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Twelve percent of all infertility cases are a result of a woman either being underweight or overweight. Fat cells produce estrogen, in addition to the primary sex organs. Too much body fat causes production of too much estrogen and the body begins to react as if it is on birth control, limiting the odds of getting pregnant. Too little body fat causes insufficient production of estrogen and disruption of the menstrual cycle. Both under and overweight women have irregular cycles in which ovulation does not occur or is inadequate. Proper nutrition in early life is also a major factor for later fertility.
A study in the US indicated that approximately 20% of infertile women had a past or current eating disorder, which is five times higher than the general lifetime prevalence rate.
A review from 2010 concluded that overweight and obese subfertile women have a reduced probability of successful fertility treatment and their pregnancies are associated with more complications and higher costs. In hypothetical groups of 1000 women undergoing fertility care, the study counted approximately 800 live births for normal weight and 690 live births for overweight and obese anovulatory women. For ovulatory women, the study counted approximately 700 live births for normal weight, 550 live births for overweight and 530 live births for obese women. The increase in cost per live birth in anovulatory overweight and obese women were, respectively, 54 and 100% higher than their normal weight counterparts, for ovulatory women they were 44 and 70% higher, respectively.
Sexually transmitted infections are a leading cause of infertility. They often display few, if any visible symptoms, with the risk of failing to seek proper treatment in time to prevent decreased fertility.
Factors that can cause male as well as female infertility are:
- DNA damage
- DNA damage reduces fertility in female ovocytes, as caused by smoking, other xenobiotic DNA damaging agents (such as radiation or chemotherapy) or accumulation of the oxidative DNA damage 8-hydroxy-deoxyguanosine
- DNA damage reduces fertility in male sperm, as caused by oxidative DNA damage, smoking, other xenobiotic DNA damaging agents (such as drugs or chemotherapy) or other DNA damaging agents including reactive oxygen species, fever or high testicular temperature
- General factors
- Diabetes mellitus, thyroid disorders, undiagnosed and untreated coeliac disease, adrenal disease
- Hypothalamic-pituitary factors
- Hyperprolactinemia
- Hypopituitarism
- The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility with an odds ratio of 1.5 and 95% confidence interval of 1.1–2.0.
- Environmental factors
- Toxins such as glues, volatile organic solvents or silicones, physical agents, chemical dusts, and pesticides. Tobacco smokers are 60% more likely to be infertile than non-smokers.
German scientists have reported that a virus called Adeno-associated virus might have a role in male infertility, though it is otherwise not harmful. Other diseases such as chlamydia, and gonorrhea can also cause infertility, due to internal scarring (fallopian tube obstruction).
A study of a population of French women from 1670 and 1789 shows that those who married at age 20–24 had 7.0 children on average and 3.7% remained childless. Women who married at age 25–29 years had a mean of 5.7 children and 5.0% remained childless. Women who married at 30–34 years had a mean of 4.0 children and 8.2% remained childless. The average age at last birth in natural fertility populations that have been studied is around 40.
In 1957, a study was done on a large population (American Hutterites) that never used birth control. The investigators measured the relationship between the age of the female partner and fertility. (Infertility rates today are believed to be higher in the general population than for the population in this study from the 1950s.)
This 1957 study found that:
- By age 30, 7% of couples were infertile
- By age 35, 11% of couples were infertile
- By age 40, 33% of couples were infertile
- At age 45, 87% of couples were infertile
A Robertsonian translocation in either partner may cause recurrent spontaneous abortions or complete infertility.
Mutations to NR5A1 gene encoding Steroidogenic Factor-1 (SF-1) have been found in a small subset of men with non-obstructive male factor infertility where the cause is unknown. Results of one study investigating a cohort of 315 men revealed changes within the hinge region of SF-1 and no rare allelic variants in fertile control men. Affected individuals displayed more severe forms of infertility such as azoospermia and severe oligozoospermia.
