PharmacologyTier 1Medical Sciences concept

Alkylating agent gonadotoxicity

Core concept

Alkylating agents crosslink DNA in any cell cycle phase, so they kill the non-dividing primordial oocyte pool as well as dividing germ cells
- This is why they, and not the cycle-specific agents, are the gonadotoxic class
Female - the primordial follicle reserve is fixed at birth and non-renewable
- Loss -> premature ovarian insufficiency, permanent
- Also direct stromal and vascular injury, and accelerated recruitment ("burnout")
Male - spermatogonial stem cells are the target
- Azoospermia may be prolonged or permanent; Leydig cells are relatively resistant -> testosterone usually preserved
- So a man can be infertile with a normal testosterone and normal virilisation

Risk determinants (female)
- Age at treatment is the strongest predictor - the older the woman, the smaller the residual reserve and the closer to natural menopause
- Cumulative alkylator dose (dose-dependent)
- Baseline ovarian reserve

Risk	Agents / regimens
High	Cyclophosphamide (highest oocyte toxicity), busulfan, melphalan, ifosfamide, chlorambucil, procarbazine; BEACOPP; myeloablative conditioning; pelvic/total body irradiation
Intermediate	Cisplatin, carboplatin, doxorubicin-based (AC)
Low	ABVD, methotrexate, 5-FU, vincristine, bleomycin, most targeted agents

Cyclophosphamide is the reference gonadotoxin in both sexes and in non-malignant use (lupus nephritis, vasculitis)
Male gonadotoxins: nitrogen mustards, other alkylators, cisplatin, procarbazine
Markers of damage
- Female: AMH (best marker of reserve, falls first), antral follicle count, inc FSH, dec oestradiol
- Male: semen analysis, inc FSH with normal LH/testosterone
Resumption of menses does not equal preserved fertility - the reserve may still be severely depleted and menopause will come early

Fertility preservation - discuss BEFORE the first cycle

Female: oocyte or embryo cryopreservation (needs ~2 weeks of stimulation), ovarian tissue cryopreservation (no delay, option in prepubertal girls), GnRH agonist co-treatment (adjunct only, evidence for ovarian protection in breast cancer, not a substitute)
Male: sperm cryopreservation before treatment starts - simple, cheap and frequently forgotten

Every patient of reproductive age needs a fertility discussion documented before cytotoxic therapy - including for benign indications such as lupus nephritis and ANCA vasculitis
- In vasculitis and lupus, prefer rituximab or mycophenolate over cyclophosphamide in young patients where efficacy allows; use the lower-dose Euro-Lupus regimen
Premature ovarian insufficiency brings osteoporosis, cardiovascular risk, vasomotor symptoms and cognitive effects - offer HRT to the age of natural menopause unless contraindicated (hormone-sensitive tumour)
Post-treatment surveillance: AMH and FSH in women, semen analysis in men, and bone density
Contraception is still required during and after treatment - teratogenicity outlasts fertility loss; avoid conception for 6-12 months

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