Abstract
Summary
We report the successful delivery of a healthy baby after intracytoplasmic sperm injection (ICSI) with frozen-thawed autologous sperm, cryostored for 26 years, the longest successful autologous sperm cryostorage reported. Sperm was cryostored for a 15-year-old boy at the time of his cancer diagnosis. Semen samples were frozen with cryoprotectant, using a graduated vapour-phase nitrogen protocol. Straws were stored in a large vapour-phase nitrogen tank until transfer for use. The couple underwent a single ICSI–in vitro fertilisation procedure using the frozen-thawed sperm with a transfer of five fertilised embryos, resulting in the live birth of a healthy baby boy. This reinforces the importance of offering sperm cryopreservation to men who have not completed their family prior to gonadotoxic treatment for cancer or other diseases. As practical, low-cost fertility insurance, it should be offered to any young man who can collect semen and it provides essentially unlimited duration of fertility preservation.
Learning points
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Gonadotoxic chemo or radiotherapy treatment for cancer or other diseases usually causes temporary or permanent male infertility.
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Sperm cryostorage serves as a practical, low-cost insurance to facilitate future paternity.
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All men who have not completed their families and are scheduled for gonadotoxic treatments should be offered sperm cryostorage.
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There is no lower age limit for young men who can collect semen.
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Sperm cryostorage offers essentially indefinite duration for the preservation of male fertility.
Background
Sperm cryostorage is the original, most widely available fertility preservation procedure, an early forerunner of the oncofertility discipline (1). By storing viable, potentially fertile mature spermatozoa frozen in liquid nitrogen, it serves as practical, low-cost fertility insurance for men scheduled to receive potentially sterilising medical treatments. The stored sperm are then available in case timely recovery of fertility is not achieved when the men have not yet completed their families. In recent decades, sperm banks are widely available with sperm cryostorage universally recommended by comprehensive cancer management guidelines. The major application for sperm cryostorage is for men embarking on gonadotoxic chemotherapy and/or radiotherapy treatments, but there is also a smaller number (~10%) for non-cancer diseases requiring gonadotoxic treatments (2). Cancer is an increasingly important public health challenge with, globally, 19.3 million new cancer cases diagnosed in 2020, among which 10.1 million were men, with predicted cancers to increase to 28.4 million in 2040 (3).
Here, we report the successful delivery of a healthy baby boy achieved with frozen-thawed sperm that was cryostored at the time of cancer diagnosis, 26 years prior to using intracytoplasmic sperm injection (ICSI), a variant of in vitro fertilisation (IVF) procedure.
Case presentation
In 1996, a 15-year-old schoolboy presented with several months of cough and 5 kg weight loss due to Hodgkin’s disease with an extensive thoracic mass. He had undergone normal puberty at 12 years and had been otherwise well. He was 172 cm in height and 54.5 kg in weight with both testicular volumes (orchidometry) of 18 mL.
Investigation
Three semen samples collected for cryostorage had between 34 and 78.7 million sperm per ejaculate and produced 54 frozen straws with post-thaw motility between 17 and 34% (Table 1). Semen was cryostored with glycerol–egg yolk–citrate cryoprotectant in 0.5 mL aliquots in heat-sealed high-security straws, using a graduated vapour-phase nitrogen protocol over 30 min. Straws were ultimately stored in a large vapour-phase nitrogen tank maintained at −196°C without any thawing incidents till his specimens were withdrawn for use.
Semen parameters and serum hormone levels before semen cryopreservation and through follow-up over a period of 24 years.