The average age of a young woman's first period (menarche) is 12 to 13 (12.5 years in the United States, 12.72 in Canada, 12.9 in the UK) but, in postmenarchal girls, about 80% of the cycles are anovulatory in the first year after menarche, 50% in the third and 10% in the sixth year. A woman's fertility peaks in her early and mid-20s after which it starts to decline. However, the exact estimates of the chances of a woman to conceive after a certain age are not clear, and are subject to debate.
According to the National Institute for Health and Clinical Excellence over 80 out of every 100 women aged under 40 who have regular unprotected sexual intercourse will get pregnant within 1 year of trying. In the second year the percentage rises to over 90%.
According to a 2004 study by Henri Leridon, PhD, an epidemiologist with the French Institute of Health and Medical Research of women trying to get pregnant, without using fertility drugs or in vitro fertilization.
- At age 30
- 75% will have a conception ending in a live birth within one year
- 91% will have a conception ending in a live birth within four years
- At age 35
- 66% will have a conception ending in a live birth within one year
- 84% will have a conception ending in a live birth within four years
- At age 40
- 44% will have a conception ending in a live birth within one year
- 64% will have a conception ending in a live birth within four years
According to a study done on a sample of 782 healthy European couples ages 19–39, fertility starts declining after age 27 and drops at a somewhat greater rate after age 35. The women were divided into four age groups: 19–26, 27–29, 30–34 and 35–39. Statistical analysis showed that the women in the 27–29 age group had significantly less chance on average of becoming pregnant than did the 19- to 26-year-olds. Pregnancy rates did not change notably between the 27–29 age group and the 30–34 age group, but dropped significantly for the 35–39 age group. The age of the male partner had a significant impact on female fertility among the women who had reached their mid-30s, but not among the younger women. However, experts said the new study was too small and there were too many variables which were too difficult to sort out, for a clear conclusion to be drawn. Some experts suggested that the main change in fertility in the older women was the fact that it took them "longer" to conceive, not necessary that they were significantly more unlikely to eventually succeed. David Dunson, a biostatistician at the U.S. National Institute of Environmental Health Sciences, said that: "Although we noted a decline in female fertility in the late 20s, what we found was a decrease in the probability of becoming pregnant per menstrual cycle, not in the probability of eventually achieving a pregnancy."
A French study found no difference between the fertility rate of women under 25 and those ages 26–30, after which fertility started to decrease. Estimating the "fertility of a woman" is quite difficult because of the male factor (quality of sperm). This French study looked at 2,193 women who were using artificial insemination because their husbands were azoospermic. The cumulative success rates after 12 cycles of insemination were 73% for women under age 25, 74% in women ages 26–30, 61% for ages 31–35, and 54% in the over 35 age group. (Note that the study is from 1982; artificial insemination techniques and success rates have evolved greatly since then.)
In Hungary, a study by the (Central Statistics Office) estimated that 7%–12% of Hungarian women younger than 30 were infertile; 13%–22% of women age 35 were infertile; and 24%–46% of women age 40 were infertile.
The below is a table containing estimates of the percentage of women who, if starting to conceive at a certain age, will fail to obtain a live birth. Note that while for the young ages researchers tend to agree, for older ages there is discrepancy.
Prognosis in unexplained infertility depends on many factors, but can roughly be estimated by e.g. the
Hunault model, which takes into account female age, duration of infertility/subfertility, infertility/subfertility being primary or secondary, percentage of motile sperm and being referred by a general practitioner or gynecologist.
The risk of pregnancy complications increases as the mother's age increases. Risks associated with childbearing over the age of 50 include an increased incidence of gestational diabetes, hypertension, delivery by caesarean section, miscarriage, preeclampsia, and placenta previa. In comparison to mothers between 20 and 29 years of age, mothers over 50 are at almost three times the risk of low birth weight, premature birth, and extremely premature birth; their risk of extremely low birth weight, small size for gestational age, and fetal mortality was almost double.
