Infertility has been defined as the inability to conceive after 1 year of unprotected sexual intercourse. Approximately 48 million couples and 186 million individuals live with infertility globally. Female infertility is the inability of a woman to conceive after 1 year of unprotected sexual intercourse. Female infertility is classified as primary infertility (woman has never become pregnant) and secondary infertility (woman has been pregnant previously; however, she is currently unable to conceive) (Gonnella et al., 2022). There are many possible causes specifically linked to female infertility, such as reproductive disorders, congenital malformations, infections, hormonal dysfunction or malformations of the tubes or uterus. In addition, impaired follicular development could also be one of the contributing factors of lower fertility levels.
Gametes and embryos interact with a myriad of “factors” in their environment, which will influence their quality. At one extreme, embryonic mortality can be caused by gross genetic abnormalities such as a brief chromosomal aberration or aberrant gonadal development causing gamete malfunction (Assersohn et al., 2021). Such gametes and embryos are generally not adequately described as abnormal but rather as biologically unviable. It is consequently not surprising that embryonic mortality occurs at the earlier cleavage stages in the majority of mammalian species, i.e., after fertilization but before the onset of morula development.
Definition and Scope
Infertility in women is considered if the couple has been unsuccessful in achieving pregnancy for a year of sexual intercourse without any contraception. Female infertility could be due to one or many reasons regarding the pre-conceptive, post-conceptive and implantation stages that occur before full-term delivery (P Aiswarya, 2018). (Gonnella et al., 2022) reported that the World Health Organization (WHO) recognises infertility as a disease impairment of the reproductive system with the inability to achieve pregnancy after 12 months or longer of regular unprotected sexual intercourse in clinically diagnosed fertile couples. Regarding the cause of infertility, women over 35 years of age are nearly twice as likely to present with unexplained infertility. Approximately 80 million women worldwide suffer from infertility. Infertility is a major public health concern that has emotional, social and economic consequences. In developing countries, infertility rates are on the rise and have reached similar levels to those of developed countries (in the range of 10%–20%).
Anatomy and Physiology of the Female Reproductive System
The female reproductive system is composed of a number of anatomical structures, arranged in a specific order, and controlled by a series of physiological actions and events. The anatomical structures include the outer external genitalia, the vagina, the uterus, the fallopian tubes, and the ovaries. Previous studies have shown that many varieties of different anatomical structures are proposed as the reasons for female infertility. These include abnormalities and obstructions of the uterus, fallopian tubes, ovaries, and vagina, pelvic adhesions, and intrauterine abnormalities. This section describes the anatomy and physiology of the female reproductive system as a basis for a better understanding of female infertility (Haller-Kikkatalo et al., 2012).
In women, the external genitalia includes the mons pubis, labia majora and minora, clitoris, external urethral orifice, vaginal orifice, and surrounding glands. The vagina, a fibromuscular tube, is lined with mucous membrane. The uterus is a hollow, muscular, pear-shaped organ that lies in the pelvic cavity, posterior to the bladder and anterior to the rectum. The uterus has three parts – the fundus, body, and cervix – and has an outer peritoneal covering, middle muscular layer (myometrium), and inner mucosal layer (endometrium). Abundant blood vessels nourish the lining, and uterine glands secrete mucus and fluids during menstruation and pregnancy. The fallopian tubes are long, narrow tubes with four parts – interstitial, isthmus, ampulla, and infundibulum – that carry ova and sperm. The ovaries are paired, almond-shaped, and the size of walnuts, lying in the pelvic cavity anterior to the fallopian tubes, and contain a female’s lifetime supply of oocytes. Each menstrual cycle, one oocyte matures and is ovulated, secondary hormones regulate the cycle and implant fertilized oocytes.
Overview of the Female Reproductive System
The female reproductive tract in higher mammals has a two-fold function. Primarily it produces and transports ova to a site of fertilization. Secondly, it nourishes the fertilized ovum subsequent to conception, leading to implantation, and subsequently provides an environment for its growth and maturation.
The mammalian female reproductive tract is divided into two main parts on the basis of its location and developmental requirements. The upper part, or urogenital tract, are mesodermally derived structures consisting of paired Müllerian ducts and their derivatives. The other portion is the lower or exterior part of the reproductive tract, and it consists of paired externally placed clitorides or labia and a single vagina. This latter structure develops from a midline fusion of the ectoderm and mesoderm (Gonnella et al., 2022). The Müllerian ducts are bilaterally located paramesonephric structures arising on the medial side of the mesonephros adjoining the metanephric kidney developmental field (Haller-Kikkatalo et al., 2012).
