Fertility treatment in women with premature ovarian failure

Abstract

Premature ovarian failure (POF) is defined as ovarian failure and early menopause before the age of 40 years. This POF occurs in 1% of women younger than 40 and up to 0.1% women younger than 30, and may have different etiologic causes, such as genetic, autoimmune, iatrogenic, toxic, enzymatic, infectious and metabolic. The etiologic cause can be diagnosed in less than half of the cases. Signs of intermittent ovarian function in karyotypically normal women have been described, but predicting the probability of spontaneous remission in a specific woman is impossible. The possible beneficial effect of treatments such as immunosuppressive therapies, gonadotropin-releasing hormone (GnRH) agonists, exogenous high-dose gonadotropins and estrogen replacement, published in numerous anecdotal case reports, is unclear, and the cause–effect relationship has not been proven by prospective randomized studies. Therefore, in order to find effective treatments, basic pathophysiologic mechanisms must be better understood. For those women who want to conceive, it seems reasonable to attempt a corrective therapy based on defined etiology, before falling back on a donor oocyte program. Iatrogenic POF after chemotherapy has gained worldwide interest owing to significantly improved survival in the last three decades, and owing to the ability to preserve future fertility and ovarian function in many young female survivors of young-age malignancy. The attempts of IVF-assisted reproductive technologies and embryos or unfertilized oocytes cryopreservation, combined with ovarian tissue cryopreservation and coadministration of GnRH agonists in parallel to chemotherapy, may maximize future fertility and minimize long-term POF in these women.

Keywords::

• fertility treatment
• GnRH agonist
• gonadotoxicity
• hypergonadotropic amenorrhea
• POF

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Release date: May 27, 2011; Expiration date: May 27, 2012

Learning objectives

• • Describe the epidemiology of POF

• • Distinguish the most acceptable means to promote fertility among women undergoing chemotherapy

• • Analyze the effects of gonadotropin-releasing hormone-agonists among women receiving chemotherapy

• • Evaluate the fertility treatment of POF related to autoimmune disease

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega

Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

AUTHOR AND CREDENTIALS

Zeev Blumenfeld

Department OB/GYN, Rambam Healthcare Campus, Technion-Faculty of Medicine, 31096 Haifa, Israel.

Disclosure: Zeev Blumenfeld has disclosed no relevant financial relationships.

Premature ovarian failure (POF) is defined as ovarian failure and early menopause before the age of 40 years [1–3]. Signs of intermittent ovarian function in karyotypically normal women have been described, but predicting the probability of spontaneous remission in a specific woman is impossible. This versatile entity has been referred to as: primary ovarian failure, hypergonadotropic amenorrhea, primary ovarian dysfunction, premature menopause and primary ovarian insufficiency. POF occurs in 1% of women younger than 40 and up to 0.1% of those younger than 30, and may have different etiologic causes. The etiologic causes cannot be diagnosed in over 50% of cases. Nevertheless, among the known etiologies different causes have been mentioned in the literature, such as genetic and chromosomal [1–5], metabolic [2,6,7], enzymatic [2,6,7], iatrogenic [2,8], toxic [1–5,9], autoimmune [1,9] and infectious causes [1–3,9].

It is beyond the scope of this article to exhaustively describe all of the published genetic syndromes and genes and review the etiologic causes of POF. Furthermore, these have been recently summarized by several comprehensive reviews by others and by our laboratory [9–13].

In some cases of POF, the etiology seems to be an incorrect immune recognition of ovarian self antigenic determinants, associated with many other autoimmune phenomena, or the presence of antibodies to different tissues in addition to the ovary [1].

Autoimmune etiology

The association between autoimmune disorders such as thyroiditis and Addison disease, and POF has been described, and POF can occur as part of an autoimmune polyglandular insufficiency including hypoparathyroidism, hypoadrenocortisolism and mucocutaneous candidiasis [1,4,9].

There have been several publications that have suspected an association of an autoimmune etiology for POF. Because of space constraints, the author refers the reader to three excellent reviews on the subject [1,4,9]. Indeed, anti-ovarian antibodies and antibodies to FSH receptors may also be detected [1,4,9]. Mutations in the AIRE gene, located on chromosome 21q22.3 and responsible for autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome, can be a causative pathophysiologic explanation of POF [1,4,9]. The specificity of the detection assays of ovarian antibodies is questionable, since positive results were received in 30% of patients with POF, 26% of patients undergoing IVF–embryo transfer, and even in sera taken from women at delivery [1,4,9]. Therefore, the diagnosis of an autoimmune etiology is extrapolated from the association with other autoimmune diseases, or the existence of antibodies [1,4,9]. Whereas in 2–10% of POF patients an association with adrenal autoimmunity can be found, there is a significantly lower prevalence of approximately 1:10,000 in the control population [1,4,9]. Antibodies against gonadotropin receptors have also been postulated and it has been speculated that these may play a possible role in the mechanism of ovarian failure [1,4,9]. Owing to the presence of these anti-FSH antibodies, several investigators used glucocorticosteroids empirically, estrogens, estrogen–progestagen combinations and gonadotropin-releasing hormone (GnRH) agonists (GnRH-a), together with high-dose gonadotropins, in an endeavor to induce ovulation and conceptions in POF infertile patients [1,4,9]. The working hypothesis of this attitude was that the high endogenous FSH levels are inactive and cannot induce ovarian response, owing to a possible anti-FSH receptor antibody blocking its stimulation. In order to free the possibly decreased FSH receptors from their occupancy by the endogenous inactive FSH, or more logically to prevent the downregulation of FSH receptors by the very high FSH concentrations, the raised FSH levels should be suppressed by GnRH analogs or birth-control pills, in parallel with glucocorticosteroid cotreatment, to suppress the possible autoimmune reaction, as well as administration of exogenous gonadotropins to stimulate the unoccupied FSH receptors [1,4,9]. Nevertheless, autoimmunity, if it plays a role in the etiology for POF, does not seem to account for the majority of cases. Whether there is a gonadotropin-resistant ovary where follicular development is impeded, removing the block exerted by downregulation of the FSH receptors by the chronically increased FSH levels may restore ovulation once the receptors and follicles return to being responsive to FSH. If this latter mechanism is operative, then theoretically reducing the elevated FSH levels may allow restoration of FSH receptors allowing the follicles to respond to endogenous and/or exogenous gonadotropins. Whereas sporadic successes and even a few pregnancies were reported, no prospective randomized study could unequivocally support these successful case reports [1,4,9,14,15]. Therefore, if pregnancy cannot be generated within three such attempts, it has been recommended to discourage the patients from further similar treatments, and proceed with the more successful egg donation (ED) [1,4,9,14]. However, more recently, in a prospective randomized study, 58 karyotypically normal idiopathic POF patients were treated with a GnRH-a and gonadotropins with corticosteroids or placebo in an attempt to restore ovarian function. Ovulation occurred in almost 20.7% of the patients in the dexamethasone group versus 10.3% in the placebo group, and two singleton pregnancies were generated in the glucocorticosteroid arm [16].