Facts about the conception of pregnancies in this age group can be difficult to determine, but they are nearly always due to the use of IVF with donor eggs.
Potential methods in unexplained infertility include oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) as well as intrauterine insemination (IUI), intracervical insemination (ICI) and in vitro fertilization (IVF).
In women who have not had previous treatment, ovarian stimulation combined with IUI achieves approximately the same live birth rate as IVF. On the other hand, in women who have had previous unsuccessful treatment, IVF achieves a live birth rate approximately 2-3 times greater than ovarian stimulation combined with IUI.
IUI and ICI has higher pregnancy rates when combined with ovarian stimulation in couples with unexplained infertility, for IUI being 13% unstimulated and 15% stimulated, and for ICI being 8% unstimulated and 15% stimulated. However, the rate of twin birth increases substantially with IUI or ICI combined with ovarian stimulation, for IUI being 6% unstimulated and 23% stimulated, and for ICI being 6% unstimulated and 23% stimulated.
According to NICE guidelines, oral ovarian stimulation agents should not be given to women with unexplained infertility. Rather, it is recommended that in vitro fertilization should be offered to women with unexplained infertility when they have not conceived after 2 years of regular unprotected sexual intercourse. IVF avails for embryo transfer of the appropriate number of embryos to give good chances of pregnancy with minimal risk of multiple birth.
A review of randomized studies came to the result that IVF in couples with a high chance of natural conception, as compared to IUI/ICI with or without ovarian stimulation, was "more" effective in three studies and "less" effective in two studies.
There is no evidence for an increased risk of ovarian hyperstimulation syndrome (OHSS) with IVF when compared with ovarian stimulation combined with IUI.
There is increasing evidence that the harmful products of tobacco smoking may damage the testicles and kill sperm, but their effect on male fertility is not clear. Some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes.
Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including:
- Hypogonadotropic hypogonadism due to various causes
- Obesity increases the risk of hypogonadotropic hypogonadism. Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreased Kiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH).
- Undiagnosed and untreated coeliac disease (CD). Coeliac men may have reversible infertility. Nevertheless, CD can present with several non-gastrointestinal symptoms that can involve nearly any organ system, even in the absence of gastrointestinal symptoms. Thus, the diagnosis may be missed, leading to a risk of long-term complications. In men, CD can reduce semen quality and cause immature secondary sex characteristics, hypogonadism and hyperprolactinaemia, which causes impotence and loss of libido. The giving of gluten free diet and correction of deficient dietary elements can lead to a return of fertility. It is likely that an effective evaluation for infertility would best include assessment for underlying celiac disease, both in men and women.
- Drugs, alcohol
- Strenuous riding (bicycle riding, horseback riding)
- Medications, including those that affect spermatogenesis such as chemotherapy, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such as phenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin
- Genetic abnormalities such as a Robertsonian translocation
Advanced maternal age is associated with adverse outcomes in the perinatal period, which may be caused by detrimental effects on decidual and placental development.
The risk of the mother dying before the child becomes an adult increases by more advanced maternal age, such as can be demonstrated by the following data from France in 2007:
Advanced maternal age continues to be associated with a range of adverse pregnancy outcomes including low birth weight, pre-term birth, stillbirth, unexplained fetal death, and increased rates of Caesarean section.
On the other hand, advanced maternal age is associated with a more stable family environment, higher socio-economic position, higher income and better living conditions, as well as better parenting practices, but it is more or less uncertain whether these entities are "effects" of advanced maternal age, are "contributors" to advanced maternal age, or common effects of a certain state such as personality type.
The human breast cancer susceptibility gene 2 (BRCA2) is employed in homologous recombinational repair of DNA damages during meiosis. A common single-nucleotide polymorphism of BRCA2 is associated with severe oligospermia.
Men with mild oligospermia (semen concentration of 15 million to 20 million sperm/ml) were studied for an association of sperm DNA damage with life style factors. A significant association was found between sperm DNA damage and factors such as age, obesity and occupational stress.
