Mark P. Trolice, M.D.

Premature ovarian failure (POF) is categorized as a lack of ovarian function associated with markedly elevated FSH levels in women less than age 40. Occurring in 1 - 5% of women, POF may be further defined as greater than six months of amenorrhea in a previously menstruating patient with FSH levels above 30 for two consecutive months and no intervening menses (to exclude a midcycle natural FSH surge). In addition to the devastating impact on reproductive capability, this column will also discuss the important medical consequences of POF, particularly bone mineral density loss.

Genetics
To understand POF, we must first review embryology. Unlike male reproduction where gametes (sperm) are continuously produced from puberty onwards, females are born with their entire cohort of gametes (oocytes). This endowment demonstrates the inefficiency of female reproduction whereby oocytes undergo rapid attrition from 6 – 7 million at 20 weeks in utero decreasing to 1 – 2 million at birth. Attrition continues through puberty with about 300,000 – 400,000 oocytes but only 1% of these are utilized via ovulation. The biologic phenomenon explaining this loss is “apoptosis” or natural cell death and is evident in other parts of the body as well. By the time a women is 37, she has approximately 10,000 oocytes remaining until about 1,000 exist at the average age of menopause, i.e. 51 years old.

Genetic XX patients present with primary amenorrhea and lack of pubertal development. Genetic XY patients require removal of the intra-abdominal Y gonad due to risk of tumor. More rare causes of ovarian failure include gonadotropin receptor mutations and enzyme deficiencies.

High FSH: Gonadal dysgenesis
There are actually two presentations of elevated FSH levels: gonadal dysgenesis and POF. The former stems from a lack of gonadal development resulting in a sexually infantile patient. In the purest form, Turner’s Syndrome patients phenotypically are short stature, webbed neck, shielded chest, among other commonly known features, as well as streak ovaries and risk of thyroid dysfunction, diabetes, and coarctation of the aorta. Recently, because of Assisted Reproduction, Turner’s Syndrome patients have become pregnant through egg donation; however concern over cardiac related mortality has arisen.

High: POF
Waxing and waning ovarian function precedes the ultimate cessation by 2 – 7 years. POF may be caused iatrogenically by chemotherapy and radiation in cancer patients. Unfortunately, the use of GnRH in children to preserve oocytes has not been clinically proven. There is a dose response of radiation and resultant amenorrhea. As expected, age is inversely proportional to the likelihood of resumption of menses after these forms cancer treatment.

Evaluation
A karyotype is recommended in POF patients less than 30 years old to exclude for the hereditary risks, including Fragile X (the most common inheritable form of learning disability) and the occult Y bearing gonad that requires extirpation (see above). Since up to 40% may be autoimmune causes, antithyroid antibodies, particularly thyroid peroxidase are an important screen. POF is also associated with IDDM, Myasthenia Gravis, and Parathyroid disease. Other screening tests should include fasting glucose and electrolytes. Though ovarian antibodies have not been studied, there is no clear validity.

The risk of polyendocrinopathy is of critical importance to the clinician. If hypothyroidism is diagnosed in this population, then normal adrenal function by morning serum cortisol must be confirmed before thyroid replacement. Otherwise, adrenal crisis may occur due to the increase in basal metabolic rate from therapy.

Treatment
No proven therapy has ever been shown to restore ovarian function and infertility. Since the patient is hypogonad, estrogen and progestin (if the uterus is present) treatment should be offered to reduce vasomotor symptoms (hot flashes, vaginal dryness) and preservation of bone mineral density. Should the patient present with POF for many years prior to the diagnosis, a DEXA bone scan is needed to determine a baseline and potential need for further follow-up.

In the peripubertal patient, breast maturation is completed by low dose estrogen in a slow step-wise fashion to avoid malformation. After breakthrough bleeding and/or in the second year of therapy of unopposed estrogen, a progestin is added to prevent endometrial hyperplasia. Rare spontaneous ovulations may occur in these patients despite low dose hormonal therapy.