Date | Abstinence (days) | Semen volume (mL) | Sperm density (M/mL) | Sperm total (M) | Motility (%) | Morph (%) | No. of straws | Post-thaw motility (%) | Serum LH (IU/L) | Serum FSH (IU/L) | Serum testosterone (nmol/L) | Serum SHBG (nmol/L) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
30/10/1996 | 9 | 5.7 | 13.8 | 78.7 | 48 | 1 | 19 | 17 | – | – | – | – |
1/11/1996 | 2 | 5.6 | 6.4 | 35.8 | 58 | 0 | 18 | 34 | – | – | – | – |
4/11/1996 | 3 | 5 | 6.8 | 34 | 57 | 1 | 17 | 22 | 5.1 | 9.3 | 16.9 | 64.8 |
14/04/1999 | 6 | 5.8 | 0 | 0 | 0 | 0 | – | – | 5.8 | 11.8 | 29.8 | 38.3 |
6/01/2010 | 3 | 11 | <0.2 | <2.2 | – | – | – | – | 6.1 | 20.8 | 18.7 | 39.8 |
27/06/2011 | 4 | 8.7 | <0.2 | <1.7 | – | – | – | – | 3.9 | 23.9 | 15.1 | 59.1 |
7/07/2014 | 3 | 7.6 | <0.2 | <1.5 | – | – | – | – | 3.4 | 22.8 | 20.4 | 64.2 |
11/12/2019 | – | – | – | – | – | – | – | – | 3.6 | 23.8 | 15.2 | – |
10/02/2020 | 4 | 6.5 | 0 | 0 | 0 | – | – | – | – | – | – | – |
Treatment
He underwent six monthly cycles of MOPP/ABV chemotherapy (nitrogen mustard 10.2 mg i.v. monthly; vincristine 2.4 mg i.v. monthly; prednisolone 35 mg oral, days 1–14 monthly; procarbazine 175 mg oral, days 1–7; doxorubicin 60 mg, day 8; bleomycin 17 mg, day 8; vinblastine 10.2 mg i.v., day 8) and was regarded as effectively cured. He remained azoospermic (Table 1) since then on multiple semen analyses. His serum follicle-stimulating hormone increased from pre-chemotherapy of 9.3 IU/L to castrate levels (between 20.8 and 23.8 IU/L) without any evidence of falling levels over time. His serum LH (3.4–5.1 IU/L), testosterone (15.1–29.8 nmol/L) and SHBG (38.3–64.8 nmol/L) remained consistently within normal limits.
Outcome and follow-up
In 2020–2021, after 11 years of using no contraception, the patient and his 35-year-old wife had sperm transferred interstate and underwent one unsuccessful intrauterine insemination (IUI procedure followed by one successful ICSI–IVF procedure using cryostored (frozen-thawed) sperm. In the IVF cycle, 27 oocytes were harvested with 21 fertilising normally overnight, resulting in 10 embryos. A single transfer of five fertilised embryos (grade 5BA) was undertaken with the remaining five embryos frozen on days 5 or 6 after fertilisation. The transfer resulted in the live birth of a healthy boy (57 cm, 4.3 kg) on 17/2/2022, 26 years after the sperm were cryostored.
Discussion
This live birth using autologous sperm cryostored for 26 years in an ICSI–IVF treatment demonstrates prolonged preservation of sperm fertilising ability during frozen storage. This surpasses the previous longest successful autologous sperm cryostorage of 21 years (4), noting also the successful use of heterologous sperm donation after about 40 years of sperm cryostorage (5). These findings reinforce the long-term utility of offering sperm cryostorage to any young men capable of providing semen samples who have not completed their families and face potentially sterilising gonadotoxic cancer or other treatments.
Although the first human artificial insemination (John Hunter) and the observation that cold storage preserved sperm functions (Lazzaro Spallanzani) were reported in the 18th century, sperm cryostorage was first proven to preserve the fertilising capacity of human spermatozoa in 1953 after which cryostored donor sperm was used in human infertility treatment for couples with untreatable male infertility, usually due to azoospermia, from 1964 (6) and then widely since the early 1970s. Autologous sperm cryostorage for fertility preservation prior to cancer treatment was suggested in 1980 (7, 8) with initially low sperm output considered a contraindication to sperm cryostorage (7). However, the subsequent adaptation to using in vitro fertilisation procedures (9, 10), meant that any ejaculated sperm could be effectively cryostored prior to gonadotoxic treatment.
The length of effective storage that preserves the fertilising ability of human sperm is not well defined. Currently, the cumulative experience of sperm banks reports the use of cryostored sperm for fertility procedures of 8% (11) with a median of 10 years (average maximum of 15 years) follow-up after storage; however, these findings likely underestimate usage due to limited and/or incomplete follow-up. The present case reinforces the likelihood that there is effectively no time limit to the duration of successful sperm cryostorage.
Hence, sperm cryopreservation prior to gonadotoxic treatment now extends to any non-zero sperm output and allows for very prolonged storage. Sperm cryostorage is a practical, low-cost fertility insurance for men embarking on gonadotoxic treatments for cancer or non-cancer diseases but who have not completed their family. It is therefore crucial for such men who can collect semen to be offered sperm cryostorage as soon as possible prior to embarking on gonadotoxic treatment, to allow them a realistic chance for paternity in the future.