Therapeutic endeavors towards fertility achievement

Although the most successful and ultimate treatment of these infertile couples is ED [9,10,12,13], many, if not most, of these women are reluctant to consent to ED upon the initial diagnostic interview, and request alternative solutions first [9–13]. Only when the alternative solutions fail, as is, unfortunately, the case in most such attempts, most POF patients may agree to the solution of ED.

Although we are far from ‘cracking the code’ of successful fertility treatment in POF, many patients feel the need to be convinced that no other resolution, except ED, is applicable in their specific case. The majority of published reports on induction of ovulation use a technique to restore sensitivity of those follicles that are resistant to FSH. Nevertheless, in a small minority of such cases, where autoimmunity may be the etiologic cause of follicular depletion, it may be possible to achieve pregnancy by the combination of a GnRH-a, ovulation induction with relatively high doses of gonadotropins and small doses of glucocorticosteroids [14,16]. However, these successes were anecdotal and no prospective randomized studies have unequivocally validated the efficiency of these combinations [15].

Merviel et al. have reviewed various studies concerning the protocols applied to infertile patients with POF [17]. They analyzed the natural cycles (or low-dose gonadotropin stimulation), increased-dose gonadotropins, clomiphene citrate and aromatase inhibitors, long-, short-, and micro-dose GnRH-a protocols, GnRH antagonist protocols, and the role of adjuvant treatments: aspirin, nitric oxide, recombinant LH, recombinant growth hormone and androgens [17]. Some of these protocols attempted to collect a sufficient number of oocytes (and thus of embryos to be transferred), making it possible to obtain reasonable rates of pregnancy [17]. However, these investigators concluded that the pregnancy rates generated in these patients depend not only on the ovarian reserve and the age, but also on the type of infertility, the cycle number and the uterus [17].

A similar attempt to summarize the published studies on controlled ovarian hyperstimulation in women with impending POF and low ovarian reserve has been carried out by Loutradis et al.[18]. These investigators have found a lack of clear, uniform definition of the poor responders and a lack of large-scale randomized studies which made data interpretation difficult [18]. Optimistic data have been presented by the use of high doses of gonadotropins, flare up GnRH-a protocols (standard or microdose), stop protocols, luteal onset of GnRH-a and the short protocol [18]. Natural cycle or a modified natural cycle seemed to be an appropriate strategy [18]. Low-dose human chorionic gonadotropin in the first days of ovarian stimulation also had promising results [18]. Molecular biology tools (mutations and single-nucleotide polymorphisms) have also been considered to assist the management of this group of patients. These investigators concluded that stimulation for infertile patients with diminished ovarian reserve and impending POF remains a great challenge for the clinician [18].

Check et al. have reported an unusual case of a successful gestational surrogate carrier pregnancy after reversing ovarian failure, inducing ovulation and transferring a frozen–thawed embryo [19]. Despite amenorrhea, failure to have withdrawal bleeding after progesterone withdrawal and resistance to gonadotropin stimulation, ovulation induction was attempted by restoring downregulated FSH receptors by lowering the elevated serum FSH and allowing stimulation by exogenous gonadotropins [19]. Oocyte retrieval was attempted if a mature follicle was obtained. GnRH antagonists were used to prevent premature oocyte release [19]. Tapering prednisone was used for the first 5 days of the cycle owing to patient’s history of autoimmune disease (vasculitis and Crohn’s disease). Intravenous immunoglobulin was given for vasculitis [19]. The reported patient had undergone 19 attempted egg retrievals for IVF during continuous natural cycles for 4 years.Oocyte retrieval was accomplished by traversing the uterus due to multiple adhesions after repeated surgeries for bilateral endometriomata and Crohn’s disease [19]. Empty follicle syndrome was encountered in four retrieval attempts and in 15 attempts, an oocyte was obtained. The sole attempt at natural fertilization failed. ICSI and assisted hatching were used in all subsequent attempts, and were successful in all but one attempt, which led to a three-pronuclei embryo that was discarded [19]. The first four single embryos retrieved (seven, four, six cells and morula) were transferred fresh to the patient, but no pregnancy resulted. All subsequent embryos were cryopreserved [19]. The transfer of four embryos (three-cell, six-cell, seven-cell and eight-cell) in two cycles to two different gestational surrogate carriers resulted in a successful delivery of a full-term healthy female neonate. Genetic testing confirmed maternal identity to be the patient, not the carrier [19]. However, it has been suggested that oocytes from women with diminished oocyte reserve are prone to a high rate of meiosis errors, leading to a high rate of aneuploidy, and thus only rare pregnancies, even if ovulation occurs. Indeed, many, if not the majority of cases of POF are related to an acceleration of the normal rate of atresia leaving not only reduced quantity, but also poor-quality oocytes, because the ‘best ones are used up first’.

