Infertility in women

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The treatment of infertility is directed at correcting any pathology and restoring reproductive function. The ultimate goal of treatment is to establish a healthy pregnancy that leads to a healthy live birth.

Guidelines advise that couples seek investigation or treatment after 1 year of active attempts at pregnancy.[1] Earlier evaluation should be done for women with a history of a disease that may affect fertility, such as ovulatory dysfunction or a known anatomic abnormality, and men with azoospermia. Earlier evaluation and treatment are also warranted for women ages 35 years or older.[105]

It is important to address and optimize any underlying or associated medical disorder, such as diabetes or thyroid disease, and include weight loss, as appropriate.[111][112][113] Although evidence for the benefit of lifestyle changes or weight loss is lacking, these aspects of care are recommended for general health and should ideally occur prior to pregnancy.[2][64][114][115] Prepregnancy counseling with obstetricians is encouraged, because medical conditions are increasingly complex and early involvement of a multidisciplinary care team is beneficial.

Counseling

It is well described that the evaluation and treatment of infertility is highly stressful, and evidence is emerging that stress is associated with treatment failure. Some evidence suggests that psychological intervention could improve pregnancy rates in patients with infertility. These interventions are typically focused on lowering anxiety and resolving communication problems, but good evidence is lacking.[116][117][118] [ ]

Ovulatory dysfunction

Controlled ovarian stimulation with selective estrogen receptor modulators, aromatase inhibitors, or gonadotropins is the mainstay of treatment. Gonadotropins are typically used as second-line treatments after selective estrogen receptor modulators or aromatase inhibitors have failed.

Ovarian stimulation can be achieved with oral agents or gonadotropin injections.

Ovulation-inducing agents aim to stimulate follicular development and achieve ovulation, which can be followed by timed intercourse or intrauterine insemination (IUI). Ideally, medication doses should be tailored with ultrasound monitoring, such that monofollicular ovulation occurs, to reduce the risk of multiple pregnancies.

Clomiphene is the most commonly used medication for the treatment of anovulation. It is taken in the early follicular phase (e.g., days 2-6 of a menstrual cycle, in which day 1 is the first day of full-flow bleeding). A selective estrogen receptor modulator, it is a competitive antagonist of estradiol at the level of the cytoplasmic nuclear receptor complex. The drug binds to estrogen receptors in the hypothalamic arcuate nucleus, disrupting negative feedback and augmenting the production of gonadotropin-releasing hormone (GnRH). This, in turn, augments endogenous production of follicle-stimulating hormone (FSH), and ovulation is achieved. A maximum treatment duration of 6 months should be considered because of concern over ovarian disease.[1]
Aromatase inhibitors, such as letrozole, are beneficial for ovulation induction and are the recommended first-line pharmacologic treatment for ovulation induction in women with polycystic ovary syndrome (PCOS) who are suffering from anovulatory infertility.[108][119][120][121] These drugs are competitive reversible inhibitors of testosterone aromatization, decreasing circulating estrogen by over 97%.[122] Similar to clomiphene, the reduction in estrogen affects hypothalamic feedback and induces greater levels of FSH. Aromatase inhibitors are taken in the early follicular phase (e.g., days 3-7 of a menstrual cycle). However, because there is no suppression of the estrogen receptor, it has been postulated that aromatase inhibitors would not negatively affect the uterus or cervical mucus, and several randomized controlled trials have demonstrated improved endometrial development on letrozole.[123] Data suggesting increased fetal abnormalities in pregnancies following the use of aromatase inhibitors have restricted their use to postmenopausal women in some countries; however, these data have been successfully challenged more recently. Multicentered randomized controlled trials (RCTs), meta-analyses and systematic reviews have concluded that the risks of fetal congenital abnormalities in those using letrozole and clomiphene were not increased (the expected anomaly rate in fertile women who did not have assisted conception is 5% to 8%).[124][125]
Gonadotropins are typically used after oral agents have failed; however, they may be first-line options for older patients, for women with hypothalamic amenorrhea, or women with abnormal gonadotropin secretion (e.g., hypopituitarism or hypogonadotropic hypogonadism). Medications available include highly purified urinary gonadotropins, recombinant FSH, and recombinant luteinizing hormone (LH). [ ] There has been debate regarding the requirement of LH supplementation for folliculogenesis. During ovulation induction for women without hypothalamic amenorrhea, there is unlikely to be a significant need for LH.[126] Women should be monitored frequently with ultrasound and measurement of estradiol levels, to assess follicular development and maturity, which enables gonadotropin dose adjustments to avoid overstimulation and ensure that only one to two follicles are recruited.[127] These medications should only be used by experienced infertility practitioners because of the high risk of ovarian hyper-stimulation syndrome and higher-order multiple gestations if women are not adequately monitored.