In the Western world, the typical age of menopause (last period from natural causes) is between 40 and 61 and the average age for last period is 51 years. The average age of natural menopause in Australia is 51.7 years. In India and the Philippines, the median age of natural menopause is considerably earlier, at 44 years.
In rare cases, a woman's ovaries stop working at a very early age, ranging anywhere from the age of puberty to age 40. This is known as premature ovarian failure and affects 1 to 2% of women by age 40.
Undiagnosed and untreated coeliac disease is a risk factor for early menopause. Coeliac disease can present with several non-gastrointestinal symptoms, in the absence of gastrointestinal symptoms, and most cases escape timely recognition and go undiagnosed, leading to a risk of long-term complications. A strict gluten-free diet reduces the risk. Women with early diagnosis and treatment of coeliac disease present a normal duration of fertile life span.
Women who have undergone hysterectomy with ovary conservation go through menopause on average 3.7 years earlier than the expected age. Other factors that can promote an earlier onset of menopause (usually 1 to 3 years early) are smoking cigarettes or being extremely thin.
In about 30% of infertile men no causative factor is found for their decrease in sperm concentration or quality by common clinical, instrumental, or laboratory means, and the condition is termed "idiopathic" (unexplained). A number of factors may be involved in the genesis of this condition, including age, infectious agents ( such as "Chlamydia trachomatis"), Y chromosome microdeletions, mitochondrial changes, environmental pollutants, and "subtle" hormonal changes.
A review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown. It found no significant relation between oligospermia and being underweight.
The cause of POF is usually idiopathic. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome and Fragile X syndrome. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had a hysterectomy tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.
There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact. Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinylestradiol (EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum anti-müllerin hormone (AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.)
- Genetic disorders
- Autoimmune diseases
- Tuberculosis of the genital tract
- Smoking
- Radiation and/or chemotherapy
- Ovarian failure following hysterectomy
- Prolonged GnRH (Gonadatrophin Releasing Hormone) therapy
- Enzyme defects
- Resistant ovary
- Induction of multiple ovulation in infertility
Genetic associations include:
Kalberer et al. have shown that despite the older maternal age at birth of the first child, the time span between the birth of the first and the second child (= interpregnancy interval) decreased over the last decades. If purely biological factors were at work, it could be argued that interpregnancy interval should have increased, as fertility declines with age, which would make it harder for the woman to get a second child after postponed birth of the first one. This not being the case shows that sociologic factors (see above) prime over biological factors in determining interpregnancy interval.
With technology developments cases of post-menopausal pregnancies have occurred, and there are several known cases of older women carrying a pregnancy to term, usually with in vitro fertilization of a donor egg. A 61-year-old Brazilian woman with implantation of a donor egg expected gave birth to twins in October 2011..
Between 5 and 10 percent of women with POF may become pregnant. Currently no fertility treatment has officially been found to effectively increase fertility in women with POF, and the use of donor eggs with in-vitro fertilization (IVF) and adoption are popular as a means of achieving parenthood for women with POF. Some women with POF choose to live child-free. (See impaired ovarian reserve for a summary of recent randomized clinical trials and treatment methods.)
Currently New York fertility researchers are investigating the use of a mild hormone called dehydroepiandrosterone (DHEA) in women with POF to increase spontaneous pregnancy rates. Published results from studies conducted on DHEA have indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POF.
Additionally, over the last five years a Greek research team has successfully implemented the use of dehydroepiandrosterone (DHEA) for the fertility treatment of women suffering with POF.The majority of the patients were referred for donor eggs or surrogacy, however after a few months of DHEA administration, some succeeded in getting pregnant through IVF, IUI, IUTPI or natural conception. Many babies have been born after treatment with DHEA.
Ovarian tissue cryopreservation can be performed on prepubertal girls at risk for premature ovarian failure, and this procedure is as feasible and safe as comparable operative procedures in children.
