OT recipients

There are many indications for OT, secondary to either a specific disease or syndrome, in the setting of non-oncologic and/or oncologic aetiologies. Ideally, OTr are immunologically matched to organ donors ensuring improved outcomes, lowering rejection, although nearly all patients will undergo immunosuppressive therapy (IST). Multiple IST regimens pose deleterious consequences to reproduction. These effects may cause direct structural organ damage or indirectly incite hormonal or gonadal reserve abnormalities. The toxicity level (gonadotoxicity) and impairment will dictate future reproductive potential. Cofactors (i.e., age and previous reproductive status) may further interfere with fertility. We briefly review some of the pathophysiologic effects of OT on reproduction. The female and male reproductive implications in OT are assessed below in an organ-specific-based classification of solid versus non-solid transplants.

Female

The number of available primordial follicles decreases throughout life from approximately one to two million at birth to 450,000 follicles in early puberty, and this number defines a woman’s ovarian reserve (OR). There is an accelerated loss of follicles after 35–37 years of age, with menopause averaging 50.1 years of age, where only 1000 follicles remain, signalling the end of the reproductive life .

The menstrual cycle is an integrated system (i.e., hypothalamic–pituitary–ovarian (HPO) axis) regulated dynamically by the feedback-loop interactions of steroid and peptide hormones. Disruption of this balance leads to reproduction abnormalities and infertility. Reproductive organ injury may be temporary or permanent, and may or may not be reversible. The return of normal menstruation post chemotherapy does not correlate or predict future fertility. Conversely, amenorrhoea has a high negative predictive value, with few recipients experiencing reproductive recovery .

Multiple hormonal measures are used to assess OR such as serum day 2–3 follicle-stimulating hormone (FSH) and estradiol (E2), and recently anti-müllerian hormone (AMH). Elevation in FSH and E2, with suggested levels between 15 and 65 mIU/mL, respectively, may represent decreased OR, higher ART cycle cancellations and low birth rates. AMH is solely produced from pre- and small-antral follicle granulosa cells, and represents a cycle-independent OR diagnostic marker, not affected by prescribed sex steroids, and is the earliest clinical indicator of age-decreased ovarian function . AMH levels decline with age, are undetectable post menopause and are useful in monitoring cancer survivors at a risk of decreased OR. Furthermore, its values correlate with the patient’s response to controlled ovarian stimulation (COS) and the number of in vitro fertilization (IVF)-retrieved oocytes . Ovarian ultrasonographic imaging for antral-follicular count (AFC) has a positive linear correlation between its decrease and poor fertility outcomes (success of COS, egg retrieval and pregnancy) especially when used in conjunction with other markers .

Male

In males, spermatogenesis begins at puberty and is cyclically renewed (74 days) from a constant pool of primordial differentiated oogonia germ cells (spermatogonia) located within the seminiferous tubules, and supported by Sertoli cells. Males undergoing OT are at a risk of premature reproductive failure (PRF). The recovery post OT of spermatogenesis is dependent on the undamaged spermatogonia ability to differentiate. The fertility assessment is based on the history and physical exam, semen analysis (SA) evaluation and hormone levels, performed at least 3 months from OT, due to the 74-day spermatogenesis cycle. In recovering patients, repetitive SA collection may be necessary to document improvement. Gonadal failure is accompanied by a sustained FSH rise, secondary to the loss of negative feedback. Here, inhibin B secreted by a Sertoli cell may aid in the diagnosis . The reproductive OTr pathophysiology is largely a consequence of either metabolic disarrangements or gonadal toxicity. Most commonly, IST is used to decrease acute–chronic graft rejection or loss. Some regimens are highly gonadotoxic, particularly alkylating agents responsible for DNA damage that directly affects the ovary. Furthermore, haematologic disorders often use myeloablative conditioning (MAC) with radiation therapy prior to bone marrow/stem cell transplant (BMT/SCT), known to induce gonadal damage and/or failure.

