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What is the Best Fertility Drug to Get Pregnant

What is the Best Fertility Drug to Get Pregnant/ Infertility means not having children after one year of regular sexual life without the use of contraception techniques (rx). Infertility is one of the major health care problems in all societies worldwide. The average prevalence of infertility in developed countries is 3.5-16.7% and in developing countries is 6.9-9.3% (rx). The overall average of infertility was reported 13.2% in Iran (rx). Causes of infertility are numerous such as anatomical, physiological and genetic factors. Many environmental and acquired factors also influence fertility and may lead to infertility. Menstrual and ovulation dysfunction and uterine factors are the most common causes of impairment in fertility. Etiology of infertility prevalence and patterns of causes of infertility in different regions are diverse. This discrepancy is due to the existence of differences in environmental conditions associated with reproductive behaviors, such as age at marriage, environmental pollution, smoking, and alcohol abuse, changing in lifestyle and diet (rx).

Treatment of Infertility

Initial treatment

Cap: Carbonail iron, Folic Acid, Vitamin B complex, Vitamin C ( 1+0+0)………….3 month

Cap: Vitamin E, Vitamin C ( 1+0+1)………….3 month

Tab: Metformin 500mg (0+1+0)……………..3 month

In women with ovulatory disorders, clomifene and metformin increase ovulation and pregnancy rates. There is some evidence that tamoxifen may have similar efficacy to clomifene, but we found no RCTs of sufficient quality comparing tamoxifen with placebo, and it is rarely used nowadays.

Gonadotrophins may increase pregnancy rates but may increase ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies.
Laparoscopic ovarian drilling may be as effective as gonadotrophins.
We don’t know whether pulsed gonadotrophin-releasing hormone (GnRH), or gonadotrophin priming of oocytes before in vitro maturation increase pregnancy rates.
Consensus suggests that in vitro fertilization may lead to pregnancy, but increases the risks of multiple pregnancies unless single embryo replacement is practiced.
We don’t know whether GnRH agonists plus gonadotrophins increase pregnancy rates compared with gonadotrophins alone but the combination treatment may be associated with an increased risk of OHSS. We don’t know how effective GnRH antagonists are because we found few trials.
We don’t know whether intrauterine insemination alone or combined with gonadotrophins or clomifene is effective for infertility caused by ovulation disorders.

In women with tubal infertility, tubal flushing may increase pregnancy rates, with oil-soluble media possibly more effective than water-soluble media; however, we found few trials solely in women with tubal infertility.

Tubal surgery before in vitro fertilization may increase pregnancy rates compared with no treatment in women with hydrosalpinges, but we don’t know whether selective salpingography plus tubal catheterization is beneficial.
Consensus suggests that in vitro fertilization is beneficial.

In women with endometriosis, adding gonadotrophins to intrauterine insemination increases live birth rates compared with no treatment and increases pregnancy rates compared with intrauterine insemination alone.

Laparoscopic ablation[rx] of endometrial deposits may increase live birth rates compared with diagnostic laparoscopy.
Drugs to induce ovarian suppression[rx] may not increase pregnancy rates.
Consensus suggests that in vitro fertilization [rx] may be beneficial.
Tubal flushing with oil-based media may increase live birth rates and pregnancy rates in women with minimal or mild endometriosis.

In women with unexplained infertility, clomifene [rx] does not increase live birth rates. It is not better than expectant management.

Intrauterine insemination without ovarian stimulation[rx] does not result in a significant increase in live birth rates.
Intrauterine insemination plus controlled ovarian stimulation [rx] may increase pregnancy rates but may increase OHSS and multiple pregnancies.
In vitro fertilization [rx] may be beneficial, however, the evidence is insufficient to make any conclusions.

