Young women find the diagnosis of premature ovarian failure particularly traumatic, and a carefully planned approach is required when informing patients of this diagnosis. It is important to emphasize that premature ovarian failure can be transient and that in most cases we can never be certain that no follicles remain in the ovary. Treatments of such patients are basically two fold. The first is hormone replacement therapy and the second to deal with the issue of infertility.
1. Hormone Replacement Therapy
Young women with premature ovarian failure need oestrogen/progestin replacement therapy to relieve symptoms of oestrogen deficiency, to maintain bone density, and to reduce the risk of cardiovascular disease. Patients with karyotypically normal spontaneous premature ovarian failure have a bone mineral density 1 standard deviation (SD) below the mean of similar age women despite taking hormone replacement therapy at least intermittently. Of note, this bone density has been associated with a 2.6-fold increased risk for hip fracture. Young women with premature ovarian failure have a nearly twofold age-specific increase in mortality rate.
All women with premature ovarian failure should fully understand that hormone replacement should be continued at least until the average age of natural menopause (approximately 50 years) and that they should have long-term follow-up by a physician with an interest in this condition. These young women usually require administration of oestrogen at a dose equivalent to 1.25 mg of conjugated estrogen, which is greater than the standard dose given to older women experiencing natural menopause. Androgen replacement should also be considered in women experiencing persistent fatigue, poor well being, and low libido despite adequate oestrogen replacement. Patients with premature ovarian failure should also be informed of the need for adequate calcium intake and physical activity.
2. Infertility-Related Therapy
Women with premature ovarian failure have intermittent ovarian function, and they have a 5-10% chance of spontaneous pregnancy. There is no treatment to restore fertility in young patients with premature ovarian failure that has been proven safe and effective in prospective controlled studies. Theoretically, these unproved therapies might even prevent one of these spontaneous pregnancies from occurring. Hormone replacement therapy does not prevent conception, and indeed these young women may even conceive while taking the oral contraceptive. Attempts at ovulation induction in these patients using clomiphene citrate, human menopausal gonadotropins, and a combination of gonadotropin-releasing hormone analog with purified urinary FSH resulted in no greater ovulation rates than those seen in untreated patients. For women with premature ovarian failure desiring fertility, oocyte donation is an option, and in fact this treatment is as successful in older women as it is in younger women. Anecdotal reports have suggested that glucocorticoid treatment may restore ovarian function in women with premature ovarian failure. However such treatment is currently investigational.
In some cases, it is possible to foresee premature menopause as in patients undergoing anticancer treatment with chemotherapy. Because dividing cells are more sensitive to the cytotoxic effects of these drugs, it has been hypothesized that inhibition of the pituitary–gonadal axis using gonadotrophin releasing hormone analogues (GnRHa) would render the germinal epithelium less susceptible to the cytotoxic effects of chemotherapy. This approach has also been advocated for young women requiring gonadotoxic treatments for SLE, organ transplantation and other autoimmune diseases.
Other fertility options for women diagnosed with cancer include cryopreservation of ovarian tissue, cryopreservation of mature and immature oocytes and IVF followed by cryopreservation of embryos. Pregnancies and life births have been reported after oocyte cryopreservation and subsequent intracytoplasmic sperm injection. Cryopreserved ovarian tissues can be transplanted and follicles can be developed from this transplanted ovary. The first live birth after orthoptic transplantation of cryopreserved ovarian tissue has been reported recently (Donnez et al., 2004).
A woman's age would be a determining factor when considering ovarian cryopreservation. Children are most likely to benefit from it as their ovary contains more primordial follicles than adult women and other alternatives of oocyte or embryo cryopreservation are unavailable for them. It is also expected that by the time these children grow up and need their ovarian tissue, the modalities for its optimal use would become available.
Ovarian tissue cryopreservation and oocyte cryopreservation thus hold promise for fertility preservation in the women likely to undergo ovarian failure following cancer treatments. This treatment may, however, be contraindicated in cases with possible metastasis to the ovaries where oocyte donation and IVF would be safer.
