Review: Influence of Radiation on Female Fertility and Pregnancy

Radiations made up of non-ionizing and ionizing radiations, this classification is based on the ionizing power and the energy of radiations. In developed and developing communities, people are continually exposed to radiations which are generated from variety sources that are naturally occurring or producing by human. The purpose of this study is to review accessible information on the influence of radiation on female fertility and to discuss the options for fertility preservation. Radiation exposure can result in impairment of tissue integrity and sometimes, leading to organs dysfunction, the impact of radiations on organs depends on site of irradiation, patient age and total radiation dose. Female patients who are treated with radiation have an increased rate of uterine dysfunction, ovaries dysfunction, impaired fertility, incidence of pregnancy complications, premature birth and miscarriage. Pre-pubertal uterus is more vulnerable to the effect of radiation, compared with the pubertal uterus due to arising ovarian estrogen production and uterus enlarges. To reduce the effects of radiations on female reproductive organ, fertility preservation procedures such as ovarian transposition, reproductive gland protection and oocyte cryopreservation should be carried out before and/or during radiotherapy.


Introduction :
Radiation is energy which could be in the form of waves or particles [1]. In developed and developing communities, people are continually exposed to non-ionizing and ionizing radiations which generate from various of sources that naturally occurring or producing by human. It could be from non-ionizing radiation (e.g., TV, mobile, solar light, and laser therapy device) or from medical applications (e.g., diagnostic imaging and radiotherapy). However, radiation associated with some biological effects, regardless the types and the source of radiation as well as the amount of the dose [1,2].
Radiations are divided into two groups, ionizing and non-ionizing, this classification is based on energy and capability of radiations to produce ions [3,4]. Energy of ionizing radiation is above 10 eV, which has sufficient energy to generate ions and have an impact on cellular level. This is a vital distinction because of the substantial difference in injuriousness to organs. Ionizing radiation could be particle such as alpha (α) and beta (β) particles. Alpha (α) particles are a positive charge particle (+2), and their emission can result in decreasing the number of proton and neutrons. Their range is about 5 cell diameters in the mammalian and are considered to have a heavy linear energy transfer (LET). This results in alpha-particle emitters to be less applicable in therapeutic aspects [5,6].
Beta particles are either negative charge particle (negatrons) or positive charge particle (positrons) [7], which emitted as a consequence of decomposing the nucleus radioactive material. Their emission can result in increasing the number of protons by one or decreasing neutron by one, and their range is much more compared to α particles. They are considered to have very low linear energy transfer (LET). Consequently, beta-particle emitters have high a therapeutic efficacy [6].
Ionizing radiation could be wave form such as X-rays and gamma (γ) rays which have been used in diagnostic imaging and anticancer treatment [5]. γ-rays originating from the nucleus, while x-rays emitted from the electron shell described as characteristic X-ray or continuous Xrays can be produced through the acceleration or deceleration of charged particles. A potential ionization produced as a result of interaction of X-rays with matter. This causes the chemical and biological effects. The capability of penetrating wave forms radiation elevated when the energy increase, decrease with elevating the atomic number of the absorbed material [8,9]. The

Biological Effects of Radiation:
Human beings are constantly exposed to radiation from variety of sources that naturally occurring or producing by human. This radiation can affect living cells, leading to ionize molecules and malfunctions in cell processes. The influence of radiation is determined by the type and energy of radiation, the amount of dose, age, sex, and the long-term exposure [15].
The first biological damage of exposure to radiation was observed by Roentgen's discovery of the X-ray in 1895, following years, the impact of radiation was based on the experience of early radiologists and workers in miners [16,17].

Mechanisms of Radiation Damage:
When radiation exposed to an organ, its damage initiate at the cellular level through absorbing radiation by cells and particularly has the potential effect on DNA. Studies showed that impaired DNA can result in mutation, and can lead to cell death [15,16].
Through two important mechanisms (direct and indirect effects) radiation can impact on cells:

Direct Effect:
In this interaction, radiation affects DNA molecule directly and resulting in ionizing DNA molecule, often cells may reproduce themselves and survive. However, sometimes cells cannot repair themselves, and leading to improper replicate of chromosomes then cells may be damaged directly. The probability of occurrence of this action is uncommon due to a small diameter of the DNA [16, 17].

