James M. Hotaling, MD, MS
Craig S. Niederberger, MD, FACS
BASICS
DESCRIPTION
• 2006 ASCO Guidelines recommend that all patients in their reproductive years undergoing cancer therapy be offered fertility preservation options (1)
• Mainstay of fertility preservation in men is referral to a reproductive specialist and sperm cryopreservation
• Sperm cryopreservation is often not covered by insurance but Livestrong Foundation and Fertile Hope offer financial support (2)
EPIDEMIOLOGY
Incidence
• 1.4 million people are diagnosed with cancer every year
• 10% of those diagnosed with cancer are <44 yr old (3)
• Testicular cancer is one of the most common cancers seen by men in their reproductive years and typically presents to urologists
Prevalence
Advances in cancer treatment have led to increased survival rates of 75–80% for those diagnosed <50 yr old (4)
RISK FACTORS
Men with male factor infertility (azoospermia) are significantly more likely to develop testis cancer
Genetics
N/A
PATHOPHYSIOLOGY
• Men presenting with cancer often have reduced semen quality (3)
• Radiation at doses of 2.5 Gy to the testis causes prolonged azoospermia
• Radical pelvic surgery can cause erectile and ejaculatory dysfunction
• Certain common chemotherapeutic agents cause prolonged azoospermia (1)
– Cisplatin (500 mg/m2)
– Chlorambucil (1.4 g/m2)
– Cyclophosphamide (19 g/m2)
– Procarbazine (4 g/m2)
– Melphalan (140 mg/m2)
– Others shown to be gonadotoxic:
Busulfan, carmustine, cytarabine, ifosfamide, lomustine, nitrosoureas
ASSOCIATED CONDITIONS
• Hematologic malignancies
– Whole-body radiation used before bone marrow transplant usually causes life-long infertility
• Prostate cancer can directly impact fertility through sperm impairment and indirectly through erectile dysfunction (5)
– Radical prostatectomy and its effect on fertility should be disclosed to the patient preoperatively
– Brachytherapy does not give a large dose of radiation to the testicles, and most men will remain fertile or recover sperm production
– External radiation is more likely to cause permanent infertility, even if the testicles are shielded
• Testicular cancer
– More than half of the patients with testicular germ cell cancer showed impaired fertility
– Retrograde ejaculation following retroperitoneal lymphadenectomy
GENERAL PREVENTION
• Radiation to the testicles can cause permanent loss of sperm production
• Unless the cancer is in the testicles, attempt to protect them from radiation by using a shield called a clam shell (5)
DIAGNOSIS
HISTORY
• Thorough reproductive history
– Gonadotoxin exposure?
– Previous difficulty with conception?
– Use of exogenous steroids?
– Varicocele surgery?
– Diagnosis of cystic fibrosis?
• Discussion of desire for future paternity
• Assessment of onset of puberty in adolescent patients
– Nocturnal emissions?
– Sexually active?