Hypothalamic or hypopituitary infertility

Gonadotropins may be first-line options for women with hypothalamic amenorrhea.[1][14] For women with a nonfunctioning pituitary gland (e.g., with Kallman syndrome), drugs such as clomiphene are ineffective; the treatment of choice, therefore, is controlled ovarian stimulation with gonadotropins.

Polycystic ovary syndrome

Women with anovulatory infertility predominantly have a diagnosis of PCOS. In addition to reproductive hurdles, these women are also at increased future risk of cardiovascular disease, gestational and type 2 diabetes, and obstructive sleep apnea.

Lifestyle and dietary advice in the population with raised body mass index (BMI), therefore, has multiple risk-reducing benefits, as well as fertility gains.[108][128] Weight loss is not recommended as first-line fertility treatment for normal-weight women with PCOS.
In women with PCOS, ovulation induction with oral agents should be first line. Letrozole has been recommended as the drug of choice, with overall improved pregnancy and live birth rates, coupled with a lower observed multiple pregnancy rate, compared with clomiphene.[108][129][130] In one systematic review, live birth rates were higher in women with PCOS treated with letrozole compared with clomiphene; rates of ovarian hyperstimulation syndrome, miscarriage, and multiple pregnancy were similar.[131] Practitioners should be cautioned of its higher cost implications and off-license use.
Gonadotropins are typically used after oral agents have failed. Typical starting doses of gonadotropins are dependent on female age, diagnosis, and prior stimulation history; however, low doses are usually used. Stimulation duration depends on response to medications.
Women with PCOS can also be treated with metformin. Metformin appears to increase ovulation and pregnancy rates, but it has not conclusively been found to improve live birth rates.[132] Some experts believe all women with PCOS may benefit, while others would give metformin only to women who are overweight/obese or who have proven insulin resistance.[108][133] In ovulation induction, there is no clear benefit of sole metformin use over clomiphene.[134] However, combination therapy with clomiphene and metformin can be recommended to improve ovulation and pregnancy rates.[108]
Derived from the original wedge resection, laparoscopic ovarian drilling may be undertaken in patients with clomiphene-resistant PCOS prior to moving to gonadotropin treatment. Although the observed reduction in multiple pregnancies might make this a more attractive approach than gonadotropin treatment, one systematic review found low quality evidence that ovarian drilling may decrease the live birth rate slightly compared with medical ovulation induction, and there are few data for the long-term outcomes of this destructive process.[128][135][136] Unilateral laparoscopic ovarian drilling may be an alternative to conventional bilateral ovarian drilling, with similar reproductive outcomes in one meta-analysis.[137] The woman's age, potential surgical risks in cohorts with high BMI, and cost implications of laparoscopic ovarian drilling compared with other fertility options should be taken into account.
In vitro fertilization (IVF) is an effective treatment option for anovulatory infertility with PCOS if conception has not occurred with sequential clomiphene, letrozole, and/or gonadotropin treatment.[128][138] Women should be counseled on the higher risks of ovarian hyperstimulation syndrome (OHSS), which can be minimized with an antagonist cycle and elective freeze-all of embryos created.[139][140] In addition, IVF treatment also confers the benefit of reducing the risk of multiple pregnancy, if adhering to elective single embryo transfer.[128]

