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In terms of ovarian reserve, a typical woman has 12% of her reserve at age 30 and has only 3% at age 40. 81% of variation in ovarian reserve is due to age alone, making age the most important factor in female infertility.
The most common methods of checking the status of the ovarian reserve is to perform a blood test on day 3 of the menstrual cycle to measure serum FSH level, alternatively a blood test to measure the serum AMH level can give similar information. Transvaginal ultrasound can also be used to “count the number of follicles” and this procedure is called Antral Follicle Count.
The American College of Obstetricians and Gynecologists recommends ovarian reserve testing should be performed for women older than 35 years who have not conceived after 6 months of attempting pregnancy and women at higher risk of diminished ovarian reserve, such as those with a history of cancer treated with gonadotoxic therapy, pelvic irradiation, or both; those with medical conditions who were treated with gonadotoxic therapies; or those who had ovarian surgery for endometriomas.
It is important to recognize that a poor result from ovarian reserve testing does not signify an absolute inability to conceive and should not be the sole criterion considered to limit or deny access to infertility treatment.
Transvaginal ultrasonography can be used to determine antral follicle count (AFC). This is an easy-to-perform and noninvasive method (but there may be some discomfort). Several studies show this test to be more accurate than basal FSH testing for older women (< 44 years of age) in predicting IVF outcome. This method of determining ovarian reserve is recommended by Dr. Sherman J. Silber, author and medical director of the Infertility Center of St. Louis.
AFC and Median Fertile Years Remaining
Note, the above table from Silber's book may be in error as it has no basis in any scientific study, and contradicts data from Broekmans, et al. 2004 study. The above table closely matches Broekmans' data only if interpreted as the total AFC of both ovaries. Only antral follicles that were 2–10 mm in size were counted in Broekmans' study.
Age and AFC and Age of Loss of Natural Fertility (See Broekmans, et al. [2004])
AFC and FSH Stimulation Recommendations for Cycles Using Assisted Reproduction Technology
Elevated serum follicle stimulating hormone (FSH) level measured on day three of the menstrual cycle. (First day of period flow is counted as day one. Spotting is not considered start of period.) If a lower value occurs from later testing, the highest value is considered the most predictive. FSH assays can differ somewhat so reference ranges as to what is normal, premenopausal or menopausal should be based on ranges provided by the laboratory doing the testing. Estradiol (E2) should also be measured as women who ovulate early may have elevated E2 levels above 80 pg/mL (due to early follicle recruitment, possibly due to a low serum inhibin B level) which will mask an elevated FSH level and give a false negative result.
High FSH strongly predicts poor IVF response in older women, less so in younger women. One study showed an elevated basal day-three FSH is correlated with diminished ovarian reserve in women aged over 35 years and is associated with poor pregnancy rates after treatment of ovulation induction(6% versus 42%).
The rates for spontaneous pregnancy in older women with elevated FSH levels have not been studied very well and the spontaneous pregnancy success rate, while low, may be underestimated due to non reporting bias, as most infertility clinics will not accept women over the age of forty with FSH levels in the premenopausal range or higher.
A woman can have a normal day-three FSH level yet still respond poorly to ovarian stimulation and hence can be considered to have poor reserve. Thus, another FSH-based test is often used to detect poor ovarian reserve: the clomid challenge test, also known as CCCT(clomiphene citrate challenge test).
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.
Serum follicle-stimulating hormone (FSH) measurement alone can be used to diagnose the disease. Two FSH measurements with one-month interval have been a common practice. The anterior pituitary secretes FSH and LH at high levels due to the dysfunction of the ovaries and consequent low estrogen levels. Typical FSH in POF patients is over 40 mlU/ml (post-menopausal range).
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 (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
- Anti-Müllerian hormone to estimate ovarian reserve.
- 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)
- Hysterosalpingography or sonosalpingography, to check for tube patency
- Sonohysterography to check for uterine abnormalities.
There are genetic testing techniques under development to detect any mutation in genes associated with female infertility.
Initial diagnosis and treatment of infertility is usually made by obstetrician/gynecologists or women's health nurse practitioners. If initial treatments are unsuccessful, referral is usually made to physicians who are fellowship trained as reproductive endocrinologists. Reproductive endocrinologists are usually obstetrician/gynecologists with advanced training in reproductive endocrinology and infertility (in North America). These physicians treat reproductive disorders affecting not only women but also men, children, and teens.
