Female infertility


Female infertility
Female infertility
Classification and external resources
ICD-10 N97.0
ICD-9 628
DiseasesDB 4786
MedlinePlus 001191
eMedicine med/3535
MeSH D007247

Female infertility refers to infertility in female humans.

Contents

Causes and factors

Causes or factors of female infertility can basically be classified regarding whether they are acquired or genetic, or strictly by location.

Acquired versus genetic

Although causes (or factors) of female infertility can be classified as acquired versus genetic, female infertility is usually more or less a combination of nature and nurture. Also, the presence of any single risk factor of female infertility (such as smoking, mentioned further below) does not necessarily cause infertility, and even if a woman is definitely infertile then the infertility cannot definitely be blamed on any single risk factor even if the risk factor is (or has been) present.

Acquired

According to the American Society for Reproductive Medicine (ASRM), Age, Smoking, Sexually Transmitted Infections, and Being Overweight or Underweight can all affect fertility.[1]

In broad sense, acquired factors practically include any factor that is not based on a genetic mutation, including any intrauterine exposure to toxins during fetal development, which may present as infertility many years later as an adult.

Age

Women become less fertile as they get older. A woman's fertility peaks between the ages of 22 to 26, after which it starts to decline, with this decline being accelerated after age 35. However, the exact estimates of the chances of a woman to conceive after a certain age are not clear, with research giving differing results. The chances of a couple to successfully conceive at an advanced age depend on many factors, such as the general health of a woman, but also the fertility of the male partner.

According to the National Institute for Health and Clinical Excellence, for women aged 35, about 94 out of every 100 who have regular unprotected sexual intercourse will get pregnant after 3 years of trying. For women aged 38, however, only 77 out of every 100 will do so.[2]

In 1957, a study was done on a large population 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 [3]:

  • 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

According to 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.[4][5]

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 19-26-year olds. Pregnancy rates did not change notably between the 27-29 age group and the 30-34 age group, but dropped sharply for women over 35. 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." [6]

In terms of ovarian reserve, a typical woman has 12% of her reserve at age 30 and has only 3% at age 40.[7] 81% of variation in ovarian reserve is due to age alone,[7] making age the most important factor in female infertility.

Some experts assert that the average woman's fertility peaks when she is 24 years of age.[8]

However a French study found no difference between the fertility rate of women under 25 and those aged 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 aged 26–30, 61% for ages 31–35, and 54% in the over 35 age group. (note however that the study is from 1982, artificial insemination techniques and success rates have evolved greatly since then).[9]

In Hungary, a study by the Statisztikai Hivatal (Central Statistics Office) estimated that 7-12% of Hungarian women younger than 30 were infertile; 13-22% of women aged 35 were infertile; and 24-46% of women aged 40 were infertile.[10]

A study by Fong, S. and McGovern, P. suggests that among women aged 35–39, about 1 in 3 have fertility problems.[11]

Most IVF centers will attempt IVF using the female partner's own eggs until about age 43-45.[3] Michael Fox, M.D., a Reproductive Endocrinologist with North Florida Gynecologic Specialists in Jacksonville, states that, with regard to assisted reproduction treatment, "in general our approach to treatment of patients over age 35 is vastly more aggressive than in younger patients".[9]

A study commissioned by RESOLVE,[12] a non-profit patient advocacy organization, states that both three out of four men and three out of four women overestimate by five years the rapid decline in female fecundity with prime childbearing age occurring up to age 32 for females and a rapid decline at 35 instead of 40 as most people commonly believe.[13] The American Society for Reproductive Medicine (ASRM) states, "...women in their 20's to early 30's are most likely to conceive."[14] and in greater detail newsletter:[15] (Even more detailed booklet:[16]). Elite egg donor agencies such as A Perfect Match that advertise in places such as Ivy League student newspapers offering up to $20,000 or even $50,000 for donor eggs seek donors under the age of 29.[17][18]

Fertility specialist and book author Dr. Sherman Silber [19] states, in a message to women (A Special Message From Dr. Silber About Your Biological Clock and Preserving Your Fertility) that "almost 25% of all women of childbearing age currently wishing to have children are infertile" and "Only 1% of women in their early 20’s are infertile but by their late 20’s, 16% [one in six] are infertile, and by their mid-30’s almost 25% [one in four] are infertile. By age 40, 60% [three in five] are infertile and by age 43 it would be a rare woman who is still fertile,"[20] (however Dr. Sherman Silber does not explain what definition of "infertility" he is referring to, and in the US the most common definition is a woman under 35 who has not conceived in 12 months and a woman over 35 who has not conceived in 6 months, a definition which has been criticized as being based on public policy - as after this period women are advised to seek medical intervention; the NICE does not accept this definition and its guidelines define infertility as failure to conceive after regular unprotected sexual intercourse for 2 years in the absence of known reproductive pathology).[21] Because one in six can be infertile (before treatment) by their late 20's Dr. Silber recommends that a woman who expects to delay childbirth beyond age 30 have her gynecologist perform an antral follicle count ultrasound at about age 25.[22] Other fertility specialists such as book author Dr. Daniel Potter [23] recommend an FSH (Follicle-stimulating hormone) or other laboratory test instead of the antral follicle count ultrasound.[22]

