Infertility & Causes
The successful implantation of an embryo and its healthy development into the uterus are directly dependent on the normal functioning of the following processes:
A well regulated hormonal interaction system coordinating normal ovulatory cycles, releasing genetically and structurally healthy eggs which can become fertilized by healthy spermatozoa within patent fallopian tubes and develop into early embryos that can be conceived in a uterus of optimal size and contour.
Any inherited or acquired condition which can compromise the normal processing of these mechanisms will subject a female sub-fertile or infertile.
When a female child is born and unless she presents a genetic predisposition her ovaries will contain more than 2 million little follicles each containing one immature egg. At puberty (~ 12 years old), most of these eggs will be absorbed and allowed to perish depleting the cohort of the ovarian reserve to approximately 350-400 thousand. On each month it is estimated that 1000 follicles are lost through a process known as atresia while a single follicle or sometimes two will reach final maturation and release one egg each. This loss of eggs is neither dependent on the lifestyle one opts to pursue nor is limited to any hormone production, nutritional supplements or the administration of an oral contraceptive pill.
Female infertility can result due to one or more of the following reasons:
- Genetic (Chromosomal and/or gene defects)
- Endocrine (hormonal)
It is a fact that fertility in the female declines with advancing age and this phenomenon is attributed to two main reasons;
(a) the depletion of the ovarian reserve and (b) the fragility of the chromosomal complex of the existing egg cohort. A couple is advised to visit a specialist for an initial consultation and assessment after failure to conceive following 13 months of regular unprotected intercourse when the female spouse is up to 34 years of age while this period is reduced to 6 months when the age is 35 or more. Over 40 the chances become substantially slimmer and eminent advice should be sought.
The prevalence of chromosomal aberrations in an embryo is almost always a consequence of maternal age. This is because a female is born with the full complement of her eggs and this number will only decline over the years, unlike the human male where the dynamic process of spermatogenesis produces new spermatozoa continuously. In the process of their final maturation, both immature eggs and sperm follow a series of cellular divisions known as mitosis and meiosis. Successful fertilisation can only be achieved through the interaction of mature gametes.
Chromosome abnormalities typically occur as a result of errors during these cellular divisions although environmental exposure may also be an associating factor. Derangements in the normal process of these cellular divisions result in the egg acquiring or losing one or more chromosomes and therefore its genetic contribution at fertilisation will cause an imbalance resulting into early embryonic senescence or a miscarriage or the birth of a defective offspring (i.e. Dawn’s Syndrome). Similar aberrations but to a much lesser extent may be the consequence of abnormal cellular divisions post-fertilization (de novo) tampering the chromosomal complement of an early developing embryo in the uterus.
While nature most often detects the chromosomal imbalance and terminates the progress of the embryo at an early stage, at times the impaired embryo may develop into an abnormal birth. The advances in laboratory medicine today allow for investigating the chromosomal constitution of embryos created in vitro, therefore, enabling the replacement of those with only a healthy status. In this way a known to a potentially new chromosomal derangement can be screened prior to the embryo implanting into the uterus.
Menstrual cycles are controlled by the interplay of hormones associated with the hypothalamus and pituitary glands and which subsequently mediate ovarian function. At the onset of the cycle, the hypothalamus triggers the release of the reproductive hormone FSH from the anterior lobe of the pituitary by secreting LHRH. The FSH acts on the ovary which recruits a number of follicles (20-50 which may be unidentified via conventional ultrasonography) from the existing cohort. One or at times two (very rarely three) of these follicles will resume growth towards final maturation. Specialised cells within the follicles namely granulosa commence active secretion of estradiol a hormone which targets the uterus. As the follicle grows in size the level of estradiol increases and that of the FSH drops. At a specific concentration (~350 pg/ml) the estradiol will notify the hypophysis to release the second reproductive hormone (LH) which triggers ovulation. The collapsed follicle which delivers the egg (subsequently taken up by the fallopian tube), seals back again (now called a corpus luteum) and starts secreting (via a different form of the granulosa cells) another hormone called progesterone which is responsible for the preparation of the uterus for embryo implantation and subsequent development.
FSH when assessed early in the menstrual cycle (normally on day 2 or day 3) and before the estradiol rises (145 pmol/l or less) is a strong indicator of the ovarian reserve while the LH index when is persistently high on the same day may be an indicator of abnormal ovarian function. While this is typically observed at menopause, when present during the reproductive years may correlate to a number of syndromes associated with ovarian dysgeneses such as Turner’s syndrome, Swyer’s syndrome, Polycystic ovarian syndrome, congenital adrenal hyperplasia or it may account for signs of premature menopause and castration (absent ovaries). On the other hand, a repeatedly diminished LH secretion is most often consistent with amenorrhea (absence of a menstrual period), abnormal function of the pituitary gland and/or the hypothalamus, a consequence of an eating disorder or hyperprolactinemia (increased prolactin secretion).