Indirect Effect (water radiolysis):
This action occurs in the presence of water, radiation interacts with water, resulting in generation of free radicals, they are characterized by an unpaired electron, which are recognizable as they are chemically highly reactive. They have capability to diffuse distance in the cells and damage DNA. Radiation-induced harm due to indirect action is more frequent compared to those harm that generate as result of direct action. Indirect action is more prominent in low linear energy transfer (LET) radiation (e.g. gamma rays and X-rays) [14,15].
An ion pair of HOH+ and e-are produced through the interaction of radiation with water, H2O + radiation → HOH + + e -. The electron recombines with HOH+ ion or it may react with another water molecule and forming a free radical that characterized by unpaired electron.
HOH -→OH -+ H* Free radicals attempt to reconnect with another oxygen, producing hydroperoxyl radicals.
The hydroperoxyl radicals may result in biological impair directly or fragment create hydrogen peroxide and oxygen: A hydroxyl radical OH* and H3O formed through the interaction of the HOH + with HOH molecule and ion H + and a hydroxyl radical producing as result of breaking down HOH + : HOH + +HOH→OH*+H3O HOH + →H + +OH* The hydroxyl radicals interact with other hydroxyl radicals, create H2O2 (hydrogen peroxide).

OH* + OH* → H2O2
The hydrogen peroxide results in about two thirds of all biological damage [15-17].

Deterministic and Stochastic Effects:
Radiation exposure result in impairment of tissue integrity and function, ICRP has classified such deleterious radiation effects into either stochastic effects or deterministic effects.

Deterministic Effects :
Deterministic effect is function of dose with threshold, which is a point below there is no observable effect. These effects are due to acute exposure. It requires the killing of many cells in the affected organ to occur. This leads to a loss of organ function. Cataracts and infertility are example of deterministic effect [16, 17].

Stochastic Effects:
Stochastic effects results from chronic exposure and have a non-threshold and the probability occurring is a function of dose. Stochastic effects are supposed to result from

Radiotherapy:
Radiotherapy is one of the standard modalities that can kill cancer cells, prevent its recurrence, or reduce symptoms. Radiotherapy uses ionization radiations that can kill cancer cells or halt their ability to reproduce, through deposition energy in the cells of the tissues [18].
Although exposing to radiation can damage normal and cancer cells, the aim of radiotherapy is to expose the maximum radiation dose to cancer cells while the minimum dose to healthy cells.
Abnormal cells have fewer capabilities to recover when compared to normal cells [19]. In order to eradicate tumors, patients receive radiotherapy as part of their treatment. Some of them need other treatments, such as chemotherapy or surgery [20].
Radiotherapy use two main approaches to deliver radiation: External or internal in the first method: photons, protons or particle radiation is delivered from outside the body to the location of the tumor, in the second modality: a radioactive source can be placed either inside the lesions or nearby. Selection of the treatment depends on the shape and size of the cancer, where the tumor is located and the type of cancer [21].

Female Reproductive Organ:
Females are born with nearly 500,000-1000,000 primordial follicles, the number is continuing to reduce with increasing age, primarily through apoptosis and atresia [22], declining to about 1000 at 50 years, which is considered as a time of menopause. Cells with high mitotic activity are more likely to be damaged when exposed to radiation, compared to those which has low mitotic activity [23,24].

Ovarian Dysfunction
Ovarian follicles are impaired by radiation through damaging DNA, resulting to follicular atrophy and reduced ovarian follicular store. This can cause reduction in follicle numbers and  that the uterine volume of young women that exposed to radiation, decreased to 40%, and showed that young female patients that exposed to radiation during their childhood as a part of their anticancer treatment were more likely to have deleterious effects on future pregnancies prepubertal age, uterine growth is less and is resistance to hormone therapy. In contrast, female who exposed to radiation at post-puberty age, can take advantage from hormone replacement therapy, as explained by growth uterine volume and function [45]. Ali and Chaudhary indicated that dose of 46Gy to endometrial can result in uterine dysfunction [46]. Table 2: Outcomes of radiation on uterus function.