Several additional anecdotal studies have demonstrated that ethinyl estradiol therapy can induce ovulation in women in apparent menopause and achieve live births [20]. The advantage of ethinyl estradiol over other estrogens to induce ovulation in hypergonadotropic women is that it does not cross-react in the assay for serum estradiol and can allow detection of estradiol secretion by the follicle. Another advantage of using ethinyl estradiol over GnRH-a and antagonists is that it is much less expensive, and helps to stimulate endometrial proliferation and production of cervical mucus.

Thus estrogen therapy is considered by some investigators the most effective treatment by far [20]. It has been hypothesized that ethinyl estradiol lowered the elevated serum FSH levels to restore possible downregulated FSH receptors in the diminished ovarian follicles. With the same rationale, lowering elevated serum FSH with GnRH-a or antagonists was also anecdotically successful in inducing ovulation in these patients [20]. A single case was published of successful ovulation and pregnancy following the induction of ovulation with the GnRH antagonist cetrorelix [21]. The authors speculate on the possibility that the ovulation was spontaneous, however, they refute it since they estimate that the chance of spontaneous ovulation and pregnancy in cases of POF is 1:9200 [21]. Others estimate the odds of spontaneous ovulation and pregnancy in cases of POF to be approximately 10% [14,15]. Despite the numerous case reports suggesting possible fertility in POF using various clinical protocols [18–27], it is still debatable and equivocal whether or not there is any reliable or consistently successful fertility treatment for POF, except ED [9,14–16]. Patients with POF and autoimmune activity, suggesting an autoimmune etiology to the ovarian failure, may respond to ovulation induction and have a conception rate of approximately 40% in three cycles, in cases where ovulation can be induced [14,16]. Those who do not conceive in three treatment cycles have a very low probability of conceiving; therefore further attempts of ovulation induction should be discouraged [9,14]. The rationale and hypothesis behind the combination of GnRH-a, low-dose glucocorticoids and exogenous gonadotropins (human menopausal gonadotropin and/or recombinant FSH [rFSH]) is to lower the high endogenous FSH levels, which are obviously ineffective in stimulating folliculogenesis, and possibly ameliorating the downregulation or desensitization of the diminished FSH receptors [9,14,20]. Thus, releasing the few FSH receptors from their occupancy by endogenous (and possibly inactive) FSH may enable the exogenously administered FSH or human menopausal gonadotropin to stimulate the receptors. In the presence of possible anti-ovarian or anti-FSH receptor antibodies, the administration of low-dose glucocorticosteroids may diminish the autoimmune process and possibly lower the level or activity of these antibodies. Indeed, Badawy et al. have shown, in a prospective randomized study, that the combination of corticosteroids with pituitary suppression followed by ovarian stimulation with gonadotropin appeared to be beneficial in restoring ovarian function in patients with idiopathic POF and normal karyotype. No serious complications from the use of dexamethasone were reported [16].

Finally, Mamas and Mamas described five women with POF who conceived after 50–75 mg capsules of dehydroepiandrosterone (DHEA) [28]. It may be possible that the DHEA is converted to estrogen, which suppresses FSH and works in a similar way to exogenous estrogen. However, more studies are needed to elaborate the physiologic mechanism and verify a possibility of the body utilizing DHEA as a prohormone, especially in women with low DHEA levels. There may also be an increase in production of testosterone by the very early follicles stimulating androgen receptors, allowing more preantral follicles to progress to more mature antral follicles.

However, some patients may spontaneously conceive in association with hormone therapy [14,29]. In conclusion, signs of intermittent ovarian function in karyotypically normal women have been described, but predicting the probability of spontaneous remission in a specific woman is impossible [29]. Therefore, various attempts of treatment for ovulation induction have been proposed to these patients. The possible beneficial effect of these treatments is unclear and the cause–effect relationship has not been proven by prospective randomized studies [9,14,15,29]. Although numerous case reports have described the return of ovarian function after using immunosuppressive therapies, the lack of a particular criteria for the diagnosis of autoimmune mechanisms and the absence of level I proof for the effectiveness of this endeavor makes such an attempt equivocal. No randomized controlled studies with immunologic monitoring have been performed that could establish the success of this therapy [9,14,29]. Therefore, in order to find effective treatments, basic pathophysiologic mechanisms must be better understood. For those women who want to conceive, and are reluctant to accept ED, it seems reasonable to attempt a corrective therapy based on defined etiology, before falling back on a donor oocyte program [9,14,15,29].