Medications and their respective effects on both male and female reproductive function

Medication	Effect on reproductive function
Anabolic Steroids	Impairment of spermatogenesis (up to one year recovery); may cause hypogonadism through pituitary–gonadal axis
Anabolic Steroids	Reversible
Antiandrogens:	Impairment of spermatogenesis; erectile dysfunction
Cyproterone acetate, danazol, finasteride, ketoconazole, spironolactone	Reversible
Antibiotics:	Impairment of spermatogenesis
Ampicillin, cephalothin, cotrimoxazole, gentamycin, neomycin, nitrofurantoin, Penicillin G, spiramycin	Reversible
Antibiotics:	Impairment of sperm motility
Cotrimoxazole, dicloxacillin, erythromycin, lincomycin, neomycin, nitrofurantoin, quinolones, tetracycline, tylosin	Impairment of sperm motility
	Reversible
Antiepiletics:	Impairment of sperm motility
Phenytoin	Reversible
Antihypertensives:	Fertilization failure
Calcium channel blockers (nifedipine)	Fertilization failure
Antihypertensives:	Erectile dysfunction
Alpha agonists (clonidine), alpha blockers (prazocin), beta blockers, hydralazine, methyldopa, thiazide diuretics	Erectile dysfunction
Anti-inflammatory 5-ASA and derivatives:	Impairment of spermatogenesis and sperm motility
Mesalazine, sulfasalazine	Reversible
Antimalarials:	Impairment of sperm motility
Quinine and its derivatives	Reversible
Antimetabolites ⁄ Antimitotics:	The arrest of spermatogenesis; azoospermia
Antimetabolites ⁄ Antimitotics:	Irreversible
Colchicines, cyclophosphamide	Irreversible
Anti-oestrogens	Impairment of endometrial development
Clomiphene citrate	reversible
Anti-progestins:	Impairment of both implantation and tubal function
Emergency contraceptive pills, progesterone-only pills	Impairment of both implantation and tubal function
Antipsychotics:	Increase prolactin concentrations that can lead to sexual dysfunction
Alpha blockers, phenothiazine, antidepressants (particularly SSRIs)
Antipsychotics:	Impairment of spermatogenesis and sperm motility
Butyrophenones	Reversible
Antischistozomal:	Impairment of spermatogenesis and sperm motility
Niridazole	Reversible
Corticosteroids	Impairment of sperm concentration and motility
Corticosteroids	Reversible
Exogenous testosterone, GnRH analogues	Impairment of spermatogenesis
Exogenous testosterone, GnRH analogues	Reversible
H2 blockers:	Increase prolactin concentrations that can lead to impairment of luteal function, loss of libido, and erectile dysfunction
Cimetidine, ranitidine
Local anaesthetics, halothane	Impair sperm motility
Metoclopramide	Erectile dysfunction
Methadone	Suppress spermatogenesis and sperm motility
Non-steroidal anti-inflammatory drugs, Cox-2 inhibitors	Impairment of follicle rupture, ovulation, and tubal function
Non-steroidal anti-inflammatory drugs, Cox-2 inhibitors	Reversible

Gonadotropin-Releasing Hormone (GnRH)

The pulsatile release of GnRH in the hypothalamus stimulates the release of FSH and LH from the anterior pituitary. In men, normal levels of FSH and LH are responsible for induction of spermatogenesis and maintaining high levels of testicular T (rx).
Pulsatile administration of GnRH is an effective treatment to replace GnRH deficiency in infertile men with hypogonadotropic hypogonadism (HH) due to a lack of secretion from the hypothalamus (e.g., Kallmann’s syndrome, idiopathic HH). Men with HH have reduced fertility that is usually restored by reestablishing the high intra-testicular T and the FSH stimulation of Sertoli cells (rx).
The goal of GnRH therapy is to stimulate the release of gonadotropins from the anterior pituitary and subsequent pathways in the HPG (rx). The most effective dose for pulsatile G

Gonadotropins

The treatment of male infertility in men with pituitary insufficiency (e.g., pituitary adenoma, systemic diseases such as hemochromatosis and sarcoidosis) is based on the use of gonadotropins, therefore spermatogenesis and T production cannot be induced by pulsatile GnRH. Gonadotropins were previously extracted from urine. With advancement in laboratory technology, human chorionic gonadotropin (rec-hCG), FSH (rec-hFSH) and LH (rec-hLH) or highly purified urinary gonadotropins are used with superior quality, activity and performance. There have been no confirmed differences in the safety, purity, or clinical efficacy among the various available highly purified or recombinant gonadotropin products (rx).

