fertility preservation

1. Fertility Preservation
By: Dr Prabhat Ranjan
Department of Medical Oncology
SRMC

2. Introductiom
• Gonadotoxic treatments including chemotherapy, radiation, and surgical
resection can permanently impair reproductive function
• However, with appropriate pretreatment planning and intervention, biologic
parenthood is possible.

3. RAPID REFERRAL FOR COUNSELING
• Clinicians should discuss the risk of treatment-induced infertility as well as
possible interventions to preserve fertility and hormone production prior to
initiating gonadotoxic therapy or extirpative surgery
• This discussion should occur as soon as possible during treatment planning
because some interventions require time and could delay the start of therapy
• Despite guidelines advocating for fertility counseling for these patients,
studies have reported both low provider awareness and variable referral rates
for fertility counseling globally

4. In Females

5. Chemotherapy-associated ovarian toxicity

6. Malignancies : ? fertility preservation

7. ASSESS PATIENT GOALS FOR THERAPY
• When considering reproductive function,one must separately address the
patient's desires for future pregnancy and potential preservation of
hormone production
• The optimal approach depends upon the planned treatment, patient age and
pubertal status, the specific disease, partner availability, cost, and
consideration of long-term future issues such as storage, use, and disposition
of frozen embryos, cells, or tissue.

8. Fertility preservation options for
women treated with gonadotoxic
therapies

12. • Egg donation – If the patient has no fresh or frozen oocytes or ovarian
tissue available, but her uterus is intact, fresh or frozen donor oocytes and
her partner's sperm can be used for in vitro fertilization (IVF)
• This is a proven approach, with success rates exceeding 60 percent per
embryo transfer.

13. • Gestational carrier – A gestational carrier (ie, surrogate) is a woman who
agrees to carry a pregnancy for another woman (intended mother)
• The intended mother provides the egg, and the intended father provides the
sperm
• IVF is used to create an embryo, which is transferred into the uterus of the
gestational carrier

14. In patients receiving Radiation alone

15. • Reported success rates of transposition are inconsistent, varying between 16 and 90
percent
• The failures are due to various factors such as scatter radiation, vascular
compromise, radiation dose, the age of the patient, and whether the ovaries are
properly shielded during the radiation procedure
• Complications, such as chronic ovarian pain, infarction of the fallopian tubes, and
formation of ovarian cysts have been reported during long-term follow-up
• Ovaries can also "migrate" back to their original position

16. OVARIAN HORMONE PRESERVATION
• Medical rationale — For premenopausal women undergoing gonadotoxic
therapy or surgery, the rationale to attempt to preserve ovarian hormone
function is that in this population, early loss of reproductive hormones is
associated with increased long-term risks of bone loss and osteoporosis,
cardiovascular disease, and mortality
• Thus, medical therapy to protect ovarian hormone function may benefit
younger women receiving gonadotoxic drugs

17. • GnRH agonists suppress ovarian function and, therefore, have been
theorized to protect the ovary in the setting of a toxic insult such as
chemotherapy
• However, the ovarian follicles are still exposed to these DNA-damaging
agents even though the ovarian hormone production is suppressed
• As primordial follicles do not express gonadotropin receptors, it is unclear
how GnRH agonist therapy would enhance survival of these cells

18. • GnRH agonists,although can be used to prevent menorrhagia in women at
risk for severe chemotherapy-induced thrombocytopenia
• GnRH agonist should be initiated at least two to three weeks before
chemotherapy to allow sufficient time for down regulation and to avoid any
flare up-related bleeding and continued until the end of chemotherapeutic
treatment
• Side effects include hot flushes and vaginal dryness

19. Other Methods
• Radical trachelectomy – In properly selected women with cervical cancer,
radical trachelectomy is an option instead of hysterectomy and preserves the
uterus for future childbearing
• Hormonal therapy for early stage endometrial cancer – In some selected
young patients with early-stage endometrial cancer wishing to preserve the
uterus, hormonal therapy using progestins alone or in combination with
progesterone-bearing intrauterine systems does not seem to affect survival
rates compared with primary surgery

20. In Males

21. General Rules
• Spermatogenesis is much more likely to be disrupted than is testosterone
production, because the germinal epithelium of the testis is more sensitive to
damage from cytotoxic drugs than the Leydig cells.
• The degree of damage to the germinal epithelium is influenced by the stage
of sexual maturation of the testis. In general, the postpubertal testis appears
to be more susceptible to damage than the prepubertal testis
• The magnitude of the effect on sperm production is both drug-specific and
dose-dependent

22. MECHANISM OF DRUG-INDUCED
INFERTILITY
• In the testis, the cells within the seminiferous tubules of the germinal epithelium have the
highest mitotic and meiotic indices, and are thus most vulnerable to the toxic effects of
chemotherapy
• While sperm counts begin to decline within a few weeks of chemotherapy, it typically takes
2-3 months for azoospermia to occur
• The severity and duration of gonadal damage induced by cytotoxic agents correlates best
with the number of stem cells that are destroyed
• If the stem cells within the tubules remain intact, spermatogenesis may begin to show
recovery approximately 12 weeks after treatment
• Therefore, drugs that damage the stem cells are likely to cause permanent infertility.