The development of the female reproductive tract in higher mammals commences embryologically when the metanephric kidney rudiment arrives on the surface of the Wolffian duct and is triggered to further development by the substrate interaction with the urogenital ridge mesenchyma. This is followed by mesodermal movements leading to the formation of a wedge-shaped thickening known as the paramesonephric ridge adjacent to the mesonephros, subsequent to which the two Müllerian ducts arise in the ventral side of the ridge. The rostral ends of the ducts grow towards each other in midline fusion, and the ducts elongate caudally. The caudal portions of the ducts fuse along the midline and then continue to grow posteriorly with the growing perineum.
Common Causes of Female Infertility
There are many possible causes specifically linked to female infertility, such as reproductive disorders, congenital malformations, infections, hormonal dysfunction, or malformations of the tubes or uterus (Gonnella et al., 2022). Impaired follicular development could also be one of the contributing factors of lower fertility levels. In the mammalian ovary, follicular development is regulated by the hypothalamic–pituitary–ovary (HPO) axis, different signaling pathways, and the bidirectional communication between oocytes and granulosa cells. Granulosa cells not only provide various energetic substrates necessary for the nourishment of the oocyte, but also have a fundamental role in the formation of corpus luteum (CL), making them indispensable for the quality of the oocyte and embryo.
There are many factors related to the individual’s lifestyle that are able to negatively affect female fertility, such as high consumption of caffeine and alcohol, competitive sports, stress, cigarette smoking, chronic exposure to environmental pollutants, and improper eating habits. There is accumulating evidence that non-modifiable risk factors, such as genetic mechanisms and old age, are involved in the onset of infertility. Moreover, epigenetic modifications, which are heritable alterations affected by the genetic variability and environmental influences, are associated with infertility. An abnormal body weight, that is, a body mass index of more than 25 kg/m2; abnormal energy intake, due to restrictions or excesses; and increased dietary consumption of carbohydrates, fatty acids, proteins, vitamins, and minerals, can have a detrimental effect on ovulatory function, affecting not only the safety of gametes but in some cases also the implantation of a healthy embryo. High-fat foods can also cause follicular deterioration due to increased oxidative stress in the follicular fluid.
Ovulatory Disorders
Ovulatory disorders are the prominent cause of female infertility (Gonnella et al., 2022). The most important symptom is the absence of regular menstrual cycles. The diagnosis is confirmed when during the follicular phase the elevated follicle-stimulating hormone (FSH) and reduced estradiol concentrations (E2) are detected in the serum. The disorder generally leads to sterility and has a pronounced effect on the reproductive health of women when it manifests at an early age (Skowrońska et al., 2023). Primary ovarian insufficiency (POI) is often thought as a disorder unrelated to lifestyle or adherence to a proper diet. The percentage of attempted pregnancies that ended in a successful birth, still remains very low among women with ovulation disorders categorized in Group III. Additionally, even in those with the lowest ovarian reserve parameters, the absence of follicles in the ovary is not always associated with complete sterility.
Structural Causes of Female Infertility
Structural irregularities in the female reproductive system can be congenital or acquired and can interfere with a woman’s ability to conceive. The uterus is normally pear-shaped and tilts forward and is about 7.5cm in length. Any developmental abnormality may be within the uterus, cervix and vagina causing either abnormal shape or size or obstruction. The developmental abnormality can be identified by hysterosalpingography (HSG), laparoscopy and hysteroscopy (P Aiswarya, 2018).
Uterus didelphys occurs when the Mullerian ducts completely fail to fuse and two uteri, two cervices and two vaginas are formed, thus having normal external anatomy resembling a double uterus. This anomaly comprises 10-15% of all uterine anomalies and presents with infertility in 15% of women. Abnormalities in fusion arise when the ducts are incompletely fused resulting in different shapes of uterine cavities. Bicornuate uterus occurs when two cavities are formed with a single cervix and fundal indentation of 1cm or more. Such uterus has a high risk for obstetric complications. Currently, laparoscopy with or without hysteroscopy is considered gold standard for diagnosing these tubal factors. Analysis of hysterosalpingography will show a delay time from injection at proximal end of the tube to imaging of peritoneal spill.