Usually reproductive endocrinology & infertility medical practices do not see women for general maternity care. The practice is primarily focused on helping their women to conceive and to correct any issues related to recurring pregnancy loss.
Symptoms-based methods of fertility awareness may be used to detect ovulation or to determine that cycles are anovulatory. Charting of the menstrual cycle may be done by hand, or with the aid of various fertility monitors. Records of one of the primary fertility awareness signs—basal body temperature—can detect ovulation by identifying the shift in temperature which takes place after ovulation. It is said to be the most reliable way of confirming whether ovulation has occurred.
Women may also use ovulation predictor kits (OPKs) which detect the increase in luteinizing hormone (LH) levels that usually indicates imminent ovulation. For some women, these devices do not detect the LH surge, or high levels of LH are a poor predictor of ovulation; this is particularly common in women with PCOS. In such cases, OPKs and those fertility monitors which are based on LH may show false results, with an increased number of false positives or false negatives. Dr Freundl from the University of Heidelberg suggests that tests which use LH as a reference often lack sensitivity and specificity.
Perimenopause is a natural stage of life. It is not a disease or a disorder. Therefore, it does not automatically require any kind of medical treatment. However, in those cases where the physical, mental, and emotional effects of perimenopause are strong enough that they significantly disrupt the life of the woman experiencing them, palliative medical therapy may sometimes be appropriate.
Diagnosis is largely achieved by obtaining a complete medical history followed by physical exam and ultrasound. If need be, laboratory tests or hysteroscopy may be used. The following are a list of diagnostic procedures that medical professionals may use to identify the cause of the abnormal uterine bleeding.
- Pelvic and rectal examination to ensure that bleeding is not from lower reproductive tract (i.e. vagina, cervix) or rectum
- Pap smear to rule out cervical neoplasia
- Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities.
- Endometrial biopsy to exclude endometrial cancer or atypical hyperplasia
- Hysteroscopy
- TSH and T4 dosage to rule out hypothyroidism
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
The term "postmenopausal" describes women who have not experienced any menstrual flow for a minimum of 12 months, assuming that they have a uterus and are not pregnant or lactating. In women without a uterus, menopause or postmenopause can be identified by a blood test showing a very high FSH level. Thus postmenopause is the time in a woman's life that takes place after her last period or, more accurately, after the point when her ovaries become inactive.
The reason for this delay in declaring postmenopause is because periods are usually erratic at this time of life. Therefore, a reasonably long stretch of time is necessary to be sure that the cycling has ceased. At this point a woman is considered infertile; however, the possibility of becoming pregnant has usually been very low (but not quite zero) for a number of years before this point is reached.
A woman's reproductive hormone levels continue to drop and fluctuate for some time into post-menopause, so hormone withdrawal effects such as hot flashes may take several years to disappear.
A period-like flow during postmenopause, even spotting, may be a sign of endometrial cancer.
An area of research is the search for endometriosis markers.
In 2010 essentially all proposed biomarkers for endometriosis were of unclear medical use, although some appear to be promising. The one biomarker that has been in use over the last 20 years is CA-125. A 2016 review found that in those with symptoms of endometriosis and once ovarian cancer has been ruled out, a positive CA-125 may confirm the diagnosis. Its performance in ruling out endometriosis; however, is low. CA-125 levels appear to fall during endometriosis treatment, but has not shown a correlation with disease response.
Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit. It has been postulated a future diagnostic tool for endometriosis will consist of a panel of several specific and sensitive biomarkers, including both substance concentrations and genetic predisposition.
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.
The European Society of Human Reproduction and Embryology (ESHRE) notes that the aim of ovulation induction should be mono-ovulation and not over-stimulation of the ovaries . The risks associated with multiple pregnancy are much higher than singleton pregnancy; incidences of perinatal death are seven times higher in triplet births and five times higher in twin births than the risks associated with a singleton pregnancy. It is therefore important to adapt the treatment to each individual patient.
Women with polycystic ovary syndrome may be particularly at risk. Multiple pregnancy occurs in approximately 15-20% of cases following cycles induced with gonadotrophins such as hMG and FSH induced ovulations.
