failure. Hum Reprod Update 2002;8: 483-91

27. Mallin SR. Congenital adrenal hyperplasia secondary to 17- hydroxylase deficiency: two sisters with amenorrhoea, hypokalemia, hypertension and cystic ovaries. Ann Intern Med 1969;70:69-75

28. Rabinovivi J, Blankstein J, Goldman B, et al. In vitro fertilisation and primary embryonic cleavage are possible in 17a- hydroxylase deficiency despite extremely low intrafollicular 17β-estradiol. J Clin Endocrinol Metab 1989; 68:693-7

29. Aittomaki K, Lucena JLD, Parkarinen P, et al. Mutation in the follicle stimulating hormone receptor gene causes hereditary hypergonadotrophic ovarian failure. Cell 1995;82:959-68

30. Latronico AC, Anasti J, Arnhold IJ, et al. Brief report: testicular and ovarian resistance to luteinising hormone caused by inactivating mutations of the luteinising hormone-receptor gene. N Engl J Med 1996;334:507-12

31. Takahashi K, Karino K, Kanasaki H, et al. Influence of missense mutation and silent mutation of LH beta-stibunit gene in Japanese patients with ovulatory disorders. Eur J Hum Genet 2003; 11:402-8

32. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005;! 1: 391-410

33. Santoro N. Research on the mechanisms of premature ovarian failure. J Soc Gynccol Investig 2001;8(1 Suppl Proceedings):S10-12

34. Forges T, Monnier-Barbarino P, Faure GC, Bene MC. Autoimmunity and antigenic targets in ovarian pathology. Hum Reprod Update 2004; 10:163-75

35. Koyama K, Hasegawa A, Mochida N, Calongos G. Follicular dysfunction induced by autoimmunity to zona pellucida. Reprod Biol 2005;5:269-78

36. Di Prospero F, Luzi S, Iacopini Z. Cigarette smoking damages women’s reproductive life. Reprod Bioincd Online 2004;8:246-7

37. Cramer DW, Harlow BL, Xu H, Fraer C, Barbieri R. Cross- sectional and case-controlled analyses of the association between smoking and early menopause. Maturitas 1995;22:7987

38. Mattison DR, Thorgeirsson SS. Smoking and industrial pollution, and their effects on menopause and ovarian cancer. Lancet 1978;i: 187-8

39. Rebar RW, Coonolly HV. Clinical features of young women with hypergonadotropic amenorrhea. Vert il Stcril 1990;53:804-810

40. Mocayo R, Moncayo HE. Premature ovarian failure: evidence of immunologie component. In Ovarian Autoimmunity: Clinical and Experimental Data, 1st edn. Austin, TX: RG Landes Co, 1995:27-75

41. Busacca M, Riparini JR, Somigliana E, et al. Post surgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynccol 2006; 195:421-5

42. Siddle N, Sarrel P, Whitehead M. The effect of hysterectomy on age at ovarian failure, l-ertil Steril 1987;47:94-100

43. Alzubaidi NH, Chapin HL, Vanderhoof HV, Calis KA, Nelson LM. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol 2002;99:720-5

44. Biscotti CV, Hart WR, Lucas JG. Cystic ovarian enlargement resulting from autoimmune oophoritis. Obstet Gynecol 1989;74:492

45. Rebar RW, Erickson GF, Yen SSC. Idiopathic premature ovarian failure: clinical and endocrine characteristics. Fertil Steril 1982;37: 35-41

46. Kirn TJ, Anasti JN, Flack MR, Kimzey LM, Defensor RA, Nelson LM. Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1997;89:777-9

47. Falorni A, Laureti S, Candeloro P, et al. Steroid-cell autoantibodies are preferentially expressed in women with premature ovarian failure who have adrenal autoimmunity. Fertil Sterit 2002;78:270-9

48. Bakalov BK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic autoimmune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod 2002;17:2096100

49. Khastgir G, Abdalla H, Studd JW. The case against ovarian biopsy for the diagnosis of premature menopause. Br J Obstet Gynaecol 1994; 101:96-7

50. Gro\ff A, Covington S, Halverson L. Assessing the emotional needs of women with spontaneous premature ovarian failure. Fertil Steril 2005;83:1734-41

51. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update 1999;5:483-92

52. Pal L, Santoro N. Premature ovarian failure: discordance between somatic and reproductive ageing. Ageing Res Rev 2002;!:413- 23

53. Kalantaridou S, Nelson L. Premature ovarian failure is not a premature menopause. Ann NY Acad Sd 2000;900:393-402

54. Demeestere I, Simon P, Englert Y, Delbaere A. Preliminary experience of ovarian tissue cryopreservation procedure: alternatives, perspectives and feasibility. Reprod Biomed Online 2003;7:572-9