Effects of Radiation on Pregnancy and Newborn:
A number of publications evaluated the deleterious effects of radiation on pregnancy in those females who treated with radiation [47][48][49]. In addition, several studies on detrimental influence radiation on pregnancy among young cancer survivors that received radiation as a part of their treatment were carried out and showed an elevation in deleterious effects of radiation on pregnancy and newborn in women patients who had received radiation during their childhood [50,51], including low weight in newborn and detaining the growing up in uterus [52,53].
Additionally, in two studied by Arrive et al., and Green et al., who pointed out treating young women with the total body irradiation (TBI) can result in premature birth and miscarriage [54,55].
The impacts of radiation on fertility are dependent on the amount of dose and whether unborn child at an embryonic or a fetal stage, for example exposing to radiation during early gestation (less than two weeks) most often results in pregnancy loss. Additionally, embryo from (2 to 7 weeks) is more likely to be affected by radiation. Also, malformations of body parts and developmental delays can happen, while occurring are based on the radiation dose, whether below or above threshold [56,57].
There are also very limited data on the increasing risk of congenital anomalies and childhood cancer in children whose parents have been treated with radiation during their childhood [58,59]. females achieved 4029 pregnancies, among these, the results were; live birth was more than 60%, abortions, and miscarriage were less than 20%, in stillbirth and in gestation had the lowest percentage which were1% and 3% respectively. More importantly, the possibility of occurring miscarriage was increased when ovaries close to radiation area. In contrast, the possibility of miscarriage was not increased when ovaries shielded. Women with pelvic irradiation are more likely to have baby with low-birthweight [54].

Measures to preserve fertility:
Infertility is still one remaining issue that experienced by survivors who were treated with radiation during their childhood [61]. Ovarian transposition is considered as preservation and results showed that abdominal can be preserved [64]. Women who are about to undergo radiotherapy have different options regarding fertility conservation. For example: • Oocyte cryopreservation: Oocyte undergo artificial hormone therapy and the unfertilized oocytes are then frozen. This technique can be performed prior to radiotherapy [63][64][65][66].
Although Oocyte cryopreservation allow female patients to delay reproduction, only 100babies reportedly born from oocyte storage prior to 2004 [67], and over 500live births generating from this technique before 2010 [68].
• Reproductive gland protection: During radiation in an area far from the pelvis, carefully placed shields can reduce the exposure of the reproductive organs to the scatter radiation [62].
• Ovarian transposition (changing the ovary position): In this procedure, the position of one or both ovaries are surgically altered, thus they are protected from the planned radiation field.
However, due to scatter radiation, the ovaries are not always protected. After treatment, the patient may need to change the position of the ovaries again or use in vitro fertilization (IVF) for pregnancy [64] [69]. In addition, several studies have assessed the efficacy of ovarian transposition and the results varied widely [70][71][72]. This is variation among these studies might refer to the differences in the amount of dose that delivered to patients and age of patients, shielding of ovaries and whether chemotherapy is present or not [73].
Additionally, a retrospective control study showed that ovarian transposition prior to radiotherapy can preserve ovarian in patients aged less than 35 years and there is ongoing debate about the safety and effectiveness of the ovarian transposition in females aged 36-40 years [74].
• Surgical removal of the cervix (radical removal of the cervix): when cervical cancer at early stage, this procedure can help preserve the uterus [66]. Furthermore, A systematic review showed that fertility-sparing can be achieved through the radical trachelectomy [75].

Conclusions:
Radiation has deleterious impacts on the female genital tract including, natural growth or reduce numbers of eggs and destroy hormones that linked to birth. The extent of the damage that occurs to uterus and ovaries depends on site of irradiation, patient age, and total radiation should be carried out before and/or during radiotherapy. It is necessary to counsel and inform patients about available fertility preservation techniques prior to performing producers by fertility specialist. To improve fertility preservation in female cancer patients, more retrospective and prospective studies needed on impact radiation on fertility.