Minimizing chemotherapy-associated POF

An iatrogenic cause of increasing POF prevalence is gonadotoxicity in young women and survivors of gonadotoxic chemo- and radiotherapy [8,9]. Owing to the significant improvement in the long-term survival of patients treated for malignancies at a young age (lymphomas and leukemia), almost 90% of young lymphoma patients may experience long-term survival [8,9,30]. Furthermore, cancer surpassed heart disease as the world’s leading killer, according to a WHO report [31]. At the start of the 21st Century, one in 1000 young adults in their third decade was a survivor of childhood cancer [9,32]. However, in 2010, one in 250 adults was estimated to be a survivor of malignancy. The 5-year survival, after cancer treatment, ranges from 63% overall, to as high as 80% for childhood cancers,and currently the goal of over 90% survival has been challenged by modern chemotherapy for young Hodgkin’s lymphoma patients [8,9,30]. These data are encouraging but come at the cost of POF, owing to the sometimes aggressive chemo- and radio-therapy [8,9,30]. Therefore, the remote effects of cancer treatment have recently gained a ubiquitous worldwide interest for protecting against iatrogenic infertility caused by chemotherapy [8,9,30]. The tremendous increases in cancer statistics, combined with the improved long-term survival led to many young cancer survivors becoming sterile owing to iatrogenic POF [8,9,30]. Indeed, 8% of long-term survivors of childhood malignancy suffer POF by the age of 40 years [32,33]. Furthermore, approximately half (20–80%) of the women in the reproductive age exposed to gonadotoxic chemo- and/or radio-therapy will suffer POF [8,9,30,34]. Therefore, several treatment avenues have been suggested in an attempt to preserve fertility and prevent POF in these young women [8,9,30,34].

The only clinically accepted and unequivocal method is the cryopreservation of embryos or fertilized oocytes after IVF and before chemotherapy [8,9,30,34]. While this alternative is relevant to those women who have a spouse, it may be suboptimal to the very young and/or single patient. Furthermore, IVF might be irrelevant or equivocal in a substantial number of patients who need urgent chemotherapy, or in diseases that may be aggravated by the pharmacological levels of estrogens, such as systemic lupus erythematosus or breast cancer [8,9,30,34]. Cryopreservation of unfertilized metaphase II (MII) oocytes has been successful in animals, and recently its efficiency in humans has significantly improved, using either conventional programmed cryopreservation or, especially, vitrification [8,9,30,34]. Transplantation of ovarian tissue is of great hope and interest, and the number of successful deliveries in humans has increased to 14 [35]. However, while some investigators report on only approximately 40 cases of worldwide ovarian transplantation of cryopreserved ovarian tissue [35], others raised the possibility of publication bias, suggesting that those cases of unsuccessful ovarian tissue transplantation may be unreported. Thus, the exact success rate of this promising technology is as yet unknown and awaits the publication of a worldwide registry of all these cases. In addition, the group who published the first successful delivery after transplantation of thawed cryopreserved ovarian tissue has recently published their disappointing results in IVF after ovarian autotransplantation:

“IVF in women with orthotopically grafted frozen–thawed ovarian tissue involves a higher risk of empty follicles, abnormal or immature oocytes, and low embryo transfer rates.”[36].

They described an empty follicle rate per retrieval of 29%; 16 oocytes were recovered, of which six were abnormal or immature (38%), three MII oocytes failed to fertilize, two showed abnormal fertilization and five normal MII oocytes successfully fertilized with subsequent normal embryo development, yielding an embryo transfer rate of only 24% per retrieval [36]. No pregnancy occurred. Therefore, we should admit we are still far from having a ubiquitous solution for all the young women facing gonadotoxic treatments. None of the endeavored avenues for fertility preservation guarantees unequivocal success in future fertility preservation. Even IVF and cryopreservation of a few embryos cannot guarantee future pregnancy. Another recent publication has detected an overall ovarian metastases rate of 8.4–55.8% in women younger than 40 years, and 13.3% in lymphoma patients [37]. These investigators concluded that, since there is no reliable method to detect minimal residual disease in the cryopreserved tissue, the safety of reimplantation cannot yet be guaranteed [37]. Therefore, several modalities should be combined and considered [38]. As a general rule, ‘an ounce of prevention is better than a pound of cure’. Its application to medicine in general and our case particularly, is that the possible prevention of POF may be superior to treating its complications.

Therefore, in addition to IVF and cryopreservation of embryos, unfertilized ova and ovarian tissue, this author and others have focused on GnRH-a administration as an adjuvant cotreatment, in parallel with chemotherapy for minimizing gonadotoxicity [8,30]. Several recent meta-analyses and reviews [8,34,39–42] have summarized the worldwide published attempts, finding a 9–11% rate of POF in the patients who were treated with GnRH-a in parallel to chemotherapy versus 55–59% in controls. Whereas most of the previous studies, although very encouraging, were not prospective randomized trials, three randomized controlled trials (RCTs) have recently published similar results [41–43]. The largest and most recent of these RCTs included 281 stage I–III hormone receptor-positive or -negative breast cancer premenopausal patients (aged 18–45 years) between the years 2003 and 2008 [42]. In one arm (A), 133 patients received chemotherapy alone, whereas in the second arm (B), 148 patients received chemotherapy plus GnRH-a [triptorelin]. In both arms median age was 39 and the median number of chemotherapy cycles was six. The median cumulative dose of cyclophosphamide was 3840 mg (range: 0–6930) in arm A and 3940 mg (range: 0–7200) in arm B. After 1 year, POF was observed in 32.3% of patients in arm A and 13.5% in arm B (p = 0.0002), with a 19% absolute reduction (95% CI: 8–29). Cyclic menstrual activity and premenopausal estradiol levels were observed in 58% of patients in arm A and in 77% in arm B (p = 0.006). Logistic regression analysis demonstrated that the GnRH-a was independently associated with a higher probability of preservation of cyclic ovarian function (p = 0.001). The conclusion of this large RCT is that temporary ovarian suppression with GnRH-a during gonadotoxic chemotherapy is associated with a significant increase in preservation of ovarian function and prevents POF.

