Causes and Factors of Infertility

Introduction

The problem of infertility has been longstanding and increasing. It is a global public health problem that affects approximately 48.5 million couples worldwide and 1 in 7 couples in the UK (Mascarenhas et al., 2012; National Institute for Health and Clinical Excellence, 2013). Infertility is defined as the inability of a couple to conceive after a year of unprotected sex, for women under the age of 35 years (Cedars and Jaffe, 2005; Ezzell, 2016). For women aged 35-40, it is the inability to conceive after 6 months of unprotected sex, and for women over age 40, after 3 months of unprotected sex. Infertility is also the inability to carry a pregnancy to term (Ezzell, 2016). It can be due to male factors

Secondary infertility

Infertility can also be secondary which is when a woman who has previously got pregnant is unable to get pregnant or carry a pregnancy to term again after a year of trying and after giving birth to at least one child; provided they didn’t receive any fertility treatments (Katib et al., 2014).

Miscarriages

A miscarriage is defined as the spontaneous loss of a pregnancy after a positive pregnancy test or after an intrauterine had been confirmed by an ultrasound. Pregnancy loss occurring after positive urinary human chorionic gonadotrophin (hCG) and serum β-hCG increase but before pregnancy confirmation by ultrasound is called a biochemical loss. When pregnancy loss occurs after ultrasound confirmation of an intrauterine pregnancy, it is called a clinical miscarriage. Miscarriages may be sporadic or recurrent, with recurrent miscarriages possibly being caused by maternal or paternal chromosomal abnormalities, maternal thrombophilia, immune disorders and endocrine disorders. Alternatively, a combination of immune dysregulation, lifestyle factors and changes in the integrity of sperm DNA in pregnancy (Larsen et al., 2013).

Causes and factors of infertility

Many factors contribute to infertility, which include male or female factors.

Males and females are equally accountable for the causes of infertility, with most couples having one of the three biggest causes of infertility: ovulatory disorders, tubal disorders and male factor (Anwar and Anwar, 2016).

Approximately one quarter of female infertility is caused by impaired ovulation (due to LH and FSH imbalance, injury of the pituitary gland or the hypothalamus, pituitary tumours, low body weight or obesity (Cedars and Jaffe, 2005). Diabetes, polycystic ovary syndrome (PCOS), premature ovarian failure (POF) and thyroid problems all affect fertility. Fertility can also be influenced by age, sexually transmitted diseases (especially chlamydia and gonorrhoea), reproductive tract problems (such as obstructed or impaired fallopian tubes, endometriosis and uterine fibroids), certain medical conditions (e.g. HIV AIDS), drugs (e.g. anti-cancer drugs, antidepressants, and recreational drugs), smoking, consuming alcohol, and exposure to radiation and certain harmful substances (e.g. toxic fumes and lead) (Cedars and Jaffe, 2005).

Luteinising hormone (LH) and follicle stimulating hormone (FSH) together stimulate follicular development and ovulation, thus an imbalance of LH and FSH can lead to infertility (Cedars and Jaffe, 2005; Raju et al., 2013). LH and FSH are produced by the pituitary gland and secreted under the control of gonadotrophin releasing hormone (GnRH), which is produced by the hypothalamus (Anwar and Anwar, 2016).

Female infertility

Female infertility is divided into three categories: defective ovulation, defective transport and defective implantation.

Defective ovulation

Defective ovulation is caused by endocrine, physical and ovarian disorders, and also endometriosis.

Endocrine disorders: Pituitary or hypothalamic dysfunction can result in elevated prolactin levels, preventing ovulation. Adrenal and thyroid glands may also result in delayed ovulation. Furthermore, if the corpus luteum produces insufficient progesterone to thicken the lining of the uterus, implantation of the fertilised egg may not be possible, causing infertility.

Physical disorders: Too much exercise, anorexia and obesity may affect the menstrual cycle

Endometriosis: A condition in which endometrial tissue starts to grow outside the uterus, in the ovaries, vagina, pelvis or fallopian tubes. As the tissue grows, it forms scars that obstruct the passageway of the egg.

Defective transport

Pelvic inflammatory disease (PID), tubal surgery, fimbrial adhesions, peritonitis, and gonorrhoea can obstruct fallopian tubes, preventing the egg from being released.

Defective implantation: uterine abnormalities such as uterine fibroids and bicornuate (horn-shaped) uterus may prevent implantation of the fertilised egg in the uterus.