During ovulation induction, it is recommended to start at a low dose and monitor the ovarian response with vaginal ultrasound, including discernment of the number of developing follicles. A cycle with supernumerary follicles is usually defined as one where there are more than two follicles >16 mm in diameter. It is generally recommended to have such cycles cancelled because of the risk of multiple pregnancy. In cancelled cycles, the woman or couple should be warned of the risks in case of supernumerary follicles, and should avoid sexual intercourse or use contraception until the next menstruation. Induction of final maturation (such as done with hCG) may need to be withheld because of increased risk of ovarian hyperstimulation syndrome(OHSS). The starting dose of the inducing drug should be reduced in the next cycle.
Alternatives to cancelling a cycle are mainly:
- Aspiration of supernumerary follicles until one or two remain.
- Converting the protocol to IVF treatment with embryo transfer of up to two embryos only.
- Selective fetal reduction. This alternative confers a high risk of complications.
- Proceeding with any multiple pregnancy without fetal reduction, with the ensuing risk of complications. This alternative is not recommended.
The most common pain scale for quantification of endometriosis-related pain is the visual analogue scale (VAS); VAS and numerical rating scale (NRS) were the best adapted pain scales for pain measurement in endometriosis. For research purposes, and for more detailed pain measurement in clinical practice, VAS or NRS for each type of typical pain related to endometriosis (dysmenorrhea, deep dyspareunia and non-menstrual chronic pelvic pain), combined with the clinical global impression (CGI) and a quality of life scale, are used.
Acquired female infertility may be prevented through identified interventions:
- "Maintaining a healthy lifestyle." Excessive exercise, consumption of caffeine and alcohol, and smoking have all been associated with decreased fertility. Eating a well-balanced, nutritious diet, with plenty of fresh fruits and vegetables, and maintaining a normal weight, on the other hand, have been 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. 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.
- "Egg freezing." A woman can freeze her eggs preserve her fertility. By using egg freezing while in the peak reproductive years, a woman's oocytes are cryogenically frozen and ready for her use later in life, reducing her chances of female infertility.
Magnetic resonance imaging (MRI) provides slightly better diagnostic capability compared to TVUS, due to the increased ability of MRI to differentiate objectively between different types of soft tissue. This is possible with MRI's higher spatial and contrast resolution. Overall, it is estimated that MRI has a sensitivity of 74% and specificity of 91% for the detection of adenomyosis. Diagnosis through MRI focuses predominately upon investigating the junctional zone. The uterus will have a thickened junctional zone with darker/diminished signal on both T1 and T2 weighted sequences.
Three objective measures of the junctional zone can be used to diagnose adenomyosis.
1. A thickness of the junctional zone greater than 8–12 mm. Less than 8 mm is normal.
2. A junctional zone width being greater than 40% of the width of the myometrium.
3. Variability in the width of the junctional zone being greater than 5 mm.
Interspersed within the thickened, darker signal of the junctional zone, one will often see foci of hyperintensity (bright spots) on the T2 weighted scans representing small cystically dilatated glands or more acute sites of microhemorrhage.
MRI is limited by other factors, but not by calcified uterine fibroids (as is ultrasound). In particular, MRI is better able to differentiate adenomyosis from multiple small uterine fibroids.
Adenomyosis can vary widely in the extent and location of its invasion within the uterus. As a result, there are no established pathognomonic features to allow for a definitive diagnosis of adenomyosis through non-invasive imaging. Nevertheless, non-invasive imaging techniques such as transvaginal ultrasonography (TVUS) and magnetic resonance imaging (MRI) can both be used to strongly suggest the diagnosis of adenomyosis, guide treatment options, and monitor response to treatment. Indeed, TVUS and MRI are the only two practical means available to establish a pre-surgical diagnosis.
Drug of choice is progesterone.
Management of dysfunctional uterine bleeding predominantly consists of reassurance, though mid-cycle estrogen and late-cycle progestin can be used for mid- and late-cycle bleeding respectively.
Also, non-specific hormonal therapy such as combined high-dose estrogen and high-dose progestin can be given. Ormeloxifene is a non-hormonal medication that treats DUB but is only legally available in India.