Tubal infertility

The utility of tubal reconstruction has been highly debated in the infertility literature.[141] Variables predictive of success include younger female age, unilateral versus bilateral tubal disease, density of the adhesions, and thickness of the tubal wall. Although pregnancy rates approximate 30%, ectopic pregnancy rates approximate 14%. As the pregnancy rates from IVF continue to improve, the value of surgical intervention (with increased surgical risk) has diminished.[142] Tubal surgery is not usually performed as the first-line treatment for infertility, having been largely superseded by IVF, unless there is a specific other indication; for example, pelvic pain.[142] The exception to this may be tubal anastomosis after voluntary sterilization.

IVF is the best option for patients with abnormal fallopian tubes. There is accruing evidence that the removal or clipping of ultrasound-evident hydrosalpinges prior to treatment can improve the outcome of IVF treatment, but there is a lack of data on long-term fertility outcomes and procedure- or pregnancy-related adverse effects.[143]

Endometriosis- or adenomyosis-related infertility

Treatment for endometriosis-related infertility is multifaceted and influenced by multiple factors, namely staging of endometriosis, duration of infertility, severity of symptoms, and female age. In young women with mild disease and minimal symptoms, fertility prognosis is not dissimilar to women with unexplained infertility, hence expectant management is not an unreasonable option. If laparoscopy is considered in this subgroup, operative laparoscopy for excision or ablation of endometriosis, rather than diagnostic laparoscopy only, is recommended, because it is associated with higher monthly fecundity and viable pregnancy rates.[144][145][146] The Endometriosis Fertility Index may be used to help predict the chance of nonassisted reproductive technology (ART) pregnancy after surgery.[147][148]

Medical interventions for endometriosis itself are generally hormonal and therefore have little role in the management of women who want to conceive, other than as symptomatic relief prior to fertility treatment.[149] In addition, the European Society of Human Reproduction and Embryology (ESHRE) recommends against the sole use of hormonal treatment for ovarian suppression to improve fertility.[147]

In women with mild endometriosis, IUI with controlled ovarian stimulation can be considered because pregnancy rates are similar to those with unexplained infertility.[147] However, if health economics are considered, the UK National Institute for Health and Care Excellence recommends against offering IUI, and considers IVF as the first-line treatment after 2 years' expectant management.[1]

IVF has the highest success rate for the treatment of endometriosis-associated infertility, especially in those with moderate to severe disease.[150] The per cycle pregnancy rate after IVF for women with endometriosis is higher than after surgery alone. This is despite the finding that endometriosis is associated with lower peak estradiol levels, fewer number of oocytes retrieved, a lower fertilization rate, and a lower implantation rate than other diagnoses (e.g., tubal infertility in women of the same age). However, IVF may not be an available treatment option for all women because the degree of pelvic damage may render normal ovarian tissue inaccessible for oocyte retrieval.

The ongoing debate about whether surgical interventions, especially in the presence of endometriomas, or IVF should be used to maximize fertility potential remains unresolved. Surgical intervention has a role in restoring pelvic anatomy and alleviating symptoms, potentially increasing chances of spontaneous pregnancy.[24][147] In those considering IVF, it may improve ovarian access as well.

By contrast, surgery carries inherent risks and a recovery period, in addition to the potential reduction of ovarian reserve, if ovarian operation is involved. It is also unclear from the evidence whether surgery has any significant benefit on IVF outcome.[151][152] Meta-analyses of observational studies suggest that surgery might improve live birth and pregnancy rates per ART cycle in women with deep infiltrating endometriosis compared with first-line ART without surgery.[152][153] However, randomized trials are lacking, and the ESHRE recommends that the decision to offer surgery for deep endometriosis should mainly be guided by pain and patient preference.[147][154]

Further considerations must be made when weighing up surgical options, on cost implications and the potential delay in commencing assisted fertility treatment, which ultimately has the highest chance of achieving a successful pregnancy.[24] The optimal treatment, therefore, must be individualized, considering all risk factors and the woman’s preferences.