Dopamine agonist

For men presenting with infertility and hyperprolactinemia, prolactin-secreting pituitary adenoma (most common functional tumors) should be considered as the underlying cause. Tumors that cause stalk compression and hyperprolactinemia should not be treated with a dopamine agonist.
Elevated levels of prolactin inhibit the pulsatile secretion of GnRH, men will present with hypogonadism and infertility, and they might also experience headaches or visual field changes secondary to the pituitary tumor compression.
In this setting, dopamine agonists are indicated for the treatment of infertility and the pituitary tumor. Both bromocriptine and cabergoline have been used in the past. However, there is evidence that cabergoline is more effective than bromocriptine in suppressing prolactin production (rx), and has been shown to normalize prolactin levels in 70% of bromocriptine-resistant patients (rx).

Aromatase inhibitor (AI) therapy

AI treatment of men with idiopathic OAT or azoospermia is an off-label use of this medication. AIs (anastrozole 1 mg daily, or letrozole 2.5 mg daily) increase T, decrease estrogen levels, and inhibit the peripheral metabolism of T. The intent is to reduce the estrogenic effect on spermatogenesis. High estrogen levels in combination with low T levels have been shown to impair proper spermatogenesis (rx).
More importantly, elevated levels of estrogen will lead to feedback inhibition of the HPG axis, and the end result is a decrease in the LH necessary for the production T, and FSH to optimize sperm production (rx).
The activity of aromatase inhibition regardless of patient BMI suggests that aromatase activity in the Leydig cells is responsible for the T to estradiol (E) conversion and impaired semen parameters (rx,rx).

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Selective Estrogen Receptor Modulators (SERMs)

SERMs are a class of compounds that act on the estrogen receptor as agonists or antagonists. Before the introduction of intracytoplasmic sperm injection, SERM’s where one of the few options available for men with idiopathic infertility.
While SERMs, such as clomiphene citrate (CC), tamoxifen, and toremifene, have been widely used in women for the treatment of breast cancer and osteoporosis, their use in the treatment of male hypogonadism and infertility is currently off-label.
CC, like other SERMs, inhibits central estrogen feedback (rx) and upregulates the production of LH and FSH, leading to induction of spermatogenesis. Because CC encompasses both a strong intrinsic estrogenic and anti-estrogenic properties, there is concern that the estrogenic effect of clomiphene can potentially have a deleterious effect on spermatogenesis.
However, studies have shown that, in hypogonadal men, clomiphene can have substantial positive effects on serum T (rx), and can increase pregnancy rates (rx).

Tamoxifen citrate

Other similar compounds toremifene and raloxifene are non-steroidal estrogen receptor antagonists with a similar mechanism of action as CC at the level of the hypothalamus and pituitary.
Randomized controlled trials in men with oligospermia or azoospermia examining the efficacy of tamoxifen (20 mg daily) or toremifene and raloxifene (60 mg daily) have reported improvements in semen parameters and pregnancy rates following three months of treatment (rx). However, other studies have shown improvements in the biochemical profile with no effect on semen parameters or fertility outcomes (rx).

Methotrexate (MTX)

Administration either intramuscularly or in the ectopic sac. MTX is a chemotherapeutic drug given at a dose of 1 mg/kg or based on the surface area calculation of 50 mg/m². It may be given in single or multiple doses.
There are currently no randomized controlled trials comparing medical treatment versus salpingectomy. Appropriate patient selection is the crux of successful treatment with MTX. β-hCG levels, size of the ectopic mass, and the presence or absence of yolk sac on ultrasound determine the success of medical therapy.