The goal of therapy should be to arrest bleeding, replace lost iron to avoid anemia, and prevent future bleeding.
Excessive movement before any treatments or surgeries will cause excessive bleeding.
A hysterectomy may be performed in some cases.
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.
Where an underlying cause can be identified, treatment may be directed at this. Clearly heavy periods at menarche and menopause may settle spontaneously (the menarche being the start and menopause being the cessation of periods).
If the degree of bleeding is mild, all that may be sought by the woman is the reassurance that there is no sinister underlying cause. If anemia occurs due to bleeding then iron tablets may be used to help restore normal hemoglobin levels.
The condition is often treated with hormones, particularly as abnormal uterine bleeding commonly occurs in the early and late menstrual years when contraception is also sought. Usually, oral combined contraceptive or progesterone only pills may be taken for a few months, but for longer-term treatment the alternatives of injected Depo Provera or the more recent progesterone releasing IntraUterine System (IUS) may be used. Fibroids may respond to hormonal treatment, and if they do not, then surgical removal may be required.
Tranexamic acid tablets that may also reduce loss by up to 50%. This may be combined with hormonal medication previously mentioned.
Anti-inflammatory medication like NSAIDs may also be used. NSAIDs are the first-line medications in ovulatory menorrhagia, resulting in an average reduction of 20-46% in menstrual blood flow. For this purpose, NSAIDs are ingested for only 5 days of the menstrual cycle, limiting their most common adverse effect of dyspepsia.
A definitive treatment for menorrhagia is to perform hysterectomy (removal of the uterus). The risks of the procedure have been reduced with measures to reduce the risk of deep vein thrombosis after surgery, and the switch from the front abdominal to vaginal approach greatly minimizing the discomfort and recuperation time for the patient; however extensive fibroids may make the womb too large for removal by the vaginal approach. Small fibroids may be dealt with by local removal (myomectomy). A further surgical technique is endometrial ablation (destruction) by the use of applied heat (thermoablation).
In the UK the use of hysterectomy for menorrhagia has been almost halved between 1989 and 2003. This has a number of causes: better medical management, endometrial ablation and particularly the introduction of IUS which may be inserted in the community and avoid the need for specialist referral; in one study up to 64% of women cancelled surgery.
About 1 out of 1000 lesions are or become malignant, typically as a leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after menopause. There is no consensus among pathologists regarding the transformation of leiomyoma into a sarcoma.
Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis. Hyperprolactinemia, characterized by high levels of the hormone prolactin, is often associated with a pituitary tumor. A dopamine agonist can often help relieve symptoms. The subsiding of the causal syndrome is usually enough to restore menses after a few months. Secondary amenorrhea may also be caused by outflow tract obstruction, often related to Asherman's Syndrome. Polycystic ovary syndrome can cause secondary amenorrhea, although the link between the two is not well understood. Ovarian failure related to early onset menopause can cause secondary amenorrhea, and although the condition can usually be treated, it is not always reversible. Secondary amenorrhea is also caused by stress, extreme weight loss, or excessive exercise. Young athletes are particularly vulnerable, although normal menses usually return with healthy body weight. Causes of secondary amenorrhea can also result in primary amenorrhea, especially if present before onset of menarche.
Primary amenorrhoea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with Turner's Syndrome, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16. A reason for this occurrence may be that a person phenotypically female but genetically male, a situation known as androgen insensitivity syndrome. If undescended testes are present, they are often removed after puberty (~21 years of age) due to the increased risk of testicular cancer. In the absence of undescended testes, an MRI can be used to determine whether or not a uterus is present. Müllerian agenesis causes around 15% of primary amenorrhoea cases. If a uterus is present, outflow track obstruction may be to blame for primary amenorrhoea.
The presence of a uterine fibroid versus an adnexal tumor is made. Fibroids can be mistaken for ovarian neoplasms. An uncommon tumor which may be mistaken for a fibroid is Sarcoma botryoides. It is more common in children and adolescents. Like a fibroid, it can also protrude from the vagina and is distinguished from fibroids. While palpation used in a pelvic examination can typically identify the presence of larger fibroids, gynecologic ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also, magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus.
Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions, there may be evidence of local invasion. A biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.
Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity are hysterosalpingography or sonohysterography.