Menopause confers:
- A possible but contentious increased risk of atherosclerosis. The risk of acute myocardial infarction and other cardiovascular diseases rises sharply after menopause, but the risk can be reduced by managing risk factors, such as tobacco smoking, hypertension, increased blood lipids and body weight.
- Increased risk of osteopenia, osteoporosis, and accelerated lung function decline.
Women who experience menopause before 45 years of age have an increased risk of heart disease, death, and impaired lung function.
Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure (aka primary ovarian insufficiency) may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH (follicle stimulating hormone) levels.
Quality of the eggs (oocytes) may also be impaired as a 1989 study by Scott et al. of 758 in vitro fertilisation (IVF) cycles showed a dramatic decline in implantation rates between high (> 25 mIU/mL) and low day three FSH (<15 mIU/mL) women even though the ages of the women were equivalent between the two groups (mean age 35 years). However, other studies show no association with elevated FSH levels and genetic quality of embryos after adjusting for age. The decline in quality was age related, not FSH related as the younger women with high day three FSH levels had higher live birth rates than the older women with high FSH. There was no significant difference in genetic embryo quality between same aged women regardless of FSH levels. A 2008 study concluded that diminished reserve did not affect the quality of oocytes and any reduction in quality in diminished reserve women was age related. One expert concluded: in young women with poor reserve when eggs are obtained they have near normal rates of implantation and pregnancy rates, but they are at high risk for IVF cancellation; if eggs are obtained, pregnancy rates are typically better than in older woman with normal reserve. However, if the FSH level is extremely elevated these conclusions are likely not applicable.
There is some controversy as the accuracy of the tests used to predict poor ovarian reserve. One systematic review concluded that the accuracy of predicting the occurrence of pregnancy is very limited. When a high threshold is used, to prevent couples from wrongly being refused IVF, only approximately 3% of IVF-indicated cases are identified as having unfavourable prospects in an IVF treatment cycle. Also, the review concluded the use of any ORT (Ovarian Reserve Testing) for outcome prediction cannot be supported. Also Centers for Disease Control and Prevention statistics show that the success rates for IVF with diminished ovarian reserve vary widely between IVF centers.
Breastfeeding is a common cause of secondary amenorrhoea, and often the condition lasts for over six months. Breastfeeding typically lasts longer than lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a women breastfeeds. Lactational amenorrhoea has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited. Breastfeeding is said to prevent more births in the developing world than any other method of birth control or contraception. Lactational amenorrhoea is 98% percent effective as a method of preventing pregnancy in the first six months postpartum.
Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping a medication. Hormonal contraceptives that contain only progestogen like the oral contraceptive Micronor, and especially higher-dose formulations like the injectable Depo Provera commonly induce this side-effect. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who use and then cease using contraceptives like the combined oral contraceptive pill may experience secondary amenorrhoea as a withdrawal symptom. The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of OCOP use and women who experience secondary amenorrhoea because of other reasons. New contraceptive pills, like continuous oral contraceptive pills (OCPs) which do not have the normal 7 days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after 1 year of treatment with continuous OCP use.
The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users.
Anti-psychotic drugs used to treat schizophrenia have been known to cause amenorrhoea as well. New research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. Metformin decreases resistance to the hormone insulin, as well as levels of prolactin, testosterone, and lutenizing hormone (LH). Metformin also decreases the LH/FSH ratio. Results of the study on Metformin further implicate the regulation of these hormones as a main cause of secondary amenorrhoea.
Economic uses of sterility include:
- the production of certain kinds of seedless fruit, such as seedless tomato or watermelon (though sterility is not the only available route to fruit seedlessness);
- terminator technology, methods for restricting the use of genetically modified plants by causing second generation seeds to be sterile;
- biological control; for example, trap-neuter-return programs for cats; and the sterile insect technique, in which large numbers of sterile insects are released, which compete with fertile insects for food and mates, thus reducing the population size of subsequent generations, which can be used to fight diseases spread by insect vectors such as malaria in mosquitoes.