Premature ovarian failure (POF) is defined as the cessation of ovarian function before 40 years of age Citation[1]. It affects approximately 1% of the female population of reproductive age and 4–18% of those with secondary amenorrhea Citation[2]. Complete depletion of the ovaries can result as the consequence of diminished numbers of follicles in the initial pool, or as an accelerated process of apoptosis.
Women with POF experience two problems: estrogen deficiency and sterility. In this editorial we will discuss the second point.
Etiology of premature ovarian failure
POF can be divided into five main categories: POF resulting from genetic abnormality, iatrogenic POF, autoimmune POF, miscellaneous POF and idiopathic POF.
Genetic abnormality
A diminished number in the initial pool of primary follicles in the fetus has been associated with chromosomal abnormalities, especially those affecting the X chromosome. The absence of one X chromosome in Turner syndrome, as well as deletions in the long arm of this chromosome, is currently under investigation in order to identify specific genes that may be involved in follicular dynamics.
Iatrogenic
These are cases in which there is a complete depletion of ovarian follicles within the ovaries as a consequence of gonadal damage from chemotherapy (CT) and radiotherapy (RT). The impact of both treatments on the ovary depends upon the age at treatment, the dose employed and the chemotherapeutic agent and dose administered Citation[3].
Young girls and adolescents are supposedly more resistant to CT owing to their high follicle availability before the treatment, while older women, with diminished ovarian reserve, present higher rates of ovarian failure after treatment.
Autoimmune
These are cases associated with an autoimmune disease without other identified cause. In some cases of POF, the role of autoimmunity can be difficult to determine. The relationship between antiovarian antibodies and POF is controversial, owing to the specific nature of these antibodies, and the different techniques employed to detect them, but it can be estimated to affect between 20 and 50% of cases Citation[4]. Screening for hypothyroidism and diabetes mellitus appears justified in patients with karyotypically normal POF Citation[5].
Miscellaneous
Cases associated with viral infections (mumps) or galactosemia Citation[6].
Idiopathic
These are cases in which there is no apparent cause. Almost 80% of POF cases remain as idiopathic owing to the lack of appropriate tools enabling the exploration of autoimmune and genetic alterations in depth.
Preservation of fertility to avoid premature ovarian failure
In women at risk of reproductive failure, potential options for fertility preservation should be considered. The risk of POF is defined by both familial factors and environmental factors that may deplete ovarian follicles. Potential options for preservation of fertility in women at risk for reproductive failure should be considered. Environmental factors that may deplete ovarian follicles and familial factors define the risk of POF.
The possibility of protecting women against side effects of CT by pituitary–ovarian downregulation is not yet fully accepted. Nonetheless, a prospective clinical evaluation of analog administration during CT, for malignant conditions, has demonstrated a protective effect Citation[7]. The effectiveness of this approach, however, remains controversial.
Cryopreservation strategies have been used with variable success rates. Embryo cryopreservation is a well known procedure with proven efficacy and must be considered in adults if the woman has a partner, or if she wishes to use banked sperm. However, this option requires IVF and the side effects of ovarian stimulation should be considered. Furthermore, this option implies a 3–4 week delay in starting any specific cancer treatment.
Oocyte cryopreservation is an option to avoid legal, moral and religious problems originating from embryo cryopreservation. Two methods have been used to freeze oocytes: slow and rapid (vitrification). A meta-analysis of the efficiency of oocyte cryopreservation showed that IVF with unfrozen oocytes resulted in significantly better rates of fertilization and implantation compared with women who underwent IVF after a slow-freezing protocol Citation[8]. Although success rates in recent studies using ocyte vitrification are optimistic Citation[9], it is still too early to confirm the safety and efficiency of this technique.
The cryopreservation of ovarian cortex obtained by laparoscopy is another method that allows treatment to proceed with minimal delay. Only one pregnancy has been reported after orthotopic transplantation Citation[10]; however, pregnancy may not have resulted from the cryopreserved tissue, since the patient had intact ovaries.
