GENETIC BASIS OF FEMALE INFERTILITY
INTRODUCTION:-
Definition: Infertility is defined as a failure to conceive in regular intercourse within 1 year for women younger than 35 years, and within 6 months for women older than 35 years.
The prevalence of infertility is between 7% to 15%. There are many causes of infertility such as ovulatory disorder, chromosomal abnormality, endometriosis, pelvic adhesions, tubal blockage and other tubal abnormalities, and hyperprolactinemia. In ovulatory disorder also include fragile X syndrome and Kallmann syndrome, ovarian leukodystrophy. Approximately 10% of infertile females have genetic abnormalities. There also evidence that chromosomal abnormalities and single-gene mutations contribute to causing infertility. If a woman keeps having miscarriages, it is also known as infertility.
Most cases of infertility in a woman are due to the problems of producing an egg. In primary ovarian insufficiency - the ovaries stop functioning before natural menopause. In PolyCystic Ovary Syndrome (PCOS) - the ovaries may not release an egg regularly or they may not release a healthy egg. As women's grow older their ability to become pregnant reduces as ovulation - the process of formation and release of an egg becomes slower and less effective.
CAUSATIVE FACTORS:-
Ovulatory disorders are the spectrum of conditions that affects a women's endocrine system, which controls her hormones and pattern of ovulation, by which a women's ovary releases an egg during her mensural cycle. The ovulatory disorder can cause infrequent and irregular ovulation as well as anovulation (absence of ovulation). During a normal mensural cycle, the endocrine system prepares the body for pregnancy by secreting hormones such as Gonadotropin-releasing hormone(GnRH), Follicle-stimulating hormone(FSH), and luteinizing hormone (LH).
GnRH and FSH are mostly responsible for an egg to mature in a women's ovary. LH is responsible for the release of a matured egg into the Fallopian tube. Through the cycle length vary, women who ovulate regularly tend to have a mensural cycle that is 28days in length and ovulate once in 28days period. women with hormonal imbalance or hormone deficiencies may experience infrequent or absence of ovulation and infertility.
2. CHROMOSOMAL ABNORMALITY:
Chromosomal abnormal embryos have a low rate of implantation in the mother's uterus which often leads to miscarriages. There are several kinds of chromosomal abnormalities such as Deletion, Inversion, Mutations, Aneuploidy, Translocations.
Translocations are most common in chromosomal abnormalities. And if any of the parents carries a translocation then the embryo may receive too much or too little genetic material which may lead to miscarriages.
Chromosomal abnormalities that cause infertility in females are:
A. Turners syndrome 45,x or 45,x del(xp) or 45,x I (xq) or 45,x mar
B. Trisomy syndrome plus G.
The most frequent chromosomal abnormalities are balanced chromosomal rearrangements (translocations), sex chromosomal mosaicism and inversions. Reciprocal translocations are one of the most common structural rearrangements observed in humans. carriers of Robertsonian translocations are also at risk for miscarriages and offsprings with mental retardation and also birth defects associated with aneuploidy.
Chromosomal abnormalities and genetic defects can determine the failure of reproduction. And for this reason, genetic analysis can play an important role in infertility.
3. INHERITED GENETIC DISEASES:
More rare existence of inherited genetic disease due to abnormal genes or mutations. In a chromosomal analysis of parents, we can find such inherited genetic causes which are less than 5% in couples. Single gene abnormalities are mutations caused by the change in the DNA sequence of a gene that produces protein. Gene mutations alter the functioning of cells due to a lack of a protein. Single gene disorders usually indicate specific genetic diseases such as Cystic Fibrosis (CF) and Tay Sachs.
4. ENDOMETRIOSIS:
Endometriosis is a common disease defined as the growth of endometrial tissue outside the urine cavity that often results in lots of problems including infertility and pelvic pain. The true incidence of endometriosis is unknown but the cases normally range from 10% to 15% for all women of reproductive age and from 25%to 35% for infertile women. Endometriosis is heritable but the mechanism remains unclear.
The Magnitude of the increased risk is more reminiscent of polygenic or multifactorial tendencies than a single mutant gene. The recurrence risk of this disease is higher than 2% to5% expected risk for polygenic inheritance. Although mendelian mechanisms cannot be excluded, polygenic inheritance seems more likely if one assumes all endometriosis is a single disorder, but not all endometriosis is the same disorder. Endometriosis is genetic heterogeneity. One or more forms of endometriosis might be mendelian despite the larger promotion being non-genetic or polygenic. This also proves peptic ulcers and adult-onset disorders.
Kennedy and his colleagues are using sibling pair analysis with polymorphic DNA marker for the identification of multiple non linked genes which would be consistent with either polygenic inheritance or genetic heterogeneity. Several regions of exclusion have been identified by Kennedy and his colleagues, but no link has been observed. In Iceland, in women, a "suggestive locus" was found on 9q that is not in the region of the Galactose-phosphate Uridyl Transferase (GALT)gene.