Elevated prolactin in the bloodstream inhibits the pulsatile secretion of LHRH by the hypothalamus and consequently the release of FSH and LH by the hypophysis resulting in menstrual cycle disturbances or arrest. This infertility cause is easily reversed by the use of simple medication aiming at restoring serum prolactin levels and therefore normal ovarian function.
TSH another hormone produced by the hypophysis stimulates the thyroid gland to produce thyroxine (also known as T4) and then triiodothyronine (T3) the two hormones which regulate the metabolism of almost every tissue in the organism. A hyperactive or underactive thyroid (hypo and hyperthyroidism respectively) results in deranged metabolism and while a female may be able to become pregnant she is prone to an early miscarriage. An abnormal thyroid function is medically managed by the use of specific medication.
While the FSH when screened early in the follicular phase of the menstrual cycle is a denominator of ovarian reserve the AMH affirms on the FSH value but mainly associates with the potential of the egg cohort to produce pregnancies. The higher the AMH the more optimal the potential is. It is important however to acknowledge that screening AMH alone may be misleading as high levels occur in females manifesting polycystic ovarian syndrome. In this respect, an objective parameter on the fertility potential can only be established following a complete hormonal profile test (FSH, LH, Estradiol and AMH) in conjunction with an internal baseline ultrasound scan (preferably between day 3-5 of menstruation) for the assessment of the ovarian status pertinent to the antral follicular count (number of existing follicles in the ovaries at the time) and ovarian volume.
Polycystic Ovaries (PCO) and Polycystic Ovarian Syndrome (PCOS)
It is important to distinguish between individuals presenting polycystic ovaries and those who manifest the syndrome associated with this condition. In essence, not everyone with ovarian cysts has PCOS. According to the Rotterdam criteria, 12 or more follicles (3 mm or less) oriented at the periphery of the ovary should be present (in the form of a string of pearls) to describe polycystic ovarian morphology with the volume of the ovary being at least 10 cc in size.
PCOS is considered as the common endocrine disorder amongst women of reproductive age and has a diverse range of causes which are presumed to be genetically predisposed. Females with ovaries presenting this particular pattern but not manifesting the syndrome will normally achieve a pregnancy without any medical management. The syndrome has been shown to account for a large collection of symptoms most important of which is anovulation, elevated androgen hormones and insulin resistance. Anovulation results in irregular menstruation, amenorrhea and infertility while the hormonal imbalance and elevated androgen production is associated with increased hirsutism and acne. The insulin resistance observed accounts for an increase in body weight (disproportionate to the volume of food consumption) which results in obesity. Individuals with PCOS and who are obese are considered to be at high risk of developing diabetes type II before the onset of menopause.
The major mechanical cause associated with female infertility is occlusion of the fallopian tubes. With this condition, the normal path between the ovary and the uterus is compromised rendering sperm and egg encounter impossible. Blockage of the tubes can result from previous infection (sexually transmitted diseases i.e. Chlamydia and Gonorrhea) and surgical procedures in the pelvis ensuing in the formation of adhesions and scar tissue at the vicinity while it can also be a consequence of a congenital defect or endometriosis. Adhesions can also affect the normal functioning and mobility of the ovaries during the synergistic association they have with the fallopian tubes impairing access to the egg following ovulation. Furthermore, adhesions can form within the uterus itself negatively affecting its receptivity to embryo implantation. Finally, adhesions which can form within the cervical canal most often due to previous surgical interventions will limit the normal progression of spermatozoa following ejaculation into the uterus and from there into the tubes.
While a single patent tube may suffice for a female to conceive, the structure of the counterpart may present a limiting factor. Infection of the delicate structure of the tube consistent with salpingitis can cause a permanent blockage which can subsequently transform into a hydrosalpinx (when blood accumulates forming a bulge) or a pyosalpinx (when the swelling is caused by pus). Since the tube on one end is obstructed the fluid which accumulates at the vicinity palidromically flows into the uterus creating a hostile environment for the embryo to implant. Certain clinicians endeavour to restore tubal patency by performing surgery but this has been proven most often a temporary solution to the problem since adhesions will reform shortly thereafter. In those cases where the presence of hydrosalpinx or pyosalpinx is diagnosed the only effective line of action is laparoscopic surgical removal.
Another common cause for tubal blockage and mechanically related infertility is endometriosis. This disorder develops when the specialised cells of the inner lining of the uterus migrate for reasons which are not well understood and adhere at sites outside the uterus. While the pelvic organs are more likely to be affected, endometriosis can be found in any internal organ of the female organism. The fact that the endometrial cells are under the influence of hormonal changes, they respond as if they were within the uterus causing bleeding and inflammation at the sites which they adhere. The inflammation which deteriorates with successive menstrual cycles can cause obstruction of the tubes (if these are affected) and adhesions between different organs compromising their normal function. When endometrial cells invade the ovaries they seriously compromise the egg cytoskeleton impairing fertilisation and subsequent early embryo quality consistent with high implantation failure and early pregnancy loss. Endometriosis is classified as I and II when it has been diagnosed as superficial (subtle or typical) while III and IV classes represent cystic ovarian endometriosis with adhesions.
