**2. Ovaries, oocytes and female reproduction**

196 Topics in Cancer Survivorship

iii. Aspiration of oocytes, followed by cryopreservation and IVF (if necessary preceded by *in vitro* maturation). This option has already been applied to a number of patients. Although the same drawbacks that apply to standard IVF are applicable, this procedure is mainly aimed at the treatment of post-pubertal girls/young women without a stable relationship. Only limited scientific data are currently available to substantiate its

iv. As an alternative, cryopreservation of small ovarian cortex strips containing primordial follicles can be offered. After the patient has been cured, these cortex strips can subsequently be retransplanted either heterotopically or orthotopically. This procedure has been successfully used to re-establish female fertility in humans in a limited number of cases. A major problem with these avascular implants however is their relative short life expectancy and follicular loss due to long term ischemic injury

v. Cryopreservation and subsequent reimplantation of intact ovaries may be a valuable addition to the existing array of options, especially for pre-pubertal girls and postpubertal girls/women without a stable relationship. An important safety issue of this procedure is obviously the chance of reintroduction of malignant cells that may be present in the cryopreserved intact ovary. For this reason, patients with solid types of tumor and diffuse types of cancer such as leukemia that have a high chance of metastasizing to the ovaries, will have to be excluded from this kind of therapy. The cryobiological and surgical aspects of the preservation and retransplantation of an organ *in toto*, is technically clearly more challenging than the cryopreservation and transfer of isolated cells or tissue strips. The advantages of this approach are obvious; immediate revascularization of the transplanted ovary ensures that less ischemic damage is inflicted to the ovarian tissue post-thawing, and that more follicles will survive. In addition menses, normal long term reproductive functions, and normal

Finally, we will go into the safety of the procedure. Inevitably the autotransplantation of cortical strips or intact ovaries carries the risk of reintroducing malignant cells from the graft

The increase in knowledge of the biology and treatment of cancer has been accompanied by an increase in the efficacy of cancer therapies. Long term survival rates for many cancer types have therefore increased accordingly (Gatta et al., 2009). Consequently, the quality of

The possibility to have genetically concordant progeny is for many people an event that is essential for an unrestricted quality of life as an adult (Schover, 2009). The loss of fertility that may result from cancer therapy, is therefore an additional complication on top of an

With this in mind, it is of the utmost importance to explore the possibilities for fertility preservation in patients that are to be treated with a gonado-toxic therapy. For post-pubertal boys and men, this can be achieved relatively easy via the cryopreservation of their semen prior to start of the therapy. For pre-pubertal boys this is not an option, as semen production is initiated during puberty. Also for this group of patients options for fertility preservation

yet involved in a stable relationship.

efficacy and long-term safety.

directly after reimplantation.

hormonal status will be restored.

life of cancer survivors is becoming an important issue.

already difficult period spent on conquering a devastating disease.

into the recipient.

are being developed.

treatment is not an option for pre-pubertal girls, or for post-pubertal girls who are not

The human ovary is spherical structure with a mean volume of 7 cm3 (range 2-15 cm3; Munn et al., 1986). The inner ovarian mass, the medulla, consists mainly of stromal cells and contains the larger blood vessels. The outer layer of the ovary consists of the cortical tissue, spanning 2-3 mm. This tissue is rich in extra-cellular matrix proteins and poor in capillaries , and contains the vast majority of the follicles containing oocytes that comprise the ovarian reserve. The most important role of the follicle is to protect the oocyte, and support its development. Follicles are comprised of layer(s) of theca cells and granulosa cells. Different stages of follicles can be distinguished, ranging from primordial follicles to primary follicles, and via secondary finally to tertiary (antral) follicles.

In contrast to males in whom spermatogenesis is a continuous process resulting in the uninterrupted generation of fresh spermatozoa, in women a fixed number of oocytes is formed during embryogenesis from 1000-2000 germ cells. These germ cells are present in the human embryo at 30 days after conception. After 9-10 weeks, these cells transform to oogonia (Baker, 1972), that degenerate for the greater part between 10 and 20 weeks of gestation. After 5 months of gestation, the first meiotic division is initiated in the remaining oogonia, resulting in the differentiation to primary oocytes. At this stage the meiotic division process is arrested, and the oocytes enter a stage of dormancy (Wandji, 1996). At birth only 300.000 to 400.000 oocytes remain in the ovaries. From birth, the number of oocytes gradually decreases, and at the beginning of puberty around 200.000 oocytes remain. Under the influence of pituitary gonadotropic hormones (Gougeon, 1996; Oktay, 1997), each month a cohort of primary oocytes is recruited, and resumes development. Usually only one primary oocyt completes the first meiotic division. This secondary oocyt again enters a stage of dormancy, and is ovulated. The second dormant stage is only lifted after fertilization by a sperm cell. Around the age of 50 years, the total oocyte reserve is almost depleted and the woman enters menopause. In addition to age, several factors may affect the follicular reserve, leading to an early exhaustion and to premature ovarian insufficiency (POI). These factors include fertility-threatening therapies that are discussed in more detail in the next section.