55. Siegel-ltskovich J. Woman gives birth after receiving transplant of her own ovarian tissue. BM/2005;331:70

56. Meirow D, Levron J, Eldar-Geva T, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemo therapy. N Eng ] Med 2005;353:318-21

57. Donnez J, Dolmans MM, Demylle D, et al. Live birth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364: 1405-10

58. SeIi E, Tangir J. Fertility preservation options for female patients with malignancies. Curr Obstet Gynaecol 2005; 17:299-308

59. Friden B, Hreinsson J, Hovatta O. Birth of a healthy infant after in vitro oocyte maturation and ICSI in a woman with diminished ovarian response: case report. Hum Reprod 2005;20: 2556-8

60. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Advice for medical practictioners regarding the use of postmenopausal hormone therapy. August 2004

61. Royal College of Obstetricians and Gynaecologists. Consensus views arising from the 47th Study Group: Menopause and Hormone Replacement. November 2004

62. Bjarnason K, Cerin A, Lindgren R, Weber T. Adverse endometrial effects during long cycle hormone replacement therapy: Scandinavian Long Cycle Study Group. Matnritas 1999;32: 161-70

63. Barrett-Connor E. The economic and human costs of osteoporotic fracture. Am J Med 1995;98(Suppl 2A):3-8s

64. Richelson LS, Wahner HW, Melton LJ, Riggs BL. Relative contributions of ageing and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;3 1 1:1273-5

65. Nordin BEC, Need AG, Chatterton BE, Horowitz M, Morris HA. The relative contributions of age and years since menopause to postmenopausal bone loss. J CUn Endocrinol Metah 1990;70:83-8

66. Ahlborg HG, Johnell O, Nilsson BE, Jeppsson S, Rannevik G, Karlsson MK. Bone loss in relation to menopause: a prospective study during years. Bone 2001;28:327-31

67. Luisetto G, Zangari M, Tizian L, et al. Influence of aging and menopause in determining vertebral and distal forearm bone loss in adult healthy women. Bone Miner 1993;22: 9-25

68. Hadjidakis DJ, Kokkinakis EP, Sfakianakis ME, Raptis SA. Bone density patterns after normal and premature menopause. Maturitas 2003;44:279-86

69. van der Voort DJM, van der Weijer PHM. Early menopause: increased fracture risk at older age. Osteoporos lut 2003; 14: 525- 30

70. Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33

71. Van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996;347:714-18

72. Cooper GS, Sandier DP. Age at natural menopause and mortality. Ann Epidemiol 1998;8:229-35

73. De Kleijn MJJ, van der Schouw YT, Verbeek ALM, Peeters PHM, Banga JD, van der Graaf Y. Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. Am J Epidemiol 2002;155: 339-45

74. Jacobsen BK, Knutsen SF, Fraser GE. Age at natural menopause and total mortality and mortality from ischemie heart disease: the Adventist Health Study. J Clin Epidemiol 1999;52:303-7

75. Hu FB, Grodstein F, Hennekens CH, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999;159:1061-6

76. Kalantaridou SN, Naka KK, Bechlioulis A, Makrigiannakis A, Michalis L, Chrousos GP. Premature ovarian failure, endothelial dysfunction and estrogen-progestogen replacement. Trends Endocrinol Metab 2006; 17:101-9

77. Kalantaridou SN, Naka KK, Papanikolaou E, et al. Impaired endothelial function in young women with premature ovarian failure: normalisation with hormonal therapy. J Clin Endocrinol Metab 2004;89:3907

78. Grodstein F, Stampfer MJ, Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Mcd 1996;335:453-61

79. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13

80. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women. The Women’s Health Initiative: a randomized trial. JAMA 2003;289:2673- 784

81. Kaplan JR, Adams MR, Anthony MS, Morgan TM, Manuck SB, Clarkson TB. Dominant social status and contraceptive hormone treatment inhibit atherogenesis in premenopausal monkeys. Atheroscler Thromb Vase Biol 1995; 15:2094-1 OO

82. Clarkson TB, Anthony MS, Klein KP. Hormone replacement therapy and coronary artery atherosclerosis: the monkey model. Br J Obstet Gynaeml 1996;103(Suppl I3):53-7

83. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 2006; 166:357-65

84. Salpeter S. Cardiovascular disease incidence and HRT use in younger and older women. Climacteric 2005;8:307-10

85. Grodstein F, Manson J, Stampfer M. Hormone therapy and coronary heart disease: the role of time since menopause and age at hormone initiation. J Womcns Health 2006; 15:35-44

86. Worboys S, Kotsopoulos D, Teede H, McGrath B, Davis SR. Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen. J Clin Endocrinol Mctab 2001 ;86: 158-61

87. Stefanick M, Anderson G, Margolis K, et al. Effects of conjugated equine estrogens on breast cancer and mammographie screening in post menopausal women with hysterectomy. JAMA 2006;295:1647-57