Patient’s perspective
At age 15, I was diagnosed with cancer, and at that time I was focused on the treatment, not on what might happen in the years after. So, when my oncologist suggested that I think about storing sperm, I decided that it was worth doing. Over the years, it was a great comfort to me knowing that it was there even if my life had not led me to starting a family just yet. When I met my wife it was something that we discussed early on. We decided to seek information on whether we should start a family early due to using frozen sperm, and we were told that, due to it being old, it should be used straight away and we should not wait. We decided to consult specialists in Sydney, where I had completed my treatment, and our minds were later laid to rest as we were told there was no evidence to suggest the quality would deteriorate over time.
In 2020, my wife and I decided to start trying for a family through the use of IVF, and in2022, a healthy baby was born, all thanks to a decision that was made 26 years ago. Having the ability to store sperm has not only delivered us our son, but over the years has given us peace of mind, knowing that we can have children whenever we choose to, no matter the age or quality of the sperm stored. We would encourage anyone who has found themselves in this situation, especially those of a young age, to consider storing if given the option.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding statement
This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent for publication of their clinical details was obtained from the patient.
Author contribution statement
All authors have contributed to the preparation of this case report.
References
- 1↑
Woodruff TK. The emergence of a new interdiscipline: oncofertility. Cancer Treatment and Research 2007 138 3–11. (https://doi.org/10.1007/978-0-387-72293-1_1)
- 2↑
Shankara-Narayana N, Di Pierro I, Fennell C, Ly LP, Bacha F, Vrga L, Savkovic S, Turner L, Jayadev V, Conway AJ, et al.Sperm cryopreservation prior to gonadotoxic treatment: experience of a single academic centre over 4 decades. Human Reproduction 2019 34 795–803. (https://doi.org/10.1093/humrep/dez026)
- 3↑
International Agency for Cancer Research. 2022 Globoscan 2020. IARC, WHO 2022. Available at: https://gco.iarc.fr/
- 4↑
Horne G, Atkinson AD, Pease EH, Logue JP, Brison DR, & Lieberman BA. Live birth with sperm cryopreserved for 21 years prior to cancer treatment: case report. Human Reproduction 2004 19 1448–1449. (https://doi.org/10.1093/humrep/deh249)
- 5↑
Szell AZ, Bierbaum RC, Hazelrigg WB, & Chetkowski RJ. Live births from frozen human semen stored for 40 years. Journal of Assisted Reproduction and Genetics 2013 30 743–744. (https://doi.org/10.1007/s10815-013-9998-9)
- 6↑
Perloff WH, Steinberger E, & Sherman JK. Conception with human spermatozoa frozen by nitrogen vapor technic. Fertility and Sterility 1964 15 501–504. (https://doi.org/10.1016/s0015-0282(1635344-4)
- 7↑
Sanger WG, Armitage JO, & Schmidt MA. Feasibility of semen cryopreservation in patients with malignant disease. JAMA 1980 244 789–790. (https://doi.org/10.1001/jama.1980.03310080023017)
- 8↑
Bracken RB, & Smith KD. Is semen cryopreservation helpful in testicular cancer? Urology 1980 15 581–583. (https://doi.org/10.1016/0090-4295(8090371-4)
- 9↑
Mahadevan MM, Trounson AO, & Leeton JF. Successful use of human semen cryobanking for in vitro fertilization. Fertility and Sterility 1983 40 340–343. (https://doi.org/10.1016/s0015-0282(1647297-3)
- 10↑
Tournaye H, Camus M, Bollen N, Wisanto A, Van Steirteghem AC, & Devroey P. In vitro fertilization techniques with frozen-thawed sperm: a method for preserving the progenitive potential of Hodgkin patients. Fertility and Sterility 1991 55 443–445. (https://doi.org/10.1016/s0015-0282(1654147-8)
- 11↑
Ferrari S, Paffoni A, Filippi F, Busnelli A, Vegetti W, & Somigliana E. Sperm cryopreservation and reproductive outcome in male cancer patients: a systematic review. Reproductive Biomedicine Online 2016 33 29–38. (https://doi.org/10.1016/j.rbmo.2016.04.002)