While symptoms can vary based on the severity of this condition, affected individuals may experience painful menstruation and coitus with extensive volume of blood discharge which can endure for several days. An elevated CA125 marker in the blood may be associated with endometriosis while a baseline ultra sound can be informative. Laparoscopy may be recommended to affirm the presence of this condition. There is virtually no effective treatment against endometriosis other than becoming pregnant although suppression drugs to cease menstruation and/or surgery can mitigate its adverse effects.
Endometriosis can occur within the uterus itself, a condition known as adenomyosis. The uterus is comprised of three distinct layers the endometrium which is the inner part and the site of embryo implantation, the middle layer (myometrium) which is made of smooth muscle and occupies most of the volume of the uterus and the outer loose tissue membrane surrounding the uterus and separating it from the rest of the pelvic organs namely the perimetrium. By definition adenomyosis is the presence of endometrial cells and glands into the myometrium. In its simpler form the uterine muscle is completely infiltrated with endometriotic tissue which diffuses throughout without a distinct line of demarcation between the two layers. Individuals presenting this condition normally manifest endometriosis too and their uterus limit embryo implantation while the risks of miscarriage are considerably elevated even at later stages of the pregnancy.
The uterus can also be associated with alternative factors which can compromise embryo implantation. Conditions such as endometrial hyperplasia, endometrial polyps, endometrial fibroids, endometrial adhesions, arcuate, septate or bicornuate uterus or infection within the uterus (endometritis) adversely affect the chances of conception.
Each organism carries a delicate immunological system whose purpose is to protect it against foreign agents ranging from simple pathogens to complex viruses. In doing so, it must be able to detect and distinguish them from the organism’s healthy tissue. For reasons which are yet to be completely elucidated the female immune system recognises and neutralizes early developing embryos as early as at the time of implantation or shortly thereafter. The exact mechanisms associated with allo-immune infertility, (where the body’s same defence system reacts against and rejects an embryo from implanting as if it is a foreign threat) have been contentious and received intense scientific scrutiny.
Strong evidence exists that certain gene compatibility such as the DQa between the male and female spouse may be responsible for the uterus to develop antibodies against the embryo causing its early developmental senescence in the uteurs. The investigation for such genetic predispositions can be performed by simple blood tests and if the result affirms compatibility between the spouses then intra-lipid infusions are recommended for administration to the female at finite times during and after IVF treatment in an endeavour to mitigate the adverse effects of NK activity. Allo-immune conditions which associate with an increased rate in the blood clotting cascade of the female partner can be a more common reason associated with early pregnancy loss. A collection of different elements involved directly with the blood clotting process, when deranged is suggestive of inadequate oxygen and nutrient supply from the mother’s bloodstream to the embryo causing its early developmental arrest. In those cases where the mother is diagnosed with an allo-immune condition the first line of action is the administration of aspirin and anticoagulant medication in the form of heparin while suppression of the immune system may be recommended with the use of low dose cortisone.
The most extensively studied group of immune cells is a type of lymphocytes (white blood cell) namely Natural Killer (NK) cells. Certain researchers fail to accept the influence which these types of cells have on the implantation embryo while criticism exists on the proposed treatments associated with counteracting their presumed inherent effects. It is, however, widely accepted that following ovulation and at the onset of conception, NK cells compromise more than 80% of the white blood cell count in the endometrial cavity. NK cells are known to produce a collection of small proteins namely cytokines which have a centralized effect on the interactions between cells their communication systems and behavioural profiles. The notion exists that an imbalance in the concentration of the cytokine may be an impediment to embryo implantation and ongoing developmental potential. An individual who had proven fertility in the past may raise antibodies against her embryo subsequently. What exactly causes the recognition of an embryo as hostile and why the mechanisms toward rejection were non-existent previously is yet to be elucidated.
The Most Common Types Of Antibodies Which
Form With An Elevated NK Cell Count Are:
1. Anti-phospholipid antibodies
2. Antithyroid antibodies
3. Anti ovarian antibodies.
What is of the essence when investigating the presence of NK cells and especially the CD69 type subgroup in females with a history of early pregnancy loss or failure to conceive, is to affirm what triggered the elevated count. It must be appreciated that the human white blood cell membrane protein CD69 is an early activation marker induced not only by the NK cells but also by T lymphocytes and B cells (the major cellular components of the adaptive immune response) in response to any inflammatory stimuli. In this respect, an elevated CD69 marker may not be a result of a hyperactive NK cell population. It is well documented that elevated counts of the CD69 marker during peripheral blood assessment may not predict an alloimmune-related response by contrast an endometrial biopsy is a more useful diagnostic tool for establishing potential involvement of NK cells.
The second type of immune response can be encountered when a female raises antibodies in her cervical mucus creating a hostile environment for sperm survival following ejaculation. In essence, anti-sperm antibodies are an immune response raised by the female where specialised white blood cells attack the sperm impairing successful passage into the uterus through the cervix leading to compromised fertility.