Premature Ovarian Failure

Premature ovarian failure

DEFINITION AND INCIDENCE

The reported median age of the menopause is 51years. Premature ovarian failure (POF) is a condition leading to amenorrhea, hypoestrogenism and elevated gonadotropins before the age of 40 years. The use of age 40 as a cut-off to define POF is largely empirical. An alternative definition proposed is to use two standard deviations from the expected age of menopause, or age 45years; however, the use of age 40 persists in the context of published research.

As early as the 1930s the presence of raised urinary gonadotropins was noted in patients with ‘premature menopause’. Atria in 1950 examined 20 patients with ‘precocious menopause’ and detailed typical clinical characteristics of POE The condition is not uncommon and may be under-reported by women who do not consider the cessation of the monthly menstrual cycle to be a medical problem. Overall, POF is responsible for 4–18% of cases of secondary amenorrhea and 10–28% of primary amenorrhea. It is estimated to affect 1% of women under 40 years of age and 0.1% under 30.

Premature Ovarian Failure

 ETIOLOGY

In the majority of women diagnosed with POF, the specific etiology and underlying pathophys iology remain elusive. Traditional texts have concentrated on describing ovarian failure as being associated with either a deficient number of primordial follicles from the onset of menarche, accelerated follicle atresia or follicles resistant to gonadotropin stimulation (idiopathic POF).

Considering the developmental stages of the ovary, germ cells migrate from the dorsal wall of the developing gut and reach the gonadal ridges at approximately 5 weeks of gestation. Here the oogonia undergo mitotic activity, resulting in around 6–8 million primary oocytes by 20 weeks of gestational age. Two-thirds of these germ cells have entered and arrested in the prophase of the first meiotic division. From 20 weeks of intrauterine life, there is gradual attrition of the primary oocytes and at birth each ovary contains around 200000 germ cells. A further 100000 oocytes will be lost before menarche, and ultimately only 400–500 follicles will develop fully and be released through the process of ovulation during the reproductive years. By the time of the normal menopausal transition there is a significant reduction in the number of remaining oocytes and at menopause there will be very few remaining. This is in contrast to patients with POF, where residual oocytes exist, albeit in reduced number. It is for  this reason that use of the term premature menopause is inappropriate. Although it is impossible to predict likelihood of spontaneous ovulation, up to 20% of patients may ovulate in the 6 months following diagnosis.

Follicular versus afollicular POF

When considering the etiology of POF, dividing the condition into follicular or afollicular subgroups suggests that knowing an individual’s status is either important or useful. In the absence of a non-invasive test to differentiate between follicular depletion or dysfunction, the only alternative is laparoscopic ovarian biopsy. The validity of single biopsies has not been established, indeed pregnancies have occurred despite histological lack of follicles after biopsy, suggesting sampling errors. In any case, laparoscopy is not without risk and the clinical management of both types of POF is similar.

Enzyme defieiencies

A number of enzyme deficiencies have been found to be associated with an increased risk of POF. The most common of these is the autosomal recessive condition of galactosemia, that occurs due to a deficiency in the enzyme galactose-1-phosphate uridyltransferase. Accumulation of galactose results in damage to the liver, eyes and kidneys. The risk of POF has been found to be as high as 81% in affected females  and the cause appears to be a galactose-induced reduction in total germ cell development during oogenesis . Other proposed mechanisms include accelerated follicular atresia and biologically inactive isoforms of follicle stimulating hormone (FSH). Other enzyme abnormalities associated with POF include deficiencies of 17α- hydroxylase, 17, 20-desmolase and cholesterol desmolase. Patients with cholesterol desmolase are not able to produce biologically active steroids and rarely survive to adulthood. The remaining enzyme disorders are similarly rare and may be associated with concomitant adrenal insufficiency.

X-linked POF

As early as 1966 the requirement for two intact X chromosomes for normal follicular development was identified. The complete absence of one X chromosome, as in Turner syndrome, results in ovarian dysgenesis and primary ovarian failure. Fragile X syndrome has been identified as placing women at higher risk of premature ovarian failure. Fragile X mutations occur at least ten times more frequently in women with POF than the general population. Following the screening of 132 women for fragile X permutations, it was found that 13% of those with familial POF and 3% with the sporadic form had fragile X permutations, compared with an expected prevalence of 1:590. A critical region on the X chromosome (POFl) ranging from Xql3 to Xq26 has been identified relating to normal ovarian function in addition to a second gene of paternal origin (POF2), located at Xq13.3-q21. Idiopathic POF can be familial or sporadic, and the familial pattern of inheritance is compatible either with X-linked (with incomplete penetrance) or with an autosomal dominant mode of inheritence.

FSH receptor gene polymorphism and inhibin B mutation

As might be expected, resistance to the action of gonadotropins can lead to the clinical features of POF and this has been demonstrated in a cohort of Finnish families.This does, however, appear to be a very rare cause of POF. More recently an analysis of 43 patients with POF demonstrated a mutation in the inhibin gene (INHα) at a frequency ten-fold higher than control patients (7% vs. 0.7%). These patients experienced ovarian failure at an early age, frequently prior to the second decade of life.

Blepharophimosis/ptosis/epicanthus (BEPS) syndrome

This rare autosomal dominant condition leads to congenital abnormalities of the eye including blepharophimosis, ptosis and epicanthus inversis. In BEPS type I, eyelid malformation cosegregates with premature ovarian failure, and has been mapped to chromosome 3q.

Iatrogenic ovarian failure

The likelihood of ovarian failure after chemotherapy or radiotherapy depends upon the agent used, dosage levels, interval between treatments and in particular the age of the patient. The prepubertal ovary is relatively resistant to the effects of chemotherapeutic alkylating agents. Attempts to suppress ovarian activity of reproductive aged women using oral contraceptives or gonodotropin releasing hormone (GnRH) analogs in order to mimic this protection have produced conflicting results.

Radiation-induced ovarian failure with a total dose greater than 6 Gy usually results in sterility. However, as with chemotherapy, prepubertal girls are more resistant to irradiation. Normal menstruation following treatment does not necessarily mean that the ovaries are unaffected and incipient POF may occur at a later date. Surgical transposition of the ovaries beyond the direct field of treatment has been described.

Autoimmune disease

POF is frequently associated with autoimmune disorders, particularly hypothyroidism. Other co-existing conditions may include Crohn’s disease, vitiligo, pernicious anemia, systemic lupus erythematosus or rheumatoid arthritis. Addison’s disease is associated with around 3% of patients with POF and may be present as part of a polyglandular failure syndrome5.The type I syndrome is associated with adrenal failure, hypoparathyroidism and chronic mucocutaneous candidiasis and mainly occurs in later with hypothyroidism and is less consistently associated with POE Hypothyroidism affects around 25% of patients with POF and diabetes mellitus affects a further 2.5%

Oophoritis

Rebar and Connolly reported a retrospective case review of a series of patients with POF finding 3.5% of patients had a previous infection, including malaria, varicella, or shigella. Mumps orchitis is well recognized in males and a similar histological phenomenon has been described in the ovary. The exact role of viral infections in the etiology of POF, however, is unclear. Lymphocytic oophoritis was found in 11% of 215 POF patients undergoing ovarian biopsy, most of whom had steroid cell antibodies and associated adrenal disease.

Demographic features

The contribution of environmental factors to the development of POF has been examined in several case studies. No consistent and reliable contribution has been demonstrated with regards to education level, socioeconomic status, oral contraceptive use, smoking habit or anthropometric characteristics. Nulliparity and lifelong irregular menstrual cycles are associated with an increased risk of POF

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