Metformin

For assisted reproduction cycles, metformin use prior to or during ovarian stimulation with gonadotropins in IVF/ICSI cycles is also not associated with better clinical pregnancy or live birth rates; however, metformin may reduce the risk of OHSS ^[rx] and miscarriage and improve the implantation rate because metformin may act directly on the endometrium ^[rx] and promote better reproductive outcomes (data not confirmed) in women with PCOS ^[rx]. However, as previously mentioned, the use of a GnRH antagonist combined with ovarian stimulation with gonadotropins in women with PCOS and the induction of final ovarian maturation with a GnRH agonist with subsequent embryo cryopreservation are more effective strategies to prevent OHSS regardless of metformin use ^[rx]. Thus, the routine use of metformin in cycles of ovarian stimulation for IVF in women with PCOS is not recommended except in the presence of a disorder in glucose metabolism ⁹.

Aromatase inhibitors

Although aromatase inhibitors have been used in women with PCOS as an alternative method to avoid the anti-estrogenic effect of CC on the endometrium, these compounds are not typically used in clinical practice to treat infertility in these patients. Their mechanism of action is based on reducing the peripheral conversion of androgens to estrogens in ovarian granulosa cells by blocking aromatase. Consequently, a decrease in estrogen serum levels and in its negative feedback in the hypothalamus and pituitary gland is noted, resulting in increased endogenous gonadotropin release ^[rx].

Counseling

Fertility clinics should address the psycho-social and emotional needs of infertile couples as well as their medical needs. The content of counseling may differ depending on the concerned couple and the existing treatment options. It usually involves treatment implication counseling, emotional support counseling, and therapeutic counseling [rx,rx].

Reviewed medical treatment of male infertility

Substance	Administration	Dosage and frequency	Current availability
GnRH	Subcutaneous infusion pump	25-200 ng/kg per pulse every 2 hours	Only in specialty centers or part of clinical trials
Human chorionic-gonadotropin (hCG)	Subcutaneous/intramuscular	1,500-3,000 IU 2 times/week	Available, FDA approved for treatment of infertility due to gonadotropin deficiency
Human menopausal gonadotropin (hMG)	Subcutaneous/intramuscular	75 IU 2-3 times/week	Available, FDA approved for treatment of infertility due to gonadotropin deficiency
Highly purified or recombinant human follicle-stimulating hormone (rhFSH)	Subcutaneous/intramuscular	100-150 IU 2-3 times/week	Available, FDA approved for treatment of infertility due to gonadotropin deficiency
Dopamine agonist	Oral	Cabergoline (0.5-1 mg twice weekly), bromocriptine (2.5-5.0 mg twice weekly)	FDA approval for treatment of hyperprolactinaemia

A study headed by Hayashi, Miyata, and Yamada investigated the effects of antibiotics, antidepressants, antiepileptics, β stimulators, H1 and H2 receptor antagonists, mast cell blockers, and sulfonylurea compounds (n = 201) [rx]. Male participants were divided so one group had medication switched or stopped and the other served as the control.

Marijuana – is one of the most commonly used drugs around the world [rx], and it acts both centrally and peripherally to cause abnormal reproductive function. Marijuana contains cannabinoids which bind to receptors located on reproductive structures such as the uterus or the ductus deferens. In males, cannabinoids have been reported to reduce testosterone released from Leydig cells, modulate apoptosis of Sertoli cells, decrease spermatogenesis, decrease sperm motility, decrease sperm capacitation and decrease acrosome reaction [rx].
Cocaine – a stimulant for both peripheral and central nervous systems which causes vasoconstriction and anesthetic effects. It is thought to prevent the reuptake of neurotransmitters [rx], possibly affecting behavior and mood. Long term users of cocaine claim that it can decrease sexual stimulation; men found it harder to achieve and maintain erection and to ejaculate [rx]. Cocaine has been demonstrated to adversely affect spermatogenesis, which may be due to serum increases in prolactin, as well as serum decreases in total and free testosterone [rx,rx]. Peugh and Belenko suggest that the effects of cocaine in men depend on dosage, duration of usage, and interactions with other drugs [rx]. While less is known about cocaine’s effects on females, impaired ovarian responsiveness to gonadotropins and placental abruption have both been reported [rx–rx].
Opiates – comprise another large group of illicit drugs. Opiates, such as methadone and heroin, are depressants that cause both sedation and decreased pain perception by influencing neurotransmitters [rx]. In men taking heroin, sexual function became abnormal and remained so even after cessation [rx]. Sperm parameters, most noticeably motility, also decrease with the use of heroin and methadone [rx,rx]. In women, placental abruption with the use of heroin may also be a cause of infertility [rx].
Antioxidant – Increased rates of infertility have been found in men with the seminal fluid containing high levels of reactive oxygen species (ROS) (rx). These ROS are associated with sperm dysfunction, germ cell DNA damage with the possibility of impaired fertility, but the exact mechanism is not completely understood. These associations have led clinicians to treat infertile men with antioxidant supplements. A variety of clinical trials have suggested that the use of antioxidant supplements have a slight benefit in improving sperm function and DNA integrity. However, most of these studies are not randomized controlled trials, and to date, there are no convincing trials that have demonstrated a significantly higher unassisted pregnancy rate after treating men with antioxidant therapy (rx).