Female

The number of available primordial follicles decreases throughout life from approximately one to two million at birth to 450,000 follicles in early puberty, and this number defines a woman’s ovarian reserve (OR). There is an accelerated loss of follicles after 35–37 years of age, with menopause averaging 50.1 years of age, where only 1000 follicles remain, signalling the end of the reproductive life .

The menstrual cycle is an integrated system (i.e., hypothalamic–pituitary–ovarian (HPO) axis) regulated dynamically by the feedback-loop interactions of steroid and peptide hormones. Disruption of this balance leads to reproduction abnormalities and infertility. Reproductive organ injury may be temporary or permanent, and may or may not be reversible. The return of normal menstruation post chemotherapy does not correlate or predict future fertility. Conversely, amenorrhoea has a high negative predictive value, with few recipients experiencing reproductive recovery .

Multiple hormonal measures are used to assess OR such as serum day 2–3 follicle-stimulating hormone (FSH) and estradiol (E2), and recently anti-müllerian hormone (AMH). Elevation in FSH and E2, with suggested levels between 15 and 65 mIU/mL, respectively, may represent decreased OR, higher ART cycle cancellations and low birth rates. AMH is solely produced from pre- and small-antral follicle granulosa cells, and represents a cycle-independent OR diagnostic marker, not affected by prescribed sex steroids, and is the earliest clinical indicator of age-decreased ovarian function . AMH levels decline with age, are undetectable post menopause and are useful in monitoring cancer survivors at a risk of decreased OR. Furthermore, its values correlate with the patient’s response to controlled ovarian stimulation (COS) and the number of in vitro fertilization (IVF)-retrieved oocytes . Ovarian ultrasonographic imaging for antral-follicular count (AFC) has a positive linear correlation between its decrease and poor fertility outcomes (success of COS, egg retrieval and pregnancy) especially when used in conjunction with other markers .

Male

In males, spermatogenesis begins at puberty and is cyclically renewed (74 days) from a constant pool of primordial differentiated oogonia germ cells (spermatogonia) located within the seminiferous tubules, and supported by Sertoli cells. Males undergoing OT are at a risk of premature reproductive failure (PRF). The recovery post OT of spermatogenesis is dependent on the undamaged spermatogonia ability to differentiate. The fertility assessment is based on the history and physical exam, semen analysis (SA) evaluation and hormone levels, performed at least 3 months from OT, due to the 74-day spermatogenesis cycle. In recovering patients, repetitive SA collection may be necessary to document improvement. Gonadal failure is accompanied by a sustained FSH rise, secondary to the loss of negative feedback. Here, inhibin B secreted by a Sertoli cell may aid in the diagnosis . The reproductive OTr pathophysiology is largely a consequence of either metabolic disarrangements or gonadal toxicity. Most commonly, IST is used to decrease acute–chronic graft rejection or loss. Some regimens are highly gonadotoxic, particularly alkylating agents responsible for DNA damage that directly affects the ovary. Furthermore, haematologic disorders often use myeloablative conditioning (MAC) with radiation therapy prior to bone marrow/stem cell transplant (BMT/SCT), known to induce gonadal damage and/or failure.

Renal transplantation

Female

Chronic renal failure (CRF) is linked to menstrual irregularities: abnormal uterine bleeding (AUB), anovulation, sexual dysfunction and subfertility . Disturbances of the HPO axis may be secondary to uremic toxins that are time dependent to the CRF onset (see Table 1 ) . Patients on chronic dialysis often have a minor improvement to the HPO axis that translates into continuing AUB and poor fertility outcomes . Adolescent patients frequently have delayed puberty with menarche averaging 15.3 years and a bone age of 12.9 years. Delays correlate with both the duration and severity of CRF. Dialysis prolongs pubertal onset to its completion. Conversely, successful renal transplantation generally leads to a prompt full pubertal maturation.

Table 1

Female and male reproductive changes in CRF and post renal transplantation.