The issues of age need to be taken up with a qualified fertility specialist such as a reproductive endocrinologist. Standard of care: Women over 35 who are attempting to conceive should seek the advice of a fertility specialist after six months of unprotected intercourse, or after one year if under the age of 35.[24]

Tobacco smoking

Tobacco smoking is harmful to the ovaries, and the degree of damage is dependent upon the amount and length of time a woman smokes. Nicotine and other harmful chemicals in cigarettes interfere with the body’s ability to create estrogen, a hormone that regulates folliculogenesis and ovulation. Also, cigarette smoking interferes with folliculogenesis, embryo transport, endometrial receptivity, endometrial angiogenesis, uterine blood flow and the uterine myometrium.[25] Some damage is irreversible, but stopping smoking can prevent further damage.[26][15] Smokers are 60% more likely to be infertile than non-smokers.[27] Smoking reduces the chances of IVF producing a live birth by 34% and increases the risk of an IVF pregnancy miscarrying by 30%.[27] Also, female smokers have an earlier onset of menopause by approximately 1–4 years.[28]

Sexually transmitted disease

Sexually transmitted diseases 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.[26]

Body weight and eating disorders

Twelve percent of all infertility cases are a result of a woman either being underweight or overweight. Fat cells produce estrogen,[29] 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.[26] Too little body fat causes insufficient production of estrogen and disruption of the menstrual cycle.[26] Both under and overweight women have irregular cycles in which ovulation does not occur or is inadequate.[26] Proper nutrition in early life is also a major factor for later fertility.[30]

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.[31]

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.[32]

Chemotherapy

Chemotherapy poses a high risk of infertility. Antral follicle count decreases after three series of chemotherapy, whereas follicle stimulating hormone (FSH) reaches menopausal levels after four series.[33] Other hormonal changes in chemotherapy include decrease in inhibin B and anti-Müllerian hormone levels.[33] Chemotherapies with high risk of infertility include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine.[34] Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin.[34] On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycinand dactinomycin and antimetabolites such as methotrexate, mercaptopurine and 5-fluoruracil.[34]

Patients may choose between several methods of fertility preservation prior to chemotherapy, including cryopreservation of ovarian tissue, oocytes or embryos.[35]

Other factors that can cause acquired infertility

Genetic factors

There are many genes wherein mutation causes female infertility, as shown in table below. Also, there are additional conditions involving female infertility which are believed to be genetic but where no single gene has been found to be responsible, notably Mayer-Rokitansky-Küstner-Hauser Syndrome (MRKH).[39] Finally, an unknown number of genetic mutations cause a state of subfertility, which in addition to other factors such as environmental ones may manifest as frank infertility.

Chromosomal abnormalities causing female infertility include Turner syndrome.

Some of these gene or chromosome abnormalities cause intersexed conditions, such as androgen insensitivity syndrome

Genes wherein mutation causes female infertility[40]
Gene Encoded protein Effect
BMP15 Bone morphogenetic protein 15 Hypergonadotrophic ovarian failure (POF4)
BMPR1B Bone morphogenetic protein receptor 1B Ovarian dysfunction, hypergonadotrophic hypogonadism and acromesomelic chondrodysplasia
CBX2; M33 Chromobox protein homolog 2 ; Drosophila polycomb class

Autosomal 46,XY, male-to-female sex reversal (phenotypically perfect females)

CHD7 Chromodomain-helicase-DNA-binding protein 7 CHARGE syndrome and Kallmann syndrome (KAL5)
DIAPH2 Diaphanous homolog 2 Hypergonadotrophic, premature ovarian failure (POF2A)
FGF8 Fibroblast growth factor 8 Normosmic hypogonadotrophic hypogonadism and Kallmann syndrome (KAL6)
FGFR1 Fibroblast growth factor receptor 1 Kallmann syndrome (KAL2)
FSHR FSH receptor Hypergonadotrophic hypogonadism and ovarian hyperstimulation syndrome
FSHB Follitropin subunit beta Deficiency of follicle-stimulating hormone, primary amenorrhoea and infertility
FOXL2 Forkhead box L2 Isolated premature ovarian failure (POF3) associated with BPES type I; FOXL2