Anovulatory infertility

Anovulation is when the follicle does not release the oocyte due to defective follicular development and rupture. This may be caused by ovarian failure, as a result of genetics, autoimmunity and other factors including chemotherapy. Ovarian dysfunction can also lead to anovulation. Specific causes including hyperprolactinaemia and Kallmann’s syndrome, as well as functional causes such as too much exercise, low body weight, drug use and idiopathic infertility. The most common causes of anovulation in women with suspect ovarian failure are hyperprolactinaemia, hypogonadotropic/hypergonadotropic hypogonadism and polycystic ovaries. Hyperprolactinaemia is when high concentrations of prolactin disrupt the secretion pulses of gonadotrophin-releasing hormone (GnRH) which may then lead to insufficient luteal phase, anovulation and absence of periods (amenorrhoea). Hypogonadotropic hypogonadism occurs when there is 20 mUI/ml, which is seen in women with premature ovarian failure, resistant ovary syndrome or genetic disorders. Polycystic ovary syndrome is primarily characterised by anovulation and elevated levels of androgens.

Tubal-peritoneal infertility (tubal factor infertility)

Fallopian tubes are the site of fertilisation and they are involved in transportation of the embryo to the uterine cavity and early embryo development so any changes in the function or anatomical structure of the tubes is linked with infertility.

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Male infertility

Defective spermatogenesis: Diabetes, hyperthyroidism and other endocrine disorders can lead to azoospermia (no sperm present in semen) or faulty sperm, unable to fertilise the egg.

Ineffective delivery: Ejaculatory dysfunction, impotence, physical disabilities, hypospadias and epispadias can cause infertility

Ejaculatory dysfunction

Some males are unable to ejaculate which is known as anejaculation and may occur following dissection of retroperitoneal lymph nodes (iatrogenesis), may be pharmacology related caused by intake of drugs such as antidepressants, antihypertensives and antipsychotics, or as a result of psychological or metabolic causes (e.g. diabetes). Ejaculation can also be retrograde and caused by trauma, drugs and iatrogenic, metabolic or physiological factors.

Fertility is age linked, particularly in females since inevitably, there is a decline in fecundity from age 32 and then a great decrease after age 37 (George and Kamath, 2010). This is because the number of primordial follicles a female has decreases after each successive menstrual cycle (Faddy et al., 1992). Natural follicular atresia causes numbers to decrease to around 25,000 at age 37 and 1,000 near menopause, from about 2 million at birth and 400,000 at the start of menstruation (Faddy et al., 1992; Tal and Seifer, 2017). On the other hand, in men, age is responsible for mostly a degeneration of sperm production function (George and Kamath, 2010).

Ovarian reserve

Ovarian reserve describes the quality and quantity of remaining oocytes a female has, as a measure of reproductive potential. Women with a diminished ovarian reserve (DOR), are of reproductive age and have regular menses, however, their response to ovarian stimulation or fecundity is low compared to other women of their age (Practice Committee of the American Society for Reproductive Medicine, 2015). This can either be physiological i.e. related to age or as a result of premature reserve decline (George and Kamath, 2010). Ovarian reserve tests (ORTs) can be run to estimate ovarian reserve and as a predictor of IVF outcome and response and are usually performed by fertility clinics as part of the assessment of women with infertility before they start treatment (Jirge, 2011).

Quality of oocytes

Oocyte quality is a reflection of the intrinsic development potential of oocytes, and normal fertilisation and embryonic development in IVF treatment are dependent on their quality. Poor oocyte quality may be responsible for unfavourable pregnancy outcomes during IVF or ICSI cycles in females who have minimal to mild endometriosis (Xu et al., 2015).

The effects of infertility can be devastating; when a couple has planned to have a family, only to find out that they are unable to conceive.

Stress and infertility

Stress may affect female reproduction by having an effect of ovaries, follicles and oocytes. Elevated levels of stress hormones for example cortisol, reduces the production of oestradiol by possibly having an effect on the granulosa cell functions in follicles, resulting in degeneration of oocyte quality (Prasad et al., 2016).

Psychological effects of infertility

Infertility can have a significant effect on a woman’s mental health. Depression and anxiety are the most commonly reported mental illnesses in fertility patients (Ezzell, 2016). Sexual self-esteem can also be affected by infertility (Ezzell, 2016).