Half of regular menstruating women with CRF are anovulatory, contributing to infertility with several hormonal irregularities . There is a change in gonadotropin-releasing hormone (GnRH) pulsatility resulting in altered luteinizing hormone (LH) secretion and increased LH-to-FSH ratios . Hyperprolactinaemia is a consequence of an increase in lactotroph secretion (up to threefold), decrease of hormone clearance (up to 1/3) and heightened sensitivity to dopaminergic inhibition. As the severity of renal dysfunction progresses, menstrual patterns become unpredictable varying between oligomenorrhoea and amenorrhoea . Dialysis does not typically resolve these dysfunctions with 90% of patients exhibiting menstrual irregularity . In 2004, Lessan-Pezeshki et al. reported infertility in 10.4% of these patients secondary to anovulation (50%), male factor (33%) and unexplained infertility (16.6%) . Reproductive recovery depends ultimately on the improvement of ovarian function and normalization of the HPO axis. Following successful graft and a stable serum creatinine (1.4 mg/dL), most patients resume normal menses within the first year of OT (average of 5–7 months) . Premature ovarian insufficiency (POI) is rare in CRF patients and varies between 4% and 20% in renal OTr , possibly related to the underlying renal aetiology and use of gonadotoxic therapy.

Liver transplantation

Approximately one third of all liver transplant recipients are female and most are of reproductive age. More than 80% of paediatric OTr live to adulthood . Infection (hepatitis C) or autoimmune diseases are present in most and, similar to ESRD patients, women with hepatic dysfunction often have HPO-axis disturbances with menstrual abnormalities. These abnormalities are thought to be related to the underlying disease, severe hepatic dysfunction sequelae, metabolic abnormalities and/or direct disturbance of the HPO axis (i.e., alcohol abuse). The elevated estradiol levels may in part be due to the porto-systemic shunting of less potent androgens (i.e., androstenedione and dehydroepiandrosterone) and to peripheral oestrogen conversion . Ovaries reveal frequently a lower number of follicles and corpora lutea. Liver transplant improves many of these abnormalities, restoring a normal menstrual pattern, normalizing the HPO axis and even recovering pubertal delay (1.1 years delay with a mean age at menarche of 14.4 years of age), secondary to early-onset organ failure . It has been reported that up to 95% of patients had menstrual recovery and variable regular menses resumption from 50% in 1 year to 90% within 7 months post OT . Fertility post liver transplantation is restored in 50–75% of OTr, with pregnancy reported as early as 1 month post surgery. Nonetheless, it is expected that up to 50% of women of reproductive age with end-stage liver disease after OT experience subfertility . Early menopause in women with alcoholic liver disease is common . These patients often need ART and are prone to have an inadequate response to GnRH agonists and clomiphene citrate (CC), secondary to diminished endogenous gonadotropin release that may be related to their reduced levels of circulating sex steroids .

Pancreas–kidney transplantation

The use of pancreas–kidney transplantation (PKT) has been ground breaking in the treatment of patients with severe type 1 diabetes mellitus . The first pregnancy was reported in 1986 . Frequently, these patients exhibit hypogonadism, with 50% and 70% of the women reporting menstrual irregularities before and a year after transplantation on IST, respectively . Conversely, there is no clear link between IST and menstrual irregularities.

In men, hypogonadism is often noticeable prior to transplant and they are at a risk of diminished sperm counts, motility and fertility rates. Low testosterone and high FSH and LH are common in patients on rapamycin, and its replacement with everolimus has not been associated with hypogonadism .