Reproductive options in women with premature ovarian failure
The main issue in the POF condition is whether the situation will be reversible once POF appears. This depends on whether the cause is a functional defect of the ovarian follicles, or whether POF is secondary due to follicular depletion. In the former case, authors have employed different approaches to reduce high serum follicle stimulating hormone (FSH) levels so as to allow the normal functioning of the pituitary and achieve pregnancy. The reports published are mostly observational and noncontrolled. Authors who have treated their POF patients with the aim of achieving conception have tried to decrease serum FSH levels as the first goal. This has been achieved mainly by using different protocols of steroid replacement regimens or analogs. Subsequently, patients have been either maintained with estrogens and progestins in an attempt to observe spontaneous ovulation, or treated with clomiphene citrate, gonadotropins or corticosteroids. The basic conclusion from these studies is that the chance of a spontaneous pregnancy is approximately 5–10%, whereas it can increase to up to 20% if medication is employed Citation[11]. However, there is no way to predict who will respond to the medication and the duration of medication needed.
For those patients with evident follicular depletion and those in whom other alternatives have failed, oocyte donation is the most realistic treatment.
Special considerations in pregnancies of women with premature ovarian failure
In women with POF who become pregnant spontaneously, the risk of transmitting some pathologies, such as Fragile X syndrome, should be considered. Women with POF related to a FMR1 premutation are at risk of having a child with Fragile X syndrome if they conceive spontaneously Citation[12].
Patients with Turner syndrome have a greater risk of abortion due to transmission of aneuploidy. However, natural pregnancies occur in at least 2% of women with Turner syndrome. Not only are these pregnancies uncommon, but their rates of miscarriage (29%), stillbirth (7%) and birth malformations (20%) are significantly higher than those of other female populations Citation[13]. Researchers believe that the miscarriages are caused by chromosomal abnormalities in the fetus, particularly trisomy 21 and Turner syndrome, which have been noted in both aborted fetuses and live-born children of these patients at a much higher rate than in the general population (4 vs 0.4% for trisomy 21 and 15 vs 0.5% for Turner syndrome) Citation[14].
Previous studies have shown that patients with POF have different success rates with oocyte donation compared with other individuals. Whereas some authors have found higher pregnancy rates and similar ongoing pregnancy rates when comparing POF patients with eugonadal patients Citation[15], others describe a higher miscarriage rate in Turner syndrome patients compared with non-Turner syndrome patients Citation[16].
Different centers have reported data from patients with Turner syndrome who were included in oocyte donation programs. Many of the centers reported a higher miscarriage rate in Turner syndrome patients (40–60%) Citation[16,17]. This suggests that miscarriages in Turner syndrome might be caused by uterine factors Citation[16], such as hypoplastic uterus or low uterine blood flow. Li et al. suggested that the endometrium of women with Turner syndrome responds suboptimally to steroid hormone stimulation. They hypothesized that this may be related to a reduced concentration of steroid hormone receptors Citation[17]. Another group has shown that Turner syndrome patients have an early implantation failure, and they suggest that an inherent endometrial abnormality, possibly associated with a deficiency in X-linked genes regulating endometrial receptivity, is the main cause Citation[13]. A study has reported similar pregnancy and implantation rates in Turner syndrome patients and patients who have POF without a cause. The authors did not find statistical differences in miscarriage rate between the groups; however, that finding was related to the size of the sample Citation[18]. We did not find any difference in implantation, pregnancy or miscarriage rates when comparing different etiological groups of POF (genetic, iatrogenic, autoimmune and idiopathic) Citation[19]. The anatomy of the uterus is altered in Turner syndrome patients and a hypoplastic uterus is a frequent finding that could be the cause of a higher rate of miscarriage in these patients Citation[20].
Owing to the short stature of women with Turner syndrome, and their associated health problems that can complicate pregnancy, it is advisable for these women to avoid multiple pregnancies. Therefore, most centers opt to transfer only one or two embryos during IVF. It is estimated that approximately 25–50% of women with Turner syndrome also hold an associated cardiovascular malformation Citation[21]. Deaths and aortic dissection have been reported in Turner syndrome patients who became pregnant through oocyte donation Citation[22]. Patients with Turner syndrome should be adequately screened using echocardiography prior to treatment.
Cancer survivors may worry about transmitting genes that could result in an increased risk of cancer in the next generation. Another concern is for the oocytes, if ovarian function is recovered after CT. There have been no human studies examining the quality of oocytes or embryos in women who have undergone CT. Studies on pregnancy outcome in cancer survivors have found no significant increase in congenital malformations or malignant neoplasms in their offspring Citation[23].