Uterine Abnormalities
Uterine abnormalities. There are several structural causes of female infertility. Uterine Abnormalities are one of the major causes. Amalgam immobilization is the most common method used in the examination of uterine anomalies (P Aiswarya, 2018). Saline infusion sonogram is a frequently used examination method that uses a saline solution introduced into the uterine cavity through the cervical canal to form a better view of the endometrium. Magnetic resonance imaging (MRI) and hysteroscopy can provide clear images of uterine anomalies that cannot be obtained by ultrasonic examination. Septate uterus is a gynecologic disease caused by failure of reabsorption of the Müllerian ducts during embryonal development, which later causes adverse obstetric outcomes and infertility in some women. On hysterosalpingography, a complete or partial separation of the uterine cavity is seen with an external contour of the uterus that is convex or straight.
The MRI examination on uterine anomalies has been well documented in the literature and has shown for Müllerian duct anomalies (MDAs) different classification systems. The American Fertility Society (AFS) classification is frequently cited and yet, because of the relevant and varying clinical and surgical approach of diagnosis and treatment of types of MDAs commonly encountered by clinicians, it still has its limitations. The ESHRE/ESGE classification will, however, provide a universally accepted classification system for MDAs. In this study, developmental and structural abnormalities of uterus are widely reported using hysterosalpingography as the screening procedure (Albalushi et al., 2023).
Hormonal Causes of Female Infertility
It is well-established that numerous intricate hormonal processes take effect during the menstrual cycle, several of which are essential for fertility to occur. The menstrual cycle, beginning at puberty in women, is an exquisite example of the interconnectedness of hormones. It is tightly regulated by the hypothalamus leading to the cyclic release of gonadotropin-releasing hormone (GnRH) (Gonnella et al., 2022). GnRH stimulates the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These hormones act on the ovary to grow and develop follicles resulting in the majority being atretic at ovulation, and to promote the secretion of hormones inhibiting further follicular growth and development together with hormones essential for fertility. Other hormones produced chiefly by the ovary include inhibins, activins, prostaglandins, and steroids (estrogens and progestogens) which together bind to various receptors on the hypothalamus and pituitary to exert negative and positive feedback known collectively as the hypothalamic-pituitary-ovarian (HPO) axis.
Polycystic Ovary Syndrome (PCOS) is an endocrine disorder that is characterized by decreased follicle-stimulating hormone (FSH) secretion and increased luteinizing hormone (LH) which leads to anovulation, infertility, hirsutism, and obesity. PCOS is the most common hormonal disorder in women of reproductive age worldwide, affecting 5 to 10% of the population, and is the leading cause of infertility in women. A hallmark of PCOS is the presence of many immature ovarian follicles that reflect abnormal folliculogenesis processes. Folliculogenesis is regulated by the delicate interplay of neuroendocrine signaling from the brain, and hormones produced in the pituitary and ovary driving growth and atresia.
Polycystic Ovary Syndrome (PCOS)
A hormonal cause of female infertility is Polycystic Ovary Syndrome (PCOS). PCOS is quickly becoming the most prevalent endocrine disorder to affect women during their reproductive years. Studies have shown there may be a genetic link between first degree female relatives in which up to fifty percent may be affected (Branfield, 2019). Women with PCOS often struggle with infertility. While many want to achieve pregnancy, many do not want to regulate menstrual cycles and/or do not want to take the pill. Most women with PCOS simply want to find an answer to the question: “what is wrong with me?” The topic of this research proposal is to further examine the Unsolved Clinical Case #2 on PCOS which presents a complex syndrome affecting multiple systems in the body. As PCOS is multifactorial, a comprehensive review of PCOS will be included with multiple variances including normal/abnormal physiology, hypothalamic-pituitary-gonadal axis hormones, environmental/occupational, lifestyle factors, etc.
Polycystic ovarian syndrome (PCOS) is one of the most common hormonal disorders in women, affecting an estimated 5-10% of reproductive-aged women worldwide. It is characterized by a cluster of symptoms, including irregular menstrual cycles, excess male hormone (androgen) levels, ovulatory dysfunction, and polycystic ovaries. PCOS is not a single disease but rather a heterogeneous syndrome manifesting as different phenotypes of clinical and biochemical hyperandrogenism (Kshetrimayum et al., 2019). Women suffering from PCOS are at an increased risk of infertility, endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, and metabolic syndrome.