23. Malignancies with abnormal gonadal
function(Pretreatment)
• Hodgkins Lymphoma
• Testicular Tumors
• Acute Leukemia

24. CHEMOTHERAPEUTIC AGENTS
ASSOCIATED WITH INFERTILITY
1. CYCLOPHOSPHAMIDE-Cumulative doses of 6 to 10 g are likely to
result in irreversible azoospermia
2. IFOSFAMIDE
3. CHLORAMBUCIL-Cumultive doses more than 400 mg
4. CISPLATIN-Cumulative doses more than 400 mg/m2
5. Methotrexate, doxorubicin, fluorouracil, fludarabine, and taxanes- Modest
but reversible effect

25. • Antiandrogens (flutamide, cyproterone, bicalutamide), and ketoconazole may
cause dysspermatogenesis by inhibiting testicular androgen production or
action
• Ionizing radiation impairs spermatogenesis. Doses as low as 0.015 Gy may
transiently suppress spermatogenesis, while doses above 6 Gy usually cause
irreversible azoospermia and infertility

26. ASSESSMENT OF DRUG-INDUCED
INFERTILITY
1. Clinical evaluation
i. Measurement of testicular size using a Prader orchidometer is key to
assessing gonadal function; in normal men, it ranges from 15 to 25 Ml
ii. Men who have received gonadotoxic chemotherapy will typically
demonstrate a significant decrease in testicular volume

27. 2. Semen analysis
i. A semen analysis is the simplest and most reliable method of assessing the
impact of chemotherapy on fertility
ii. It is recommended that a sample be collected after a minimum of 48 hours
and not longer than seven days abstinence
iii. If the first sample gives an abnormal result, two more samples should be
obtained several weeks apart to permit adequate interpretation

28. • Current reference limits for semen analyses:
i. Semen volume – 1.5 mL
ii. Sperm concentration – 15 million spermatozoa/mL
iii. Total sperm number – 39 million spermatozoa per ejaculate
iv. Morphology – 4 percent normal forms
v. Vitality – 58 percent live
vi. Progressive motility – 32 percent
vii. Total (progressive + nonprogressive motility) – 40 percent

29. 3. Hormonal Evaluation
i. FSH and inhibin B levels — FSH is a very sensitive hormonal indicator of
seminiferous tubular damage
Serum FSH concentration may be increased 5 to 10-fold in men who have
received cytotoxic chemotherapy
The mechanism of the increase is a decrease in the peptide hormone,
inhibin B, which is secreted by Sertoli cells and inhibits FSH secretion

30. ii. LH — In vivo, LH secretion is pulsatile, so a single LH measurement may be
misleading and should always be interpreted in the context of a concomitant
serum testosterone level. LH levels are typically normal or slightly elevated
following cytotoxic chemotherapy
iii. Total testosterone- tends to remain in the lower end of the normal range

31. PREVENTION OF GONADAL TOXICITY
• Semen cryopreservation — The simplest strategy for preserving fertility is to
obtain a semen sample for cryostorage prior to initiating therapy
• Limitations:
i. Pretreatment semen parameters are abnormal in a significant number of patients
ii. The process of freeze-thawing has an additional negative impact on sperm
function causing a further decrease in sperm motility
iii. Cryopreservation is not typically pursued for patients who are still prepubertal

32. • Hormonal manipulation — The demonstration that the prepubertal testis
appears to be less susceptible to the gonadotoxic effects of chemotherapy
than the mature adult testis led to the hypothesis that suppression of
testicular function in adult men undergoing chemotherapy might preserve
their fertility
• While studies in a variety of animal models, including the rat and mouse,
have yielded encouraging results, the experience to date in the human has
been disappointing

33. • All men scheduled for potentially gonadotoxic chemotherapy who are
interested in future paternity should be informed about the risk of infertility
and referred for sperm banking
• In the past, men who developed azoospermia after chemotherapy were
considered to be sterile. Now, many of these men are able to undergo
successful testicular sperm extraction and intracytoplasmic sperm injection.