Is premature ovarian failure premature menopause?
Dr. S. Selva, MBBS (Mal), FRCOG (London), FICS (USA)
Master of Reproductive Medicine (Sydney)
Consultant Obstetrician and Gynaecologist,
IVF Clinician, Mahkota Medical Centre, Melaka
President, Obstetricial and Gynaecological Society of Malaysia

Premature ovarian failure or premature menopause is defined as cessation of menstruation before 40 years of age. Even though these two terms are used interchangeably “Is premature ovarian failure really premature menopause?”

Madam KSL was first seen here on the 28/2/1999. She was 30 years of age married for 2 years with no children. She complained that her menstruation had stopped for 8 months. She underwent blood tests and 2 repeated blood tests showed that her follicular stimulating hormone (FSH ) and luteinizing hormone (LH) levels were above 40IU (hypergonadotrophic hypogonadism) indicating that she is in menopause. Ultrasound showed that her uterus and ovaries were normal. Chromosomal analysis was normal. She was diagnosed as a case of premature ovarian failure. She was started on cyclical hormone replacement therapy and she regained her normal menstrual cycle. After 2 years of regularly taking her HRT, she missed her periods for 2 months in March 2001. She underwent an ultrasound which revealed that she was pregnant. The pregnancy progressed normally, and she delivered a healthy child in November 2001.

This case above illustrates the difference between natural menopause and premature ovarian failure. Women become menopausal when the ovaries are depleted of oocytes. Natural menopause is an irreversible condition resulting from ovarian follicle depletion at an average age of 50.

Whereas in young women with premature ovarian failure, there are still many oocytes which will produce oestrogen intermittently despite the presence of high levels of gonadotrophin and so ovulation is still possible. However, the follicles in most cases are not functioning normally.

In these patients even though the women cease to menstruate, the ovaries still contain oocytes. There oocytes may ovulate and in such instances pregnancy can occur. It is difficult to predict which patients will ovulate and achieve a pregnancy. There have been many reports of spontaneous pregnancies occurring after premature ovarian failure. As such, some would not like to call premature ovarian failure as premature menopause.

Premature ovarian failure (POF) causing high levels of gonadotrophins (FSH and LH) occur in 1% of women. In majority of cases the underlying cause is not identified. The known causes include: (a) Genetic (b) Autoimmune diseases (c) Iatrogenic following surgical, radiotherapeutic or chemotherapeutic interventions as in malignancies. (d) Environmental factors like viral infections and toxins.

Premature ovarian failure may present as either primary (no menses at all) or secondary amenorrhea. The majority of the patients have secondary amenorrhoea. Approximately 50% of the patients have a history of reduced menstrual flow (oligomenorrhea) or irregular menstruation (dysfunctional uterine bleeding), 25% develop amenorrhea (cessation of menstruation) acutely, some postpartum, and some after stopping oral contraceptives. Primary amenorrhea is not associated with symptoms of oestrogen deficiency. Symptoms in cases of secondary amenorrhea may include hot flushes, night sweats, fatigue, and mood changes. Incomplete development of secondary sex characteristics may occur in women with primary amenorrhea, whereas these characteristics are usually normal in women with secondary amenorrhea. These young patients generally have normal fertility before developing premature ovarian failure.

MANAGEMENT OF PREMATURE OVARIAN FAILURE

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. Treatment of such patients is basically two fold. The first is hormone replacement therapy and the second to deal with the issue of infertility.

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. Young women with premature ovarian failure have a nearly twofold age-specific increase in mortality rate. Hormone replacement therapy should be continued at least until the average age of natural menopause (approximately 50 years). These women should have long-term follow-up by an interested physician. 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.

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. 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 have not been successful. 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.

In some cases, it is possible to foresee premature menopause as in patients undergoing anticancer treatment with chemotherapy. 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. The first live birth after orthoptic transplantation of cryopreserved ovarian tissue has been reported recently .

 
FOLLOW-UP OF PATIENTS WITH PREMATURE OVARIAN FAILURE
Young women with premature ovarian failure should be monitored annually regarding their compliance with hormone replacement therapy. Moreover, these patients should be followed up for the presence of signs and symptoms of associated autoimmune endocrine disorders, such as hypothyroidism, adrenal insufficiency, and diabetes mellitus. Additional testing should be performed as clinically indicated.

 
CONCLUSIONS
Normal menopause occurs at an average age of 50 and results from ovarian follicle depletion. Normal menopause is an irreversible condition, whereas premature ovarian failure is characterized by intermittent ovarian function in half of these young women. As such premature ovarian failure is not synonymous with premature menopause. These young women produce oestrogen intermittently and sometimes even ovulate. Indeed, pregnancy has occurred after a diagnosis of premature ovarian failure. No treatment to restore fertility in young patients with premature ovarian failure has been proven safe and effective in prospective controlled studies.

Early loss of ovarian function has both significant psychosocial sequelae and major health implications. Young women with premature ovarian failure have a nearly twofold age-specific increase in mortality rate. They need a thorough assessment, sex steroid replacement, and long-term surveillance to monitor their therapy. Also, these young patients should be followed up annually for the presence of associated autoimmune endocrine disorders such as hypothyroidism, adrenal insufficiency, and diabetes mellitus.