5. PELVIC ADHESIONS:
All organs in a women's abdomen are covered with a slippery tissue layer that prevents them from sticking to each other. When the surface of the organs becomes damaged or inflamed scar tissue can be formed. This scar tissue is called pelvic adhesion and can cause infertility and also has a risk of developing a tubal (ectopic) pregnancy.
The organs in the abdomen need to be able to glide past each other for pregnancy to occur. The fallopian tube must be mobile so that the finger-like projection on the end of the tube, the fimbria, can pick up the ovulating egg as it comes out of the ovary. If the tube or ovary is stuck to other organs or the side of the pelvis or will not be in the appropriate position for an egg to fertilise.
6. POLYCYSTIC OVARY SYNDROME (PCOS):
Polycystic ovary syndrome is a hormonal disorder that prevents the egg in the ovaries from maturing properly often creating numerous fluid-filled sacs known as ovarian follicles. This often causes irregular mensural cycles and infertility. PCOS is characterised by excess levels of androgen and higher than average insulin levels than in normal females. Elevated levels of testosterone contribute to the changes seen in ovarian function.
Commonly experienced symptoms are hormone imbalance, male pattern of hair growth (upper lip, chin, face, chest and abdomen), abnormal urine bleeding. They have a high risk of Hypertension, Cardiovascular disease, Stroke and Type 2 diabetes. PCOS is likely hereditary and genetic abnormalities have changed the pathways involved in hormone production within the body. The high prevalence of insulin resistance and abnormalities in insulin secretion suggest the gene for insulin or its receptor may be involved.
7. OVARIAN LEUKODYSTROPHY:
Ovarian leukodystrophy is also known as ovarioleukodystrophies comprises a group of rare leukodystrophies associated with primary premature ovarian failure. Some of the patients have a variant of "vanishing white matter disease" with mutations in subunits of eukaryotic initiation factor 2B (EIF2B).
A 38-year-old woman who developed neurological signs related to an extensive Leukoencephalopathy on MRI (magnetic resonance imaging) in the context of amenorrhea since the age of 18 years was found to be homozygous for a mutation in the EIF2B5 gene. That woman had progressive disease with the development of tetraparesis in less than 6 years. The scientist's observation has confirmed that ovarian failure in the context of leukodystrophy warrants mutational analysis of the gene encoding the sub-units of EIF2B.
8. SCARRING OF FALLOPIAN TUBE:
According to the scientists, the Transformation growth factor - beta1 (TGF - Beta1) signal system may be an important ring-joint in the adhesion formation of the human fimbria tube.
SYMPTOMS:
- Infrequent ovulation - It may cause due to body stress such as Eating disorders, Rapid weight gain or weight loss, and Obesity.
- Some hormonal abnormalities - Thyroid problems, POS(polycyclic ovarian syndrome), Pituitary gland problems, adrenal gland problems etc.
- Miscarriages
- Abortions
- Urine Infections
DIAGNOSIS:
- Early morning check of body temperature.
- Ovulation predictor test.
- Consistency of Veginal mucus.
- Examining the structure of pelvic organs.
- Hysterosalpingogram:- It is an x-ray study wherein a liquid gel is injected into the uterus. It helps in finding polyps, fibroids, blockages in the fallopian tube etc.
- Ultrasound
- Hysteroscopy and Laparoscopy
THINGS TO DO TO PREVENT INFERTILITY:
- Exercise moderately
- Maintain healthy weight
- Avoid smoking
- Limit caffeine
- Review your medication with your doctor
DIET TO FOLLOW:
- Eating more beans, nuts, other fertility-boosting plant proteins.
- Eating more whole grains.
- Avoid sugary soda.
- Having a glass of whole milk and other full-fat dairy food every day (an occasional small portion of ice cream as well).
TREATMENT:
- Fertility drugs:- Infertility may be associated with infrequent or absence of ovulation. This often can be treated with hormone medications. These are called fertility drugs.
- Surgical procedure:- After treatment with fertility drugs, eggs can be allowed to travel naturally from the ovary into the uterus if the fallopian tubes are healthy. Sometimes surgery is used to harvest the matured egg after fertility drug treatment.
- Intrauterine insemination (IUI): It is a procedure in which sperms are directly inserted into the uterus using a special catheter or a syringe.
- In Vitro fertilization (IVF): The eggs that the ovary has been stimulated to release are surgical, the eggs and the sperms are combined in the laboratory, to produce embryos. One or more embryos are inserted into the uterus. IVF does not guarantee a pregnancy, on the other hand sometimes more than one embryo implants in the uterus. The can result in twins or multiple pregnancies. IVF requires treatment with hormones before ahead.
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