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Assisted Conception

The following methods are currently available for assisted conception.

Intrauterine insemination (IUI) – At the time of ovulation, a fine catheter is inserted through the cervix into the uterus to place a sperm sample directly into the uterus. The sperm is washed in a fluid and the best specimens are selected. The woman may be given a low dose of ovary stimulating hormones. IUI is more commonly done when the man has a low sperm count, decreased sperm motility, or when infertility does not have an identifiable cause. It can also help if a man has severe erectile dysfunction.
In-vitro fertilization (IVF) – Sperm are placed with unfertilized eggs in a petri dish, where fertilization can take place. The embryo is then placed in the uterus to begin a pregnancy. Sometimes the embryo is frozen for future use.
Intracytoplasmic sperm injection (ICSI) – A single sperm is injected into an egg to achieve fertilization during an IVF procedure. The likelihood of fertilization improves significantly for men with low sperm concentrations.
Sperm or egg donation – If necessary, sperm or eggs can be received from a donor. Fertility treatment with donor eggs is usually done using IVF.
Assisted hatching – The embryologist opens a small hole in the outer membrane of the embryo, known as the zona pellucid. The opening improves the ability of the embryo to implant into the uterine lining. This improves the chances that the embryo will implant at, or attach to, the wall of the uterus. This may be used if IVF has not been effective, if there has been poor embryo growth rate, and if the woman is older. In some women, and especially with age, the membrane becomes harder. This can make it difficult for the embryo to implant.
Electric or vibratory stimulation to achieve ejaculation – Ejaculation is achieved with electric or vibratory stimulation. This can help a man who cannot ejaculate normally, for example, because of a spinal cord injury.
Surgical sperm aspiration – The sperm is removed from part of the male reproductive tract, such as the vas deferens, testicle, or epididymis.

Surgical Treatment

Surgery’s aim is to remove macroscopic endometriosis implants and restore normal pelvic anatomy. However, surgery may not be able to completely restore pelvic anatomy or to stop the inflammatory process. Hence, it is important to weigh up benefits versus harm to the surgical procedure. Laparoscopy is preferred to laparotomy because of advantages of minimal tissue damage, or magnification, of faster recovery, and shorter hospital stay (rx).

Is there a benefit of surgical treatment of stage I–II of endometriosis and successful pregnancy rate?

Several studies demonstrated that, in infertile women with endometriosis stage I/II of the American Fertility Society/American Society for Reproductive Medicine (AFS/ASRM), clinicians should perform operative laparoscopy (excision or ablation of endometriosis lesions) including adhesiolysis, rather than performing diagnostic laparoscopy only, since there is a positive effect in regards to living birth and ongoing pregnancy at 20 weeks of amenorrhea (rx, rx).
According to ESHRE guidelines, and concerning the management of women with stage I–II of endometriosis, clinicians may consider CO₂ laser vaporization of endometriosis, instead of monopolar electrocoagulation, since laser vaporization is associated with higher cumulative spontaneous pregnancy rates (rx).

Is there a benefit of surgical treatment of stage III–IV of endometriosis and successful pregnancy rate?