Many patients will see an improvement in their fertility after the transplant. The NTPR, as well as others, have collected data on 79 pregnancies reported worldwide in 45 PKT recipients. In 2007, Fichez et al. published the first case of IVF pregnancy in a PKT recipient 10 years post surgery . PKT patients undergoing IVF do have risks. Ovarian hyperstimulation exposes them to high levels of oestrogen that increases their risk of thromboembolism (TE). It is important to emphasize that secondary to physiologic and anatomic changes, pregnancy is an independent factor for TE, increasing their risk fourfold to fivefold . These patients are also at a risk of ovarian hyperstimulation syndrome (OHSS) that can cause coagulopathy, and it might be prudent to consider prescribing antiplatelet or anticoagulant therapy when clinically indicated. Ectopic kidney and pancreatic anatomic relocation may predispose to injury from inadvertent puncture and damage during oocyte retrieval. Smyth et al. (2011) reported a case of a 25-year-old female with a 6-year-old PKT with both allografts located in the pelvic fossae. The patient underwent COS, producing a singleton pregnancy, delivered prematurely at 26 weeks due to deterioration in renal function, and had a complicated postpartum period by hypertension. The case exemplifies the potential risks for patients receiving PKT . Pregnancy outcomes in PKT are at an increased risk of spontaneous abortion (14%), ectopic pregnancy (2%), hypertension disorders (75%), urinary tract infections (55%) and pre-eclampsia (35%) .

Heart and/or lung transplant

Heart and lung transplantation (HLT) may be performed either individually or combined. The increase in the number of successful pregnancy outcomes in these patients has changed the indications and the traditional belief that pregnancy should be discouraged (see Table 2 ). The first successful pregnancy in heart transplant (HT) occurred in 1986, and since then multiple case reports have been published . To date, there are no publications on the use of ART in this population, and several considerations should be anticipated in its future application.

Patients undergoing HT may have specific challenges related to graft and known hemodynamic changes in pregnancy (i.e., increase in cardiac output, fluid retention, volume expansion and reduction in systemic vascular resistance). Pregnancy in heart recipients does not seem to increase the risk of graft rejection, reported to be up to 21%. Armenti et al. additionally reported no additional graft loss within 3 years of pregnancy, a fact perhaps explained by the immune-privileged site uterus model . When HT is performed secondary to a congenital heart disease (i.e., mitochondrial myopathies and dilated cardiomyopathy), the offspring are at a risk of similar anomalies and a preconception genetic counselling is warranted (see Table 2 ). Similarly, recurrence of peripartum cardiomyopathy (PPCM) should be anticipated, although Morini et al. did not identify any recurrence risk in a small case series .

When ART is indicated, COS may pose a risk secondary to vascular fluid shifts. Moreover, these patients may be on medication that modifies coagulation homeostasis, and therefore potential bleeding complications exist from egg retrieval, which mandates a clinical laboratory evaluation and medication adjustment accordingly.

There are many female patients post HLT of reproductive age, with the majority of recipients reporting normal fertility. These patients experience a 5- and 10-year survival rate of approximately 50% and 25%, respectively .

There is very limited information on pregnancy after isolated lung transplant (LT). Their fertility potential may be related to the pulmonary failure aetiology. Cystic fibrosis patients have increased cervical mucus plugging, inherited ovarian follicular abnormalities, seminiferous tube blockage and spermatogenesis abnormalities . Timing pregnancy in LT patients is still debated, although most recommend an interval of 2 years after the transplant, as >50% experience acute rejection in the first year post transplantation. The NTPR database has reported a graft loss in 27% during pregnancy and 21% within 2 years of OT . After 2 years, recipients have a significantly lower rejection risk and are maintained at lower IST dosages, decreasing their risk of infection. Progesterone levels increase during pregnancy and have a central respiratory stimulatory effect that may increase the tidal volume and minute ventilation, further complicating dyspnoea, gas exchange and cardiovascular homeostasis .

Non-solid organ transplants

The use of BMT/SCT in the past three decades has greatly improved the life expectancy of patients suffering from malignant (i.e., leukaemia and lymphoma) and non-malignant diseases (i.e., sickle cell anaemia). The improvement in longevity and quality of life has led to an increased desire for fertility in many patients. Yet, prescribed gonadotoxic therapies (pharmacologic and radiation) are associated with POI, affecting >90% of female patients . Less than 1% of these patients experience ovarian function recovery and normal fertility. There are few spontaneous pregnancy cases documented in the literature after either autologous or allogeneic SCT .