Endometriosis and adenomyosis frequently coexist, and management options for adenomyosis-related infertility are similar in practice. However, women with concurrent adenomyosis and endometriosis have a significantly lower live birth rate with IVF than women with endometriosis alone.[155] Limited evidence from retrospective studies suggests that GnRH agonist pretreatment may improve IVF outcomes in women with adenomyosis, but further studies are needed to confirm this.[156][157][158] Uterine-sparing surgery may be considered for women with symptomatic adenomyosis, but it is controversial due to uncertain impact on reproductive outcomes and an increased risk of complications such as adhesions and uterine rupture.[156][159][160]

Age-related infertility

Although there is no specific treatment for age-related infertility, controlled ovarian hyperstimulation with selective estrogen receptor modulation, aromatase inhibitors, or gonadotropins have been used to optimize fertility outcomes. In this population, gonadotropins are the first-line options. Success rates, however, are dependent on female age, and therefore ovarian stimulation may confer little benefit. Despite that, clinical improvements in assisted reproductive technology are evident in reports from the UK, in which birth rates are observed to steadily increase for all women up to the age of 43 years.[161]

Oocyte donation is also a successful option for women with diminished ovarian reserve or ovarian failure. This process requires IVF.[109] A healthy donor undergoes ovarian stimulation and the oocytes are retrieved. During this process the intended recipient uterus is synchronized with the donor. The oocytes are fertilized and then transferred to the recipient, with success rates correlated closely to the donor’s age.

Damaged or missing uterus

Surrogacy may be used if the uterus is damaged or missing (e.g., Mayer-Rokitansky-Kuster-Hauser syndrome affects 1 in 5000 women).[162][163] For some women, carrying a pregnancy may be hazardous to their health. Increased age is not necessarily an indication for surrogacy, because the uterus is capable of normal function late in menopause (i.e., with egg donation). The surrogate may act as an egg donor in addition, and pregnancy achieved by insemination with the commissioning partner’s sperm. Alternatively, embryos produced by IVF using the commissioning couple’s eggs and sperm can be transferred into the surrogate’s uterus to achieve pregnancy.

Endometrial polyps or uterine septum

If endometrial polyps are detected during the infertility workup, it is standard practice to remove them. Evidence suggests that hysteroscopic polypectomy may improve outcomes with natural conception and intrauterine insemination, irrespective of polyp size.[107][164][165] Polyp removal may also be considered for women planning IVF, but it is unclear whether polypectomy improves IVF outcomes, especially for polyps detected incidentally during IVF stimulation.[107]

Surgical correction of a uterine septum (hysteroscopic metroplasty) may also be considered in women with infertility, but the American Society for Reproductive Medicine (ASRM) guideline concludes that it is uncertain whether this improves live birth rate.[166][106][167] Uterine septa are the most common congenital uterine anomaly and are associated with an increased risk of recurrent pregnancy loss and other adverse pregnancy outcomes such as preterm birth, malpresentation, and fetal growth restriction. However, the association between uterine septa and infertility is less clear, and treatment is controversial.[106][168] One meta-analysis of observational studies suggests that septum removal reduces the rate of miscarriage and may improve live birth rate.[169] Conversely, one randomized controlled trial found no difference in live birth rate compared with expectant management in women with a history of infertility, pregnancy loss, or preterm birth, but the study was limited by a small sample size and a long recruitment period.[170]

Further treatment is based on any other underlying cause of infertility (i.e., ovulatory dysfunction, tubal, endometriosis-/adenomyosis-related, age-related, or unexplained).

Unexplained infertility

A diagnosis of unexplained infertility is reached in about 25% of couples, if clinical investigations fail to identify any male or female barriers to conception. In these couples, expectant management is an accepted approach, supported by evidence that it is effective in a well-selected group of patients.[1][144][171] It may be appropriate to consider intervention earlier in older women with unexplained subfertility. Female age has an important impact on fecundity rates, making it a strong predicting factor in achieving live birth by natural conception or assisted fertility treatment.[12][13]

Other management options for unexplained infertility can be confusing not only to couples, but also to nonfertility experts, because treatment options are varied and compounded further by different patient demographics.