There is no randomized controlled trial or meta-analysis to assess whether surgery is positively effective or not on pregnancy rates in moderate to severe endometriosis. The lack of randomized trials or meta-analysis is not due to lack of research effort but to the unethical aspect of such studies that is to do nothing to a patient with stage III or IV endometriosis who is already under anesthesia could be ethically unacceptable.

How should we behave with ovarian endometrioma in case of infertility?

According to the ESHRE Guideline (rx) in infertile women with ovarian endometrioma of >3 cm in size, surgeons should perform excision of endometrioma capsule instead of ablative surgery that is drainage and electrocoagulation of the endometrioma wall since it increases the spontaneous postoperative pregnancy rate.
Excision of endometriomas involves the opening of the cyst (using scissors or electrosurgical or laser energy). After identifying the plane of cleavage between the cyst wall and ovarian tissue, the cyst wall is then excised or “stripped away” by applying opposite bimanual traction and counter actin with two grasping forceps. The ovarian edges could be sutured or inverted by light application of bipolar coagulation or kept as they are. Ablative surgery also involves the opening and drainage or fenestration (making a window in the wall of the cyst) of the endometrioma, followed by the destruction of the cyst wall using either electrosurgical current, cutting or coagulating current or a form of laser energy.

Is there any association between endometrioma and risk of ovarian cancer?

The ESHRE’s GDG concluded that there is no evidence that endometriosis causes cancer, though some cancers are slightly more common in women with endometriosis such as non-Hodgkin’s lymphoma and ovarian cancer (rx).
A very large study (rx) showed a higher risk of histological subtypes of ovarian cancer in case of endometriosis. Self-reported endometriosis was associated with significantly increased risk of clear cell ovarian cancer, low-grade serous ovarian cancer, and endometrial invasive ovarian cancer. Clinicians should be aware of this increased risk and future efforts should be focused on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.

Prevention

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. The 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.^[rx] 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.^[rx]

Some strategies suggested or proposed for avoiding male infertility include the following:

Avoiding smoking^[rx] as it damages sperm DNA
Avoiding heavy marijuana and alcohol use.^[rx]
Avoiding excessive heat to the testes.^[rx]
Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity^[rx] and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).^[rx]
Wearing a protective cup and jockstrap to protect the testicles, in any sport such as baseball, football, cricket, lacrosse, hockey, softball, paintball, rodeo, motocross, wrestling, soccer, karate or other martial arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin.
Diet – Healthy diets (i.e. the Mediterranean diet) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality.