Patients that have not yet undergone ablative therapy for BMT/SCT may undergo fertility preservation techniques (oocyte, embryo or ovarian tissue and sperm banking) (see ‘ART MANAGEMENT in OTr’ section for further details). Nevertheless, there is a concern that the use of cryopreserved gametes could reseed malignant cells, especially in autologous SCT . Strategies to reduce POI risk include replacing known gonadotoxic regimens such as ABVD (adriamycin, bleomycin, vincristine and doxorubicin) with less harmful agents or using reduced-intensity conditioning (RIC) . The use of GnRH agonists prior to chemotherapy is a fertility-sparing option, with unclear proven benefits . In a recent meta-analysis, female oncology patients who were never exposed to gonadotoxic therapy had lower numbers of retrieved oocytes compared to healthy controls . This unexpected finding may require individualized COS protocols. One of the first case reports by Atkinson et al. (1994) documents a successful pregnancy after transfer of three cryopreserved embryos, 4 years post allogeneic transplantation for chronic myeloid leukaemia. This case illustrates the importance of timely planning and using all the up-to-date resources .

The current guidelines from the American Society of Clinical Oncology (ASCO) and the American Society for Reproductive Medicine (ASRM) concur on the need for oncologists and reproductive specialists to counsel patients regarding fertility preservation. In two recent publications, it was concluded that when given the opportunity, 23–42% of patients chose fertility preservation through ART . Fertility is affected in patients who undergo SCT prior to MAC, having a decrease in OR, especially after 30 years of age . Gonadal function recovery is uncommon following MAC regimens, although there are case reports to the contrary, as noted in a 22-year-old woman who spontaneously conceived after high-dose total body irradiation (TBI) and BMT for acute myeloid leukaemia (AML) . Haukvik et al. (2006) investigated the long-term risk of developing POI in young women treated for Hodgkin’s lymphoma. The group documented POI in 34% of patients treated at <30 years of age . Recently, a large cohort study of Hodgkin patients concluded that non-alkylating chemotherapy is associated with minimal risk of POI compared with a positive dose–response relationship between alkylating use and age. The options for POI patients desiring children will typically be adoption or oocyte donation with a few case reports documenting its use, particularly when SCT/BMT was performed before adolescence .

Male gametes are similarly affected by chemotherapy and radiation. Gonadotoxic drugs such as alkylating agents in high doses (cyclophosphamide >7.5 g∖m ² ) (19, 20) are known to cause permanent damage . Recovery is seldom present, estimated in most studies to be <1% . Recent studies have suggested the possibility of gonadal failure being linked to the disease itself. At the time of diagnosis of Hodgkin’s lymphoma and prior to treatment, up to 80% of the cases demonstrate an abnormal SA . In a retrospective study of a cohort of 474 Hodgkin’s lymphoma patients, approximately 90% had ‘good’ to ‘intermediate’ quality SA and 3% were azoospermic. There was no apparent correlation between sperm quality, age and clinical stage of the disease similar to other oncologic aetiologies. It has been hypothesized that the underlining mechanism of gonadal failure may be related to the action of proinflammatory cytokines. It has been estimated that adolescent sperm banking rates are at most 25%. One of the most important barriers to banking, especially in younger males, relates to a lack of appropriate counselling from the referring doctor. Cryopreserving sperm following guidelines defined by ASCO and the American Academy of Pediatrics (AAP) is recommended . It has been documented that 12-year-old males have already motile sperm in their ejaculates and are able to benefit from cryopreservation . Preadolescent patients may require an alternative non-voluntary collection method, such as testicular biopsy . Advances in ART, such as freezing methods and intracytoplasmic sperm injection (ICSI), have improved fertility outcomes with cryopreserved sperm.