Furthermore, in the only prospective randomized study where histological counts of the follicles have been done, in female Rhesus monkeys, Ataya et al. have shown that GnRH-a administration in parallel to cyclophosphamide significantly decreased the daily rate of follicular decline and the total number of follicles lost during the chemotherapeutic insult, compared with cyclophosphamide alone (without GnRH-a) [44]. Similarly, Imai et al. have shown that GnRH-a decreases the in vitro gonadotoxic effect of chemotherapy, independently of the hypogonadotropic milieu [45]. These investigators have demonstrated direct in vitro protection from doxorubicin-induced granulosa cell damage by GnRH-a [45].

Criticism has been raised regarding GnRH-a usage for fertility preservation, claiming that prepubertal children are not protected against the gonadal-damaging effects of chemotherapy. However, two recent manuscripts, by Sklar et al.[33] and Edgar and Wallace [46] found an 8% cumulative rate of POF by 40 years of age in survivors of childhood malignancy. These data are in agreement with this authors and others’ results, demonstrating a POF rate of 7–11% in young women receiving GnRH-a in parallel to gonadotoxic chemotherapy compared with a 40–59% POF rate for those receiving similar chemotherapy without the agonist [8,29,37–43]. As has been clearly demonstrated [8,29,37–44], the coadministration of GnRH-a does not completely eliminate the gonadotoxic effect of chemotherapy but it does significantly decrease it; thus, the primordial follicle loss was 65% in the Rhesus monkeys that were treated with cyclophosphamide and placebo versus only 29% loss (p < 0.05) in the monkeys who received GnRH-a during the chemotherapeutic insult [44]. It may be concluded that the GnRH-a simulates the prepubertal hormonal milieu, and the rate of POF in these young survivors is 7–11% [8,29,37–43], almost identical to the 8% long-term POF rate by 40 years in survivors of childhood malignancy [33,46]. As Edgar and Wallace correctly cite, the cumulative risk of POF in adult Hodgkin’s disease patients was found to be 48% when treated with melphalan–oncovin–procarbazine–prednisone chemotherapy [46], which is almost identical to our results (50% POF rates for Hodgkin’s disease female patients on the same protocol) [8,29,47]. The rate of POF in the general healthy population is around 1%, whereas for survivors of childhood malignancy it is 8%, again, with a high similarity to the 7–11% POF rate in the patients with Hodgkin’s disease who received the GnRH-a cotreatment [8,29,46]. Thus, not only do the Edgar and Wallace [46], and Sklar et al.[33] findings not contradict the rationale of GnRH-a cotreatment for minimizing chemotherapy-associated gonadotoxicity in young women, they significantly support it.

Furthermore, in contradiction to the unsubstantiated fears and speculations whereby GnRH-a may possibly decrease the effect of chemotherapy on malignant cells in breast cancer patients, the projected overall survival rates of the GnRH-a-treated patients at 5 and 10 years were 96 and 91%, respectively [48–50], and were better than in GnRH-a-untreated controls. Furthermore, two recent meta-analyses, one in the Lancet[51] and the second, a Cochrane meta-analysis [52], have concluded that the addition of GnRH-a reduced recurrence by 12.7% (p < 0.02) and death after recurrence by 15.1% (p < 0.03). Thus, for premenopausal women with early breast cancer who are not estrogen-receptor negative, the use of an GnRH-a is likely to reduce the risk of recurrence and delay mortality [52].

A total of five possible pathophysiologic mechanisms have been put forward to possibly explain the beneficial effect of GnRH-a cotreatment in preventing POF [8,30,47,53]:

• • Temporarily creating a prepubertal, hypogonadotropic milieu;

• • Decreasing ovarian perfusion, and subsequently decreasing ovarian cumulative exposure to gonadotoxic chemotherapy;

• • Direct effect on ovarian GnRH receptors;

• • Upregulation of a gonadal protective molecule, such as sphingosine-1-phosphate, which may prevent germ cell destruction or follicular atresia;

• • Protection of possible undifferentiated germinative stem cells in the ovary.

It is beyond the scope of this article to exhaustively elaborate on these suggested mechanisms and the readers are referred to other reviews [8,30,47,53].

We have recently published the first report of spontaneous pregnancies and two successful deliveries after two repeated bone marrow transplantations (BMTs) and aggressive therapy in a lymphoma patient, treated with GnRH-a in parallel to aggressive conditioning chemotherapy [54]. The odds of spontaneous conception after one BMT is very low, estimated to be 0.6%, whereas after two BMTs, it is negligible [54]. Recently, Remerand et al. described four spontaneous pregnancies and successful deliveries in a patient after prepubertal high-dose busulfan and cyclophosphamide conditioning and BMT, demonstrating that successful pregnancies are possible in patients undergoing prepubertal BMT [55]. Similarly, our case of repeated spontaneous pregnancies and two successful deliveries after repeated autologous stem cell transplantations and GnRH-a treatment, in a postpubertal lymphoma patient suggested that the prepubertal milieu induced by the GnRH-a cotreatment might have contributed to the preserved fertility despite repeated BMT [54]. Only 0.6% of patients conceived after one autologous or allogeneic BMT according to an extensive survey involving 37,362 female patients [56]. Thus, the estimated odds for pregnancy after two BMTs are negligible (theoretically: 0.006 × 0.006 = 0.000036) [56]. Similarly, in another study conducted with 619 patients, only 3% conceived after one BMT [57]. Thus, theoretically, according to their findings, the estimated odds for conceiving after two stem cell transplantations are 0.03 × 0.03 = 0.0009, approximately one out of 1000. The administration of a GnRH-a before and in parallel to the gonadotoxic conditioning chemotherapy simulated a prepubertal hormonal milieu, and through this mechanism, and/or possibly others [8,30,47,53,54], might have minimized the gonadotoxic effect and augmented the odds of ovulations, conceptions and deliveries.