PHYSICAL EXAM
• Assessment of Tanner stage in adolescent males
• Focused testicular exam
– Longitudinal testicular axis
– Presence of vas deferens
– Presence of epididymis
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Evaluation of baseline FSH, LH, estradiol, total testosterone, sex hormone binding globulin (SHBG), and albumin (to calculate bioavailable T)
• Values for optimal spermatogenesis
– Bioavailable T >155 ng/dL
– FSH <4.5
– Total testosterone:estradiol ratio > 10:1
• Semen analysis by a high-volume lab: WHO 5th edition lower limits of normal
– Sperm concentration >39 million/mL
– Motility >40%
– Total motile count >15 million
– Morphology >4% normal by Kruger strict criterion
Imaging
N/A
Diagnostic Procedures/Surgery
If men are found to be azoospermic on semen analysis consider microsurgical testicular sperm extraction (microTESE)
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
N/A
TREATMENT
GENERAL MEASURES
• Semen analysis with cryopreservation of ejaculated sperm by a high-volume lab
– Men with testis cancer or Hodgkin disease should bank multiple times given known lower recovery rates (3,6)
– Any sperm obtained from semen analysis should be banked
– Patients should abstain from ejaculation for 2 days before banking sperm but not more than 3 days
– At least 2–3 samples should be banked for each patient
– A frank discussion with the patient regarding the ongoing costs of cryopreservation and methods for patient contact in the future is vital
• Attempts to obtain and bank seminiferous tubules from prepubertal males for use in future-assisted reproductive technologies should only be done under an IRB-approved research protocol (4)
• All discussions for adolescents and children should involve both the patient and their parents
• Electroejaculation or vibratory stimulation may be used for patients with a spinal cord injury
MEDICATION
First Line
• To convert a retrograde ejaculation to an antegrade ejaculation
– In the United States, ephedrine is most often used
– In Europe, imipramine is also used
• α-adrenergic agents (dosing highly variable)
– Pseudoephedrine 60 mg
– Ephedrine 25–50 mg
– Imipramine 25–50 mg (may cause dizziness and nausea); commonly used in Europe
– Frequency ranges from QD to QID
– Duration ranges from 2 to 14 days
– Side effects: HTN, tachycardia
Second Line
N/A
SURGERY/OTHER PROCEDURES
In men who are azoospermic, aspiration of seminiferous tubules from the testis, sperm from the epididymis or microTESE with extraction of sperm and cryopreservation is a viable option and should be offered
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
Roughly 30% of men who receive gonadotoxic chemotherapy or radiotherapy will remain azoospermic permanently
COMPLICATIONS
N/A
FOLLOW-UP
Patient Monitoring
• Men should have a repeat interrogation of their male endocrine axis and another semen analysis by a reproductive health specialist when they desire paternity
• Some men may be hypoandrogenic after completion of treatment and referral to a reproductive health specialist is essential to ensure that they are offered medication other than testosterone for androgen repletion
Patient Resources
• Oncofertility Consortium: http://oncofertility.northwestern.edu/
• Fertile Hope: www.fertilehope.org
• ASRM Cancer and Fertility Preservation: http://www.asrm.org/Cancer_and_Fertility_Preservation/
REFERENCES
1. Lee SJ, Schover LR, Partridge Ah, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006;24:2917–2931.
2. Woodruff TK. The Oncofertility Consortium–addressing fertility in young people with cancer. Nat Rev Clin Oncol. 2010;7:466–475.
3. Hotaling JM, Lopushnyan NA, Davenport M, et al. Raw and test-thaw semen parameters after cryopreservation among men with newly diagnosed cancer. Fertil Steril. 2013;99:464–469.
4. Trost LW, Brannigan RE. Oncofertility and the male cancer patient. Curr Treat Options Oncol. 2012;13:146–160.
5. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/radiation/radiationtherapyprinciples/radiation-therapy-principles-side-effectsof-radiationto-specific-areas (accessed June 14, 2014).
6. Jeruss JS, Woodruff TK. Preservation of fertility in patients with cancer. N Engl J Med. 2009;360:902–911.
ADDITIONAL READING
WHO laboratory manual for the examination and processing of human semen, 5th edition, http://whqlibdoc.who.int/publications/2010/9789241547789_eng.pdf
See Also (Topic, Algorithm, Media)
• Kruger Strict Sperm Morphology
• Retrograde Ejaculation
• Semen Analysis, Abnormal Findings, and Terminology
• Semen Analysis, Technique, and Normal Values
• Tanner Stage
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 606.8 Infertility due to extratesticular causes
• V26.82 Encounter for fertility preservation procedure
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• N46.024 Azoospermia due to radiation
• Z31.84 Encounter for fertility preservation procedure
CLINICAL/SURGICAL PEARLS
• <10% of men who bank sperm retrieve it for use in assisted reproductive technologies.
• Referral to a reproductive specialist and sperm cryopreservation prior to initiation of gonadotoxic chemotherapy, radiation, or radical oncologic surgery is essential.
• Cost of sperm cryopreservation typically ranges from $200 to $500 initially usually with an annual maintenance fee.