Previous reports have shown that patients with irradiation- or CT-induced POF had a lower pregnancy rate following oocyte donation Citation[24]. In fact, Letur-Konirsch and collaborators studied the results of oocyte donation in 15 patients lacking functional ovaries who had a previous history of cancer. Pregnancy was not achieved in any of the treatments, despite the fact that the ultrasound appearance of the endometrium under estrogen–progestogen treatment showed no differences in either thickness or echogenicity, compared with women not treated with CT nor RT. The standard histology revealed the absence of anomalies in both glandular density and secretory transformation Citation[25].
More recently, we studied the reproductive outcome in patients with POF after CT and pelvic RT for Hodgkin’s and non-Hodgkin’s disease. They had received donated oocytes and were compared with patients with idiopathic POF. We found no differences in pregnancy, implantation or miscarriage rates between the two groups Citation[26].
Furthermore, oocyte donation also avoids transmission of genetic material to the next generation, thus, abolishing the possibility of transmitting hereditary cancer from the affected woman. The protocol of recruiting oocyte donors includes the declaration of the absence of any previous history of familial cancer.
Patients with POF and the presence of autoimmune activity may respond to ovulation induction and are the etiology group with the best chance of conceiving using their own oocytes Citation[27]. As miscarriage has been associated with autoimmune mechanisms, the crucial questions are: do the antibodies affect the oocyte inside the ovary? Does the autoimmune mechanism diminish the chance of implantation only if the oocyte has been affected previously? Will the embryos in the pregnant woman be attacked regardless of the origin of the oocytes? If the answer to the last question is affirmative, we should expect to see more miscarriages in the group with autoimmune processes. The answers remain elusive.
We analyzed the reproductive outcome of patients with idiopathic POF in our oocyte donation program, and compared them with those of patients with true menopause and patients who had received donated oocytes due to low response to ovarian stimulation, and we did not find differences in pregnancy, implantation or miscarriage rates between the groups Citation[28]. POF is a syndrome with different causes and pregnancy can be achieved with a woman’s own or, more commonly, with donated oocytes. The etiology of POF should be explored prior to conception or in the case of spontaneous pregnancy, and potential options for fertility preservation should be offered to women at risk of reproductive failure. Specific considerations should be made in women with POF according to the etiology; miscarriage risk and cardiac risk in Turner syndrome and the transmission of genetic abnormalities in women with genetic POF.
Many questions remain unsolved in the evolution of pregnancy in patients with POF. The majority of studies have been retrospectives with patients. Until we are able to identify the cause and understand the pathogenesis of POF, the therapeutic options remain elusive. Further studies are needed to answer the questions that still remain about pregnancy and reproductive health in patients with POF.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Writing assistance from M Foley (BSc, MSc in TESP) in the manner of proofreading was utilized in the production of this manuscript.
References
- de Moraes-Ruehsen M, Jones GS. Premature ovarian failure. Fertil. Steril.18, 440–461 (1967).
- Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet. Gynecol.67, 604–606. (1986).
- Sherins RJ. Gonadal dysfunction. In: Cancer–Principles and Practice of Oncology. de Vita VT Jr, Hellman S, Rosenberg SA (Eds). JB Lippincott Co., PA, USA 2395–2406 (1993).
- Chattopadhyay D, Sen MR, Katiyar P, Pandey LK. Antiovarian antibody in premature ovarian failure. Indian J. Med. Sci.53, 254–258 (1999).
- Kim TJ, Anasti JN, Flack MR, Kimzey LM, Defensor RA, Nelson LM. Routine endocrine screening for patients with karyotypically normal spontaneous premature ovarian failure. Obstet. Gynecol.89, 777–779 (1997).
- Forges T, Monnier-Barbarino P, Leheup B, Jouvet P. Pathophysiology of impaired ovarian function in galactosaemia. Hum. Reprod. Update12, 573–584 (2006)
- Blumenfeld Z, Avivi I, Linn S, Epelbaum R, Ben-Shahar M, Haim N. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum. Reprod.11, 1620–1626 (1996).