Expert commentary

All fertility treatments, except for ED, in women with POF, are unsuccessful and disappointing in most cases. All other anecdotal publications of successful treatments await validation by level I evidence, and have not been unequivocally proven by randomized controlled studies. If at all possible, it is recommended attempting to prevent premature menopause and ovarian failure in female patients younger than 40 undergoing gonadotoxic treatments, such as chemotherapy, for neoplastic or autoimmune diseases.

Combining the various methods and endeavors for fertility preservation may increase the chances of preservation of future fertility. Ovarian cryopreservation may be combined with GnRH-a administration and egg retrieval for IVF and embryo freezing, or unfertilized oocyte cryopreservation for young patients or those without a partner. Whenever the antineoplastic treatment did cause POF, as is frequently the case in total-body irradiation and BMT, the patient can use as an alternative the stored frozen cryopreserved primordial follicles, or cryopreserved embryos or ova [8,30,47,53,54]. GnRH-a administration for the prevention of POF can be helpful in neoplastic diseases as well as in female patients suffering from autoimmune diseases such as systemic lupus erythematosus or nephropathy exposed to gonadotoxic chemotherapy, especially alkylating agents such as cyclophosphamide [8,30,47,53].

Minimizing follicular loss by using GnRH-a in parallel to chemotherapy may prevent POF, preserve fertility in survivors and prevent hypoestrogenism-associated osteopenia or osteoporosis.

Five-year view

The future endeavor of possibly producing ova or spermatozoa from stem cells is fascinating. If this dream one day comes true, it may solve many ethical and economic problems associated with ED.

Furthermore, in vitro maturation in alginate 3D systems of human primordial follicles through incubation with activin, GDF, bone morphogenic proteins or other growth factors and different combinations may enable fertility in survivors of malignant diseases without the possible risk of reintroducing malignant cells to a cured patient through reimplantation of cryopreserved ovarian tissue, which has been taken before chemotherapy administration.

It may also be possible, in the future, that the development of molecules, such as sphingosine-1-phosphate, AS101, or others may protect the gonads, in vivo, and prevent POF.

Until these future hopes and endeavors are realized, we, the healthcare providers, should be very careful to supply the patients at risk of developing POF with all the available information. Combining IVF and ovarian tissue cryopreservation and GnRH-a cotreatment is suggested for maximizing patients’ odds of fertility preservation and POF prevention. Until prospective RCTs correctly predict which method will guarantee fertility preservation, we should offer all of the options to these young patients.

Key issues

• • Premature ovarian failure (POF) may occur in approximately 1% of women in the general population before the age of 40 years and 0.1% before the age of 30 years.

• • POF may be associated with versatile etiologies, such as genetic, autoimmune, iatrogenic, toxic, enzymatic, infectious, and metabolic.

• • Only egg donation has been unequivocally successful in achieving successful deliveries in POF patients.

• • POF may be preventable in most females exposed to gonadotoxic chemotherapy for either cancer and neoplastic diseases or nonmalignant autoimmune disorders.

• • Administration of gonadotropin-releasing hormone-agonist in parallel to gonadotoxic chemotherapy, together with IVF and cryopreservation of embryos, unfertilized eggs and ovarian tissue, may minimize the risk of POF and maximize the chance for fertility preservation in young women.