88. Curb JD, Prentice RL, Bray PF, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006; 166:772-80

89. Bermudez JA, Moran C, Herrera J, Barahona E, Perez MC, Zarate A. Determination of the steroidogenic capacity in premature ovarian failure. Fertil Stcril 1 993;60:668-71

90. Doldi N, Belvisi L, Bassan M, Fusi FM, Ferrari A. Premature ovarian failure: steroid synthesis and autoimmunity. Gynecol Endocrinol 1998; 12:23-8

91. Hartmann BW, Kirchengast S, Albrecht A, Laml T, Soregi G, Huber JC. Androgen serum levels in women with premature ovarian failure compared to fertile and menopausal controls. Gynecol Obstet Invest 1997;44: 127-31

92. Davis S. Androgen replacement therapy in women: a commentary. J Clin Endocrinol Metab 1999;84:1886-91

93. Anasti JN, Kalantaridou SN, Kimzey LM, Defensor RA, Nelson LM. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 1998;91:12-15

94. Davis SR, McCloud P, Strauss BJG, Burger H. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227-36

95. Barrett-Connor E, Young R, Notelovitz M, et al. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. J Reprod Med 1999;44:1012- 20

96. Savvas M, Studd JW, Norman S, Leather AT, Garnett TJ, Fogelman I. Increase in bone mass after one year of percutaneous and oestradiol implants in post-menopausal women who have previously received long-term oral oestrogens. Br J Obstet Gynaecol 1992;99:757- 60

97. Kalantaridou SN, Calis KA, Mazer NA, Godoy H, Nelson LM. A pilot study of an investigational testosterone transdermal patch system in young women with spontaneous premature ovarian failure. J Clin Endocrinol Metab 2005;90:6549-52

98. Davis SR, Burger HG. The role of androgen therapy. Best Pract Res Clin Endocrinol Metab 2003;17:165-75

99. Maki PM. Hormone therapy and cognitive function: is there a critical period for benefit? Nenmsciencc 2006; 138:1027-30

100. Ross JL, Stefanatos GA, Kushner H, et al. The effect of genetic differences and ovarian failure: intact cognitive function in adult women with premature ovarian failure versus Turner syndrome. J Clin Endocrinol Metab 2004;89: 1817-22

101. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative memory study: a randomized controlled trial. JAMA 2003;289:2651- 62

102. Shumaker SA, Legault C, Rapp SR, et al. Conjugated equine estrogen and the incidence of probable dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative memory study: a randomized controlled trial. JAMA 2004;291: 2947-58

103. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA 2002;288:2170-2

104. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7:1342-6

105. Swanton A, Child T. Reproduction and ovarian ageing. J Br Menopause Soc 2005;11:126-31

106. Burger HG, Dudley EC, Hopper JL, et al. The endocrinology of the menopausal transition: a cross sectional study of a population based sample. J Clin Endocrinol Metab 1995;80: 3537-45

107. Burger HG, Dudley EC, Hopper JL, et al. Prospectively measured levels of serum follicl\e stimulating hormone, estradiol and the dimeric inhibins during the menopausal transition in a population based cohort of women. J Clin Endocrin Metab 1999;84:4025- 30

108. Visser JA, de Jong FH, Laven JSE, Themmen APN. Anti- mullerian hormone: a new marker for ovarian function. Reproduction 2006; 131:1-9

109. de Vet A, Laven JS, de Jong FH, Themmen APN, Fauser BC. Antimullerian hormone serum levels: a putative marker for ovarian ageing, fertil Steril 2002;77:357-62

110. Tremellen KP, KoIo M, Gilmore A, Lekamge DN. Antimullerian hormone as a marker of ovarian reserve. Aust N Z J Obstet Gynaecol 2005;45:20-4

111. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: a review of the evidence for the US preventative services task force. Ann Intern Med 2002; 137:529-41

T. A. Nippita* and R. J. Baber*,[dagger]

*Department of Obstetrics and Gynaecology, Royal North Shore Hospital, St Leonards; [dagger]University

of Sydney, Australia

Correspondence: Associate Professor R. J. Baber, 3rd Floor, North Shore Private Hospital, Westbourne Street, St. Leonards, NSW 2065, Australia

REVIEW

2007 International Menopause Society

DOI: 10.1080/13697130601 135672

Received 26-06-06

Revised 09-09-06

Accepted 05-10-06

Conflicts of interest Dr Nippita nil. Associate Professor Baber has conducted clinical trials sponsored by several pharmaceutical companies involved in the manufacture of phytoestrogens, hormone replacement therapy and bone-sparing treatments and has given continuing education talks on management of the menopause sponsored by Schering, Organon, Wyeth Ayerst, Servier Laboratories, Novartis and Novogen Laboratories.

Source of funding Nil.

Copyright Taylor & Francis Ltd. Feb 2007

(c) 2007 Climacteric. Provided by ProQuest Information and Learning. All rights Reserved.