Premature Ovarian Failure (POF), also known as premature ovarian insufficiency, primary ovarian insufficiency (this is the most accurate term as some women may still conceive), premature menopause, primary ovarian failure, hypergonadotropic hypogonadism, as well as gonadal dysgenesis (obsolete), is the loss of function of the ovaries before age 40. A commonly cited triad for the diagnosis is amenorrhea, hypergonadotropinism, and hypoestrogenism.

Fuller Albright et al. in 1942 first reported a syndrome in young women characterized by menopausal levels of follicle stimulating hormone (FSH), low estrogen levels and amenorrhea. They named the condition "primary ovarian insufficiency" to distinguish the condition from secondary ovarian insufficiency, which is the failure of the pituitary to secrete FSH. Chapter 28 of the early Qing dynasty work F?? Q??ngzh?? N??k?? (????????????????????? F?? Q??ngzh??'s Gynecology ) describes the cause and appropriate treatment for premature menopause (?????????????????? ni??nw??il??o j??ngshu??du??n, glosses as: 'age not old menstrual water cut off').

It has been estimated that POF affects 1% of the population. It affects approximately 1-4% of the female population in the U.S.

On average, ovaries supply women with eggs until age 51, the average age of natural menopause.

POF is not the same as a natural menopause, in that the dysfunction of the ovaries, loss of eggs, or removal of the ovaries at a young age is not a natural physiological occurrence.

Infertility is the result of this condition, and is the most discussed problem resulting from it, but there are additional health implications of the problem, and studies are ongoing. For example, osteoporosis or decreased bone density affects almost all women with POF due to an insufficiency of estrogen. There is also an increased risk of heart disease, hypothyroidism in the form of Hashimoto's thyroiditis, Addison's disease, and other auto-immune disorders.

Hormonally, POF is defined by abnormally low levels of estrogen and high levels of FSH, which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear shriveled.

Age of onset can be as early as the teenage years but varies widely. If a girl never begins menstruation, it is called primary ovarian failure. The age of 40 was chosen as the cut-off point for a diagnosis of POF. This age was chosen somewhat arbitrarily, as all women's ovaries decline in function over time, however an age needed to be chosen to distinguish usual menopause from the abnormal state of premature menopause. Premature ovarian failure however often has components to it that distinguish it from normal menopause.

By the age of 40, approximately one percent of women have POF. Women suffering from POF usually experience menopausal symptoms, which are generally more severe than the symptoms found in older menopausal women.

The cause of POF is usually idiopathic. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome and Fragile X syndrome. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had their tubes tied, or who have had hysterectomies, tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.

There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact. Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinyl estradiol (EE) or with a GnRH-a the receptor sites are freed and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum anti-m??llerin hormone (AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.)

The POF Fact Sheet lists potential causes of POF in various languages:

http://www.pofsupport.org/information_center.asp

Serum follicle-stimulating hormone (FSH) measurement alone can be used to diagnose the disease. Two FSH measurements with one-month interval have been a common practice. The anterior pituitary secretes FSH and LH at high levels due to the dysfunction of the ovaries and consequent low estrogen levels. Typical FSH in POF patients is over 40 mlU/ml (post-menopausal range).

Between 5 and 10 percent of women with POF may spontaneously become pregnant. Currently no fertility treatment has officially been found to effectively increase fertility in women with POF, and the use of donor eggs with In-Vitro Fertilization (IVF) and adoption have become more popular as a means of becoming parents for women with POF. Some women with POF choose to live child-free. (See Impaired Ovarian Reserve for a summary of recent randomized clinical trials and treatment methods.)

Over the last five years a Greek research team has successfully implemented the use of dehydroepiandrosterone (DHEA) for the fertility treatment of women suffering with POF.

The majority of the patients were referred for donor eggs or surrogacy, however after a few months of DHEA administration they succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Until now a great number of babies have been born after treatment with DHEA.

It is important to initiate the hormonal replacement therapy after the diagnosis of POF, as untreated patients are at a great risk of bone loss due to increased osteoclast activities, resulting in osteopenia as well as osteoporosis. Furthermore, most of the patients develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness, both of which respond to estrogen therapy effectively. There are several contraindications of estrogen supplement, including smokers over 35 years of age, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of thromboemboli events. If the patient has strong family history of thromboemboli events, care must be taken to proceed with the hormonal replacement therapy. As the minimum, testing for Factor V Leiden, Protein C, and Protein S should be performed to ensure the low risk of developing thromboemboli events while on the estrogen replacement.

The transdermal estradiol patch (typically 100 mcg) is commonly recommended because of several advantages. It provides the replacement by steady infusion rather than by bolus when taking daily pills. It also avoids the first-pass effect in the liver.

Impaired Ovarian Reserve

• International Premature Ovarian Failure Association

• POF Fact Sheets, FAQ

• POF Awareness Campaign for patients and health care providers

• National Institutes of Health publication No. 03-5159, Do I have Premature Ovarian Failure?

• National Institutes of Health's Premature Ovarian Failure website