References

• Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr. Rev.18, 107–134 (1997).
   PubMed Web of Science ®Google Scholar
• Skillern A, Rajkovic A. Recent developments in identifying genetic determinants of premature ovarian failure. Sex. Dev.2(4–5), 228–243 (2008).
   Google Scholar
• Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Ann. NY Acad. Sci.1135, 146–154 (2008).
   PubMed Web of Science ®Google Scholar
• Goswami D, Conway GS. Premature ovarian failure. Hum. Reprod. Update11(4), 391–410 (2005).
   PubMed Web of Science ®Google Scholar
• Krauss CM, Turksoy RN, Atkins L, McLaughin C, Brown L, Page DC. Familial premature ovarian failure due to an interstitial deletion of the long arm of the 3 chromosome. N. Engl. J. Med.317, 125–131 (1987).
   PubMed Web of Science ®Google Scholar
• Chen YT, Mattison DR, Feigenbaum L, Fukui H, Schulman JD. 1981 reduction in oocyte number following prenatal exposure to a diet high in galactose. Science214, 1145–1147 (1981).
   PubMed Web of Science ®Google Scholar
• Forges T, Monnier-Barbarino P, Leheup B, Jouvet P. Pathophysiology of impaired ovarian function in galactosaemia. Hum. Reprod. Update12(5), 573–584 (2006).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z, von Wolff M. GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy. Hum. Reprod. Update14, 543–552 (2008).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z. Premature ovarian failure: etiology and possible prevention. Expert Rev. Endocrinol. Metab.4, 173–181 (2009).
   PubMedGoogle Scholar
• Shelling AN. Premature ovarian failure. Reproduction140(5), 633–641 (2010).
   PubMed Web of Science ®Google Scholar
• Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J. Mol. Endocrinol.45(5), 257–279 (2010).
   PubMed Web of Science ®Google Scholar
• Rebar RW. Premature ovarian failure. Obstet. Gynecol.113(6), 1355–1363 (2009).
   PubMed Web of Science ®Google Scholar
• De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet376(9744), 911–921 (2010).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z, Halachmi S, Peretz BA et al. Premature ovarian failure – the prognostic application of autoimmunity on conception after ovulation induction. Fertil. Steril.59, 750–755 (1993).
   PubMed Web of Science ®Google Scholar
• van Kasteren YM, Hoek A, Schoemaker J. Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation. Fertil. Steril.64, 273–278 (1995).
   PubMed Web of Science ®Google Scholar
• Badawy A, Goda H, Ragab A. Induction of ovulation in idiopathic premature ovarian failure: a randomized double-blind trial. Reprod. Biomed. Online15, 215–219 (2007).
   PubMed Web of Science ®Google Scholar
• Merviel P, Lourdel E, Boulard V et al. Premature ovarian failure: which protocols? Gynecol. Obstet. Fertil.36, 872–881 (2008).
   Google Scholar
• Loutradis D, Drakakis P, Vomvolaki E, Antsaklis A. Different ovarian stimulation protocols for women with diminished ovarian reserve. J. Assist. Reprod. Genet.24, 597–611 (2008).
   Google Scholar
• Check JH, Srivastava M, Brasile D, Amui J, Choe JK, Dix E. Successful pregnancy with frozen embryo transfer into a gestational carrier from eggs obtained from a woman in premature menopause. Clin. Exp. Obstet. Gynecol.36, 154–157 (2009).
   Google Scholar
• Check JH. Pharmacological options in resistent ovary syndrome and premature ovarian failure. Clin. Exp. Obstet. Gynecol.33, 71–77 (2006).
   Google Scholar
• Check JH, Katsoff B. Ovulation induction and pregnancy in a woman with premature menopause following gonadotropin suppression with the gonadotropin releasing hormone antagonist, cetrorelix – a case report. Clin. Exp. Obstet. Gynecol.35, 10–12 (2008).
   PubMed Web of Science ®Google Scholar
• Check JH, Katsoff B. Successful pregnancy with spontaneous ovulation in a woman with apparent premature ovarian failure who failed to conceive despite four transfers of embryos derived from donated oocytes. Clin. Exp. Obstet. Gynecol.33, 13–15 (2006).
   Google Scholar
• Check ML, Check JH, Kaplan H. Pregnancy despite imminent ovarian failure and extremely high endogenous gonadotropins and therapeutic strategies: case report and review. Clin. Exp. Obstet. Gynecol.31, 299–301 (2004).
   Google Scholar
• Check JH, Summers D, Nazari A, Choe J. Successful pregnancy following in vitro fertilization–embryo transfer despite imminent ovarian failure. Clin. Exp. Obstet. Gynecol.27, 97–99 (2000).
   Google Scholar
• Check JH, Nowroozi K, Nazari A. Viable pregnancy in a woman with premature ovarian failure treated with gonadotropin suppression and human menopausal gonadotropin stimulation. A case report. J. Reprod. Med.36, 195–197 (1991).
   Google Scholar
• Check JH, Chase JS, Wu CH, Adelson HG. Ovulation induction and pregnancy with an estrogen–gonadotropin stimulation technique in a menopausal woman with marked hypoplastic ovaries. Am. J. Obstet. Gynecol.160, 405–406 (1989).
   Google Scholar
• Check JH, Chase JS, Spence M. Pregnancy in premature ovarian failure after therapy with oral contraceptives despite resistance to previous human menopausal gonadotropin therapy. Am. J. Obstet. Gynecol.160, 114–115 (1989).
   PubMed Web of Science ®Google Scholar
• Mamas L, Mamas E. Premature ovarian failure and dehydroepiandrosterone. Fertil. Steril.91, 644–646 (2009).
   PubMed Web of Science ®Google Scholar
• Barbarino-Monnier P. From pathological diagnosis to ovulation induction. The case of ovarian insufficiency. [Article in French]. Gynecol. Obstet. Fertil.29, 39–48 (2001).
   Google Scholar
• Blumenfeld Z. GnRH-agonists in fertility preservation. Curr. Opin. Endocrinol. Diabetes Obes.15, 523–528 (2008).
   PubMedGoogle Scholar
• Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin.61(2), 69–90 (2011).
   PubMed Web of Science ®Google Scholar
• Bath LE, Wallace WH, Critchley HO. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. Br. J. Obstet. Gynaecol.109, 107–114 (2002).
   Google Scholar
• Sklar CA, Mertens AC, Mitby P et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J. Natl Cancer Inst.98, 890–896 (2006).
   PubMed Web of Science ®Google Scholar
• van der Kaaij MA, van Echten-Arends J, Simons AH, Kluin-Nelemans HC. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol. Oncol.28(4), 168–179 (2010).
   PubMed Web of Science ®Google Scholar
• Donnez J, Jadoul P, Squifflet J et al. Ovarian tissue cryopreservation and transplantation in cancer patients. Best Pract. Res. Clin. Obstet. Gynaecol.24, 87–100 (2010).
   PubMed Web of Science ®Google Scholar
• Dolmans MM, Donnez J, Camboni A et al. IVF outcome in patients with orthotopically transplanted ovarian tissue. Hum. Reprod.24, 2778–2787 (2009).
   PubMed Web of Science ®Google Scholar
• Kyono K, Doshida M, Toya M, Sato Y, Akahira J, Sasano H. Potential indications for ovarian autotransplantation based on the analysis of 5,571 autopsy findings of females under the age of 40 in Japan. Fertil. Steril.93, 2429–2430 (2010).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z. Fertility preservation and GnRH-a for chemotherapy: debate. Arch. Gynecol. Obstet.282(5), 585–586 (2010).
   Google Scholar
• Clowse ME, Behera MA, Anders CK et al. Ovarian preservation by GnRH agonists during chemotherapy: a meta-analysis. J. Womens Health18(3), 311–319 (2009).
   PubMed Web of Science ®Google Scholar
• Beck-Fruchter R, Weiss A, Shalev E. GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data. Hum. Reprod. Update14(6), 553–561 (2008).
   PubMed Web of Science ®Google Scholar
• Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil. Steril.91, 694–697 (2009).
   PubMed Web of Science ®Google Scholar
• Del Mastro L, Boni L, Michelotti A et al. Role of luteinizing hormone-releasing hormone analog (LHRHa) triptorelin (T) in preserving ovarian function during chemotherapy for early breast cancer patients: results of a multicenter Phase III trial of Gruppo Italiano Mammella (GIM) group. J. Clin. Oncol.28(Suppl. 15), (2010) (Abstract 528).
   Google Scholar
• Sverrisdottir A, Nystedt M, Johansson H, Fornander T. Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial. Breast Cancer Res. Treat.117, 561–567 (2009).
   PubMed Web of Science ®Google Scholar
• Ataya K, Rao LV, Laurence E, Kimmel R. Luteinizing hormone-releasing agonist inhibits cyclophosphamide induced ovarian follicular depletion in Rhesus monkeys. Biol. Reprod.52, 365–372 (1995).
   PubMed Web of Science ®Google Scholar
• Imai A, Sugiyama M, Furui T, Tamaya T, Ohno T. Direct protection by a gonadotropin-releasing hormone analog from doxorubicin-induced granulosa cell damage. Gynecol. Obstet. Invest.63, 102–106 (2007).
   PubMed Web of Science ®Google Scholar
• Edgar AB, Wallace WHB. Pregnancy in women who had cancer in childhood. Eur. J. Cancer43, 1890–1894 (2007).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z, Avivi I, Eckman A et al. Gonadotropin releasing hormone agonist decreases chemotherapy induced gonadotoxicity and premature ovarian failure in young female patients with hodgkin lymphoma. Fertil. Steril.89, 166–173 (2008).
   PubMed Web of Science ®Google Scholar
• Moore HCF. Ovarian Failure After Chemotherapy for Breast Cancer and the Role of Gonadotropin-Releasing Hormone Analogs in Protection of Ovarian Function. ASCO Educational Book, Spring, 39–42 (2008).
   Google Scholar
• Recchia F, Saggio G, Amiconi G et al. Gonadotropin-releasing hormone analogues added to adjuvant chemotherapy protect ovarian function and improve clinical outcomes in young women with early breast carcinoma. Cancer106, 514–523 (2006).
   PubMed Web of Science ®Google Scholar
• Del Mastro L, Catzeddu T, Boni L et al. Prevention of chemotherapy-induced menopause by temporary ovarian suppression with goserelin in young early breast cancer patients. Ann. Oncol.17, 74–78 (2006).
   PubMed Web of Science ®Google Scholar
• Cuzick J, Ambroisine L, Davidson N et al. LHRH-agonists in early breast cancer overview group. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet369, 1711–1723 (2007).
   PubMed Web of Science ®Google Scholar
• Sharma R, Hamilton A, Beith J. LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women. Cochrane Database Syst. Rev.8(4), CD004562 (2008).
   Google Scholar
• Blumenfeld Z. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. Oncologist12, 1044–1054 (2007).
   PubMed Web of Science ®Google Scholar
• Blumenfeld Z, Zuckerman T. Repeated spontaneous pregnancies and successful deliveries after repeated autologous stem cell transplantation and GnRH-agonist treatment. Oncologist15, 59–60 (2010).
   PubMed Web of Science ®Google Scholar
• Remérand G, Merlin E, Froissart R et al. Four successful pregnancies in a patient with mucopolysaccharidosis type I treated by allogeneic bone marrow transplantation. J. Inherit. Metab. Dis. DOI: 10.1007/s10545-009-1095-y (2009) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Salooja N, Szydlo RM, Socie G et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet358, 271–276 (2001).
   PubMed Web of Science ®Google Scholar
• Carter A, Robison LL, Francisco L et al. Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the bone marrow transplant survivor study. Bone Marrow Transplant.37, 1023–1029 (2006).
   PubMed Web of Science ®Google Scholar