The ASRM, the Canadian Fertility and Andrology Society (CFAS), and the ESHRE have published evidence-based treatment recommendations for couples with unexplained infertility.[2][144][171] They recommend initial therapy with ovarian stimulation with oral agents and IUI followed by IVF, if initial treatment is unsuccessful. The UK National Institute for Health and Care Excellence (NICE) recommends against the use of oral ovarian stimulation agents alone for unexplained infertility.[1]

Compared with expectant management, ovarian stimulation (with oral agents or gonadotropins) coupled with IUI is associated with superior pregnancy outcomes.[2][144] Although ovarian stimulation with IUI is less expensive than IVF, the trade off of multiple pregnancy, potential cycle cancellation, and cumulative costs of repeated treatments may make this option overall less attractive.

The CFAS also suggests a benefit of advancing therapy to IVF in terms of improved live birth rates per cycle and reduced multiple pregnancy, but note that this approach is invasive and costly.[144] Further to evidence on treatment outcomes, NICE has also made recommendations for management options that take into account cost-effectiveness within the UK health economic model.[1] In 2014, the UK NICE guidance recommended IVF as first-line treatment for couples with unexplained infertility who have not conceived after 2 years of expectant management.[1] This strategy was associated with high pregnancy rate and shorter time to pregnancy compared with other treatment modalities with ovarian stimulation and IUI, especially if female age is above 38 years old. Although the success of IVF is evidence based, its access may be prohibited by cost implications and acceptability to the woman because of invasiveness and religious beliefs.

All other treatment modalities (i.e., natural cycle IUI, oral agents with or without timed intercourse) are not recommended for unexplained infertility because no superiority was demonstrated over expectant management.[144]

Assisted fertility treatments

IVF is the first-line treatment option for women with abnormal fallopian tubes, and is an appropriate treatment option for other infertility diagnoses such as anovulatory infertility, if conception has not occurred within 6-12 ovulatory cycles or if ovarian stimulation has proved difficult to control.[128] During IVF, the ovaries are stimulated to produce multiple follicles, and eggs are removed from the follicles by a minor surgical procedure (usually transvaginal retrieval with ultrasound guidance undertaken under sedation). [ ] Eggs and sperm are combined, creating embryos that are then transferred back to the uterus. [ ] [ ] To reduce multiple gestation and its associated risks, guidelines recommend elective single embryo transfer as standard for most patients.[172][173] Double embryo transfer is associated with an increased risk of adverse obstetric and perinatal outcomes, even when the result is a singleton birth.[174] In 2021, the final cumulative outcome per egg retrieval cycle in the US was 50.7% live births in women ages under 35 using their own eggs.[175] This declined with age: 36.3% for women ages 35-37 years; 23.3% for women ages 38-40 years; 7.9% for women ages over 40 years.[175] Age-related decline is less significant in embryo transfer cycles using donor eggs or embryos (range 37.4% to 50.0% across all recipient ages) because donors are typically in their 20s or early 30s.[10] There are international variations in success rates for assisted reproductive techniques. Local guidance documents should be consulted.[176][177]
IUI can be performed on a natural cycle or coupled with controlled ovarian stimulation, such as an oral ovulation induction agent or gonadotropins. The treatment involves depositing a washed and prepared sperm sample, from either a partner or a donor, directly into the uterine cavity timed closely around ovulation. The prerequisites for this treatment method are at least a single patent fallopian tube, confirmation of ovulation and optimal semen parameters. IUI is less invasive and expensive compared with IVF but is offset by a lower success rate and the necessity of multiple cycles. Its success rate can be increased if it is performed with controlled ovulation stimulation, paying extra attention to the risk of multiple pregnancy, if growth of more than one follicle is observed. This assisted fertility treatment option has become more popular in recent years, especially amongst single women and same sex female couples. It can also be offered to women who have difficulty in having vaginal intercourse or couples who are viral discordant and at risk of potential transmission.[1]

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