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Glossary

Anovulation	is the failure to ovulate (expel a mature oocyte) owing to dysfunction of the ovary or suppression by drug treatment. Anovulation is a common cause of female infertility. Most often, women who do not ovulate also do not menstruate (amenorrhoea).
Assisted hatching procedure	Assisted hatching is a process to breach the zona pellucida of an embryo, by either laser or chemical processes, potentially to improve its implantation potential.
Delayed in vitro fertilisation	In vitro fertilisation treatment after 6 months of being assessed in an infertility clinic after at least 12 months of infertility.
Endometriosis	is a progressive disease that occurs when the endometrial tissue lining the uterus grows outside the uterus and attaches to the ovaries, fallopian tubes, or other organs in the abdominal cavity. Symptoms include painful menstrual periods, abnormal menstrual bleeding, and pain during or after sexual intercourse.
Gonadotrophin priming of oocytes	This is the in vitro maturation of oocytes using gonadotrophins (hormones stimulate and control reproductive activity) from the germinal vesicle (early) stage of development to the metaphase II (mature) stage.
High-quality evidence	Further research is very unlikely to change our confidence in the estimate of effect.
Hydrosalpinges	is the abnormal distension of one or both fallopian tubes owing to fluid build up, usually because of inflammation.
Hydrotubation	Flushing of the fallopian tubes through the cervix and uterine cavity to remove surgical debris and reduce the incidence of tubal reocclusion.
Immediate in vitro fertilisation	In vitro fertilisation treatment within 6 months of being assessed in an infertility clinic after at least 12 months of infertility.
In vitro fertilisation	(IVF) is a technique where female oocytes (eggs) are fertilised with sperm from a male partner outside the body in a fluid medium in the laboratory. Embryos are transferred later to the uterus using a special catheter.
Long agonist protocol	is the most widely used protocol for an in vitro fertilisation (IVF) cycle, which involves starting the gonadotrophin-releasing hormone (GnRH) agonist usually on the 21st day of the menstrual cycle. Ovarian stimulation with follicle-stimulating hormone (FSH) then starts a couple of days after the onset of menstruation.
Low-quality evidence	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Macrosurgery	Surgery without dedicated optical magnification.
Microsurgery	Surgery involving optical magnification to allow the use of much finer instruments and suture material in addition to a non-touch technique, with the aim of minimising tissue handling and damage.
Moderate-quality evidence	Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Ovarian hyperstimulation syndrome (OHSS)	can occur in mild, moderate, and severe forms. Mild ovarian hyperstimulation syndrome is characterised by fluid accumulation, as shown by weight gain, abdominal distension, and discomfort. Moderate ovarian hyperstimulation syndrome is associated with nausea and vomiting, ovarian enlargement, abdominal distension, discomfort, and dyspnoea. Severe ovarian hyperstimulation syndrome is a life-threatening condition, in which there is contraction of the intravascular volume, tense ascites, pleural and pericardial effusions, severe haemoconcentration, and the development of hepatorenal failure. Deaths have occurred, caused usually by cerebrovascular thrombosis, renal failure, or cardiac tamponade.
Ovulation disorders	are defined by the failure of an ovum to be expelled owing to a malfunction in the ovary. Ovulation disorders are a major cause of infertility and can often be corrected with medication. Ovulation disorders often result in infrequent menstruation (oligomenorrhoea).
Pituitary downregulation (long protocol)	This is the process by which the release of gonadotrophins from the pituitary gland is stopped after repeated administration of gonadotrophin-releasing hormone (GnRH) analogues; this in turn controls reproductive function.
Polycystic ovary syndrome (PCOS)	results from an accumulation of incompletely developed follicles in the ovaries owing to chronic anovulation. PCOS is characterised by irregular or absent menstrual cycles, multiple small cysts on the ovaries (polycystic ovaries), mild hirsutism, and infertility. Many women also have increased insulin resistance.
Pulsatile gonadotrophin-releasing hormone	is a hormone produced and released by the hypothalamus at intervals (pulses). Pulsatile gonadotrophin-releasing hormone controls the production and release of gonadotrophins from the pituitary gland, which in turn controls reproductive function.
Salpingography	is a technique used to diagnose blockages in the fallopian tubes. It involves the radiographic imaging of the fallopian tubes after the injection of radio-opaque contrast medium (dye) through the cervix to the uterine cavity. If the fallopian tubes are open the dye flows into the tubes and then spills out to the abdominal cavity. This is documented in a series of x-ray images during the procedure. If tubes are blocked from the proximal end, a very narrow catheter is introduced under radiographic imaging (selective salpingography and tubal catheterisation) to remove the obstruction if possible.
Second look laparoscopy	Laparoscopy performed some time after tubal surgery (either open or laparoscopic) with the aim of dividing adhesions relating to the initial procedure.
Tubal flushing	involves injecting an oil or water soluble contrast medium into the fallopian tubes to flush out any blockages in the tubes. Flushing out any tubal “plugs” that may be causing proximal tubal occlusion using oil or water soluble media may have a fertility enhancing effect.
Tubal infertility	is the inability to conceive owing to a blockage in one or both fallopian tubes and is a common cause of infertility. The tubal blockages are usually caused either by pelvic infection, such as pelvic inflammatory disease (PID) or endometriosis. Blockages may also be caused by scar tissue that forms after pelvic surgery.
Tubal surgery	techniques are used to restore the patency of the fallopian tubes in women with tubal infertility as an alternative to in vitro fertilisation. Surgery may either be open microsurgery or laparoscopic microsurgery.
Very low-quality evidence	Any estimate of effect is very uncertain.