Fertility treatment in women with premature ovarian failure

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 22-year-old nulligravid woman who was recently diagnosed with Hodgkin lymphoma. She is referred to your clinic by her oncologist because she is concerned regarding her future fertility. She is currently engaged to be married in 9 months and was hoping to have children in 3–5 years. What can you tell her regarding the epidemiology and etiology of premature ovarian failure (POF)?

• □ A POF occurs in 10% of women younger than 40 years of age

• □ B POF occurs in approximately 14% of women of reproductive age exposed to chemotherapy and/or radiation therapy

• □ C The probability of spontaneous remission can usually be predicted upon consideration of the etiology of POF

• □ D The etiology of POF is unknown in over half of cases

2. What is the most clinically acceptable method now to preserve fertility in this patient scheduled to undergo chemotherapy?

• □ A Harvesting and later transplantation of preserved ovarian tissue

• □ B Cotreatment with GnRH-a during chemotherapy

• □ C Cryopreservation of unfertilized oocytes

• □ DIn vitro fertilization (IVF) and cryopreservation of embrya

3. The patient proceeds with chemotherapy. Which of the following statements regarding cotreatment with GnRH-a is most accurate?

• □ A GnRH-a can reduce her risk for POF

• □ B GnRH-a is not effective in reducing POF among women with breast cancer

• □ C GnRH-a appears to reduce the efficacy of chemotherapy

• □ D GnRH-a should be avoided in cases requiring bone marrow transplantation (BMT)

4. Which of the following statements regarding the treatment strategy for POF related to an autoimmune etiology is most accurate?

• □ A The use of GnRH analogs will help increase production of endogenous follicle-stimulating hormone (FSH)

• □ B The use of ethinyl estradiol should be avoided among these women

• □ C The use of exogenous gonadotropins can stimulate unoccupied FSH receptors

• □ D Only 1 cycle is required as a trial of therapy in such cases