402C --> G mutations associated with human granulosa cell tumours

FMR1 Fragile X mental retardation Premature ovarian failure (POF1) associated with premutations
GNRH1 Gonadotropin releasing hormone Normosmic hypogonadotrophic hypogonadism
GNRHR GnRH receptor Hypogonadotrophic hypogonadism
KAL1 Kallmann syndrome Hypogonadotrophic hypogonadism and insomnia, X-linked Kallmann syndrome (KAL1)
KISS1R ; GPR54 KISS1 receptor Hypogonadotrophic hypogonadism
LHB Luteinizing hormone beta polypeptide
LHCGR LH/choriogonadotrophin receptor Hypergonadotrophic hypogonadism (luteinizing hormone resistance)
DAX1 Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 X-linked congenital adrenal hypoplasia with hypogonadotrophic hypogonadism; dosage-sensitive male-to-female sex reversal
NR5A1; SF1 Steroidogenic factor 1 46,XY male-to-female sex reversal and streak gonads and congenital lipoid adrenal hyperplasia; 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency
POF1B Premature ovarian failure 1B Hypergonadotrophic, primary amenorrhea (POF2B)
PROK2 Prokineticin Normosmic hypogonadotrophic hypogonadism and Kallmann syndrome (KAL4)
PROKR2 Prokineticin receptor 2 Kallmann syndrome (KAL3)
RSPO1 R-spondin family, member 1 46,XX, female-to-male sex reversal (individuals contain testes)
SRY Sex-determining region Y Mutations lead to 46,XY females; translocations lead to 46,XX males
SOX9 SRY-related HMB-box gene 9 Autosomal 46,XY male-to-female sex reversal (campomelic dysplasia)
TAC3 Tachykinin 3 Normosmic hypogonadotrophic hypogonadism
TACR3 Tachykinin receptor 3 Normosmic hypogonadotrophic hypogonadism

By anatomic location

Hypothalamic-pituitary factors

  • Hypothalamic dysfunction
  • Hyperprolactinemia[41]

Ovarian factors

  • Anovulation. Female infertility caused by anovulation is called "anovulatory infertility", as opposed to "ovulatory infertility" in which ovulation is present.[42]
  • Premature menopause
  • Luteal dysfunction[43]

Tubal (ectopic)/peritoneal factors

  • Tubal occlusion[46]
  • Tubal dysfunction

Uterine factors

Cervical factors

  • Cervical stenosis[49]
  • Antisperm antibodies[50]

Vaginal factors

Diagnosis

Diagnosis of infertility begins with a medical history and physical exam. The healthcare provider may order tests, including the following:

  • Lab tests
    • hormone testing, to measure levels of female hormones at certain times during a menstrual cycle
    • day 2 or 3 measure of FSH and estrogen, to assess ovarian reserve
    • measurements of thyroid function[52] (a thyroid stimulating hormone (TSH) level of between 1 and 2 is considered optimal for conception)
    • measurement of progesterone in the second half of the cycle to help confirm ovulation
  • Examination and imaging
    • an endometrial biopsy, to verify ovulation and inspect the lining of the uterus
    • laparoscopy, which allows the provider to inspect the pelvic organs
    • fertiloscopy, a relatively new surgical technique used for early diagnosis (and immediate treatment)
    • Pap smear, to check for signs of infection
    • pelvic exam, to look for abnormalities or infection
    • a postcoital test, which is done soon after intercourse to check for problems with sperm surviving in cervical mucous (not commonly used now because of test unreliability)
    • special X-ray tests

There are genetic testing techniques under development to detect any mutation in genes associated with female infertility.[40]

Diagnosis and treatment of infertility should be made by physicians who are fellowship trained as reproductive endocrinologists. Reproductive Endocrinologists are usually Obstetrician-Gynecologists with advanced training in Reproductive Endocrinology & Infertility (in North America). These highly educated professionals and qualified physicians treat Reproductive Disorders affecting not only women but also men, children, and teens.

Prospective patients should note that reproductive endocrinology & infertility medical practices do not see women for general maternity care. The practice is primarily focused on helping their patients to conceive and to correct any issues related to recurring pregnancy loss.

Prevention

Some cases of female infertility may be prevented through identified interventions:

  • Maintaining a healthy lifestyle. Excessive exercise, consumption of caffeine and alcohol, and smoking are all associated with decreased fertility. Eating a well-balanced, nutritious diet, with plenty of fresh fruits and vegetables (plenty of folates), and maintaining a normal weight are associated with better fertility prospects.
  • Treating or preventing existing diseases. Identifying and controlling chronic diseases such as diabetes and hypothyroidism increases fertility prospects. Lifelong practice of safer sex reduces the likelihood that sexually transmitted diseases will impair fertility; obtaining prompt treatment for sexually transmitted diseases reduces the likelihood that such infections will do significant damage. Regular physical examinations (including pap smears) help detect early signs of infections or abnormalities.
  • Not delaying parenthood. Fertility does not ultimately cease before menopause, but it starts declining after age 27 and drops at a somewhat greater rate after age 35.[6] Women whose biological mothers had unusual or abnormal issues related to conceiving may be at particular risk for some conditions, such as premature menopause, that can be mitigated by not delaying parenthood.

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  • Female genital mutilation — Description Partial or complete removal of the external female genitalia, or other injury to the female genital organs, for non medical reasons Areas practiced Western, eastern, and north eastern Africa, Middle East, Near East, Southeast Asia… …   Wikipedia


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