Fortunately, the problem of infertility can be overcome by medical intervention, which can either involve the use of medications or surgery to restore fertility, or the use of assisted reproductive technology (ART), but this depends on cause of infertility, duration of infertility, and age. Fertility drugs (FSH/LH injections or clomiphene), are the main method of treatment for women who have problems with ovulation and may be used with intrauterine insemination (IUI). Surgical treatment may be used in cases of endometriosis or obstructed fallopian tubes. Assisted reproductive technology includes egg/embryo donation, in vitro fertilisation (IVF), and intra-cytoplasmic sperm injection (ICSI) (Cedars and Jaffe, 2005). In this project the focus will be on IVF and ICSI.

IVF

IVF is the fertilisation of eggs by inseminating them with sperm in a culture dish, then implanting the fertilised eggs into the uterus (Merchant, Gandhi and Allahbadia, 2011). Following hormonal stimulation (of the ovaries), oocytes (eggs) are obtained by transvaginal oocyte retrieval. Contained in microdroplets of culture medium, the oocytes are inseminated with a sufficient quantity of sperm in a culture dish and incubated overnight. Oocytes are viewed under a microscope after 16-20 hours and those that are fertilised are transferred into embryo culture medium (microdroplets) and incubated for 24 hours. Four cell grade A embryos are chosen and drawn into an embryo transfer catheter and inserted into the (inside the womb). Eight-cell stage embryos may be transferred instead, on day 3 or blastocysts may be transferred on day 5. The number of embryos transferred is usually up to 3 but the optimal number is this is agreed by the clinician. Pregnancy is confirmed either after two weeks by beta human chorionic gonadotrophin (b-hCG) assessment, or by identification of a gestational sac on an ultrasound after four weeks (Merchant, Gandhi and Allahbadia, 2011).

ICSI

ICSI is very similar to IVF, except a single sperm is injected into the oocyte using a pipette instead of leaving the egg and sperm to fertilise (Merchant, Gandhi and Allahbadia, 2011). The sperm cell is immobilised in an immobilising medium and rinsed in culture medium, before being drawn into an injection pipette containing a small amount of medium. A holding pipette is used to secure the oocyte in medium so that the spermatozoon (sperm) can be injected into the oocyte (Merchant, Gandhi and Allahbadia, 2011). Pregnancy is confirmed in the same way as IVF (Merchant, Gandhi and Allahbadia, 2011). ICSI is used in cases of severe male factor infertility and failed fertilisation, post IVF cycle (Eftekhar et al., 2012).

Outcome of IVF and IVF is most significantly affected by factors including the technique used and precision of the technique, maturity and motility of sperm, the indication for treatment (male factors vs. non-male factor), and surgical or medical therapy prior to treatment (Merchant, Gandhi and Allahbadia, 2011).

Clinical data shows that the success of IVF and ICSI differs between different ethnicities (Jayaprakasan et al., 2014). However, many studies have compared IVF/ICSI outcomes in black African or black Caribbean women with white British women but not with other black ethnicities, therefore the focus of this report is whether there are differences in IVF/ICSI outcomes between these similar ethnicities and whether age and other variables are confounding factors.

Methods and Materials

This report is based on the analysis of anonymised fertility data obtained from the Human Fertilisation and Embryology Authority (HFEA) register between 2000-2010, involving 47, 558 patients from different ethnicities who had fertility treatment (IVF or ICSI) in the UK.

None of the women included had ovarian hyperstimulation syndrome (OHSS). Variables extracted included age at the time of treatment, number of fresh cycles received, ethnicity, duration of infertility, cause of infertility, type of infertility, treatment type (IVF/IVSI) number of eggs collected and mixed, number of embryos created and transferred, fresh cycle transfer stage (days), early outcome (biochemical) (positive pregnancy test) and live birth outcome (successful delivery of a baby). Early outcome and live birth outcome were used as a measure of success and the number of positive pregnancy tests and live births in black African and black Caribbean women was compared. Women who got pregnant but didn’t have a live birth was classed as miscarriage and was also used as a measure of success. The number of women who didn’t get pregnant was also compared.

The effect of age on IVF/ICSI success between the two ethnicities was measured to see if it was a confounding factor. The effect on IVF/ICSI success of duration of infertility, cause of infertility, type of infertility, number of eggs collected and mixed, number of embryos created and transferred, fresh cycle transfer stage and number of fresh cycles received, cofounding factors. The data analysis was performed using pivot tables and graphs in Microsoft Excel 2019.