Primary Ovarian Insufficiency: A More Accurate Term for Premature Ovarian Failure

Corrine K. Welt


Clin Endocrinol. 2008;68(4):499-509. 

In This Article

Summary and Introduction

Premature ovarian failure (POF) is a disorder with a complicated clinical presentation and course that is poorly defined by its name. A more scientifically accurate term for the disorder is primary ovarian insufficiency (POI), a term that can be appropriately modified to describe the state of ovarian function. In recent years, the known aetiologies of POI have expanded, although the cause of POI in a majority of clinical cases remains undefined. The most common aetiologies should be ruled out clinically including chromosomal abnormalities, fragile X premutations and autoimmune causes. Management should be directed at symptom resolution and bone protection, but most importantly should include psychosocial support for women facing this devastating diagnosis.

Women are endowed with their maximum number of follicles at approximately 20 weeks of gestation.[1] The normal process of atresia then commences, independent of ovulation. At birth, the number of oocytes would be decreased from 6-7 million to 700 000. At puberty, only 400 000 follicles remain and continued atresia along with monthly ovulation leave few follicles remaining at menopause.[2] As a result of this constant oocyte atresia, early menopause could occur in any woman who begins life with a decreased number of follicles, or experiences accelerated follicle apoptosis or destruction.

Premature ovarian failure (POF) is a term classically defined as 4-6 months of amenorrhoea in women under the age of 40 years, who have elevated FSH and low oestradiol levels. However, this definition does not take into account the longitudinal progression towards the final menstrual cycle. Indeed, the process of ovarian senescence in this condition may resemble that of natural menopause, which is preceded several years by elevated FSH levels and menstrual irregularity. It has even been suggested that POF be regarded as early ovarian ageing in the continuum of ovarian ageing across the population.[3]

Although there has been no longitudinal examination of women with POF, a poor response to gonadotrophin stimulation for assisted reproductive therapy in women with regular menses and a normal FSH level has been associated with early menopause.[4,5] In one large study (n = 4601),[6] the chance of transitioning to or reaching menopause was almost four times higher if a woman had a poor response to gonadotrophins (zero to three oocytes retrieved) during assisted reproduction or a cancelled cycle, even after adjusting for age. Thus, infertility may be the earliest manifestation of POF.

When POF has been diagnosed, ovarian function may be different than in natural menopause. Indeed, there is evidence that follicle development and ovulation are common.[7,8,9] In three studies, women with POF and amenorrhoea for 3-6 months had follicle growth as demonstrated by ultrasound and oestradiol levels. In fact, 50%-84% of subjects had new follicle growth and 16%-49% ovulated. The variability in the rates of follicle development and ovulation may be explained by the differences in duration of amenorrhoea in these studies, particularly because the rate of ovulation appears to decrease with the duration of amenorrhoea.[10] Taken together, the continuum of POF may begin with infertility and persist with follicular development in late stages. These findings suggest that the term POF is not accurate.

Based on evidence that POF has a long and variable clinical course that is not encompassed by its label, it has been proposed by Nelson et al. that physicians reach back to the more accurate term used by Fuller Albright; primary ovarian insufficiency (POI).[11,12,13] POI is not only more accurate but also informative for patients who may not experience the end of ovarian function at the time of diagnosis. The term POI may be preceded by descriptors that identify the severity of ovarian dysfunction. The descriptors are presented in Table 1 , as modified from the transcripts of a multidisciplinary group meeting sponsored by the National Institutes of Health (NIH) and the American Society for Reproductive Medicine.[14] For purposes of this review, the new terminology will be used throughout.


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