- Oktay K, Pelin Cil A, Bang H. Efficiency of oocyte cryopreservation: a meta-analysis. Fertil. Steril.86, 70–80 (2006).
- Kuwayama M, Vajita G, Kato O, Leibo SP. Highly efficient vitrifiation method for cryopreservation of human oocytes. Reprod. Biomed. Online11, 300–308 (2005).
- Donnez J, Dolmans MM, Demylle D et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet364, 1405–1410 (2004).
- van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum. Reprod. Update5, 483–492 (1999).
- Corrigan EC, Raygada MJ, Vanderhoof VH, Nelson LM. A woman with spontaneous premature failure gives birth to a child with fragile X syndrome. Fertil. Steril.84, 1508 (2005).
- Hovatta O. Pregnancies in women with Turner’s syndrome. Ann. Med.31, 106–110 (1999).
- Swapp GH, Johnston AW, Watt JL, Couzin DA, Stephen GS. A fertile women with non-mosaic Turner’s syndrome. Case report and review of the literature. Br. J. Obstet. Gynaecol.96(7), 876–880 (1989).
- Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte donation at the University of South California: assessing the effect of age and infertility diagnosis on pregnancy and implantation rates. J. Assist. Reprod. Genet.11, 92–96 (1994).
- Yaron Y, Ochshorn Y, Amit A, Yovel I, Kogosowski A, Lessing J. Patients with Turner’s syndrome may have an inherent endometrial abnormality affecting receptivity in oocyte donation. Fertil. Steril.65, 1249–1252 (1996).
- Li TC, Dockery P, Ramsewak SS, Klentzeris L, Lenton EA, Cooke ID. The variation of endometrial response to a standard hormone replacement therapy in women with premature ovarian failure. An ultrasonographic and histological study. Br. J. Obstet. Gynaecol.98(7), 656–561 (1991).
- Press F, Shapiro HM, Cowell CA, Oliver GD. Outcome of ovum donation in Turner’s syndrome patients. Fertil. Steril.64, 995–998 (1995).
- Muñoz EA. The aetiology of POF does not influence the reproductive outcome. Presented at: 21st. Annual Meeting of the European Society for Human Reproduction and Embryology. Copenhagen, Denmark, 19–22 June 2005.
- Khastgir G, Abdalla H, Thomas A, Korea L, Latarche L, Studd J. Oocyte donation in Turner’s syndrome: an analysis of factors affecting the outcome. Hum. Reprod.12, 279–285 (1999).
- Sybert VP. Cardiovascular malformations and complications in Turner syndrome. Pediatrics101(1), E11 (1998).
- Beauchesne LM, Connolly HM, Ammash NM, Warnes CA. Coarctation of the aorta: outcome of pregnancy. J. Am. Coll. Cardiol.38(6), 1728–1733 (2001).
- Hawkins MM. Pregnancy outcome and offspring after childhood cancer. Br. Med. J.309, 1034 (1994).
- Pados G, Camus M, Van Waesberghe L, Liebaers I, Van Steirteghem A, Devroey P. Oocyte and embryo donation: evaluation of 412 consecutive trials. Hum. Reprod.7, 1111–1117 (1992).
- Letur-Konirsch H, Guis F, Duymes M, Alnot MO, Fernandez H. Precocious menopause after antimitotic therapy. Is in vitro fertilization with oocyte donation the only appropriated response? Contracept. Fertil. Sex.25, 647–653 (1997).
- Busso C, Budak EB, Melo MAB, Simon C, Pellicer A, Remohí J. Oocyte donation in patients with premature ovarian failure after chemotherapy and pelvic irradiation for Hodgkin’s and non Hodgkin’s disease. Presented at: 23rd Annual Meeting of the European Society for Human Reproduction and Embryology. Lyon, France, 1–4 July 2007.
- Blumenfeld Z, Halachmi S, Alik Peretz B et al. Premature ovarian failure – the prognostic application of autoimmunity on conception after ovulation induction. Fertil. Steril.59(4), 750–755 (1993).
- Muñoz EA, Muñoz M, Navarro J, Simon C, Remohí J, Pellicer A. Reproductive outcome of premature ovarian failure. Presented at: 18th Annual Meeting of the European Society for Human Reproduction and Embryology. Vienna, Austria, 30 June – 3 July 2002.