Summary: Levels of Evidence of Statements

The initial growth of primordial follicles (also referred to as primary recruitment) is random, being independent of FSH. The cohort size of healthy early antral follicles recruited during the luteofollicular transition is around 10 per ovary.

3

Inhibin A, secreted by maturing follicle and corpus luteum, has a direct endocrine role in the negative feedback on pituitary FSH production.

2b

Although the LH surge is believed to be the physiological signal for peri-ovulatory events, a mid-cycle bolus of FSH can replace LH and elicit oocyte maturation, ovulation, early luteinization of granulosa cells, and successful pregnancy.

2b

The major roles of E2 on uterine endometrium are for endometrial growth and for enabling P to act on the tissue.

2b

Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion (5,6).

2b

Chronic anovulation is a major cause of subfertility.

3

Chances for ovulation and pregnancy decrease when the duration of the menstrual cycle is prolonged.

3

Establishing the diagnosis of PCOS is complicated in adolescents and menopausal women.

4

Patients with less severe metabolic derangement will be added to the PCOS group using the Rotterdam criteria instead of the NIH criteria.

3

WHO class 1 anovulation results from either congenital or acquired causes.

4

Based on the presence or absence of an olfaction defect, CHH is divided into two groups: CHH with anosmia/hyposmia and idiopathic CHH with normal olfaction.

4

Beside anosmia/hyposmia, Kallmann syndrome may include craniofacial, neurosensorial, and dysmorphic anomalies.

4

FHA represents 15% of cases of secondary amenorrhea and is the second leading cause of acquired HH after hyperprolactinemia.

4

FHA is a reversible form of GnRH deficiency due to a negative energy balance.

4

30%–50% of patients with FHA have polycystic ovarian morphology at ultrasound without real PCOS.

4

Most anovulatory women with normal gonadotrophin and estradiol levels have PCOS.

3

Normogonadotropic normoestrogenic anovulation without PCOS may be caused by other endocrine disorders, for example, thyroid disease, hyperprolactinemia, pathology of the adrenal gland.

3

Long-term health consequences in women with normogonadotropic normoestrogenic anovulation but without PCOS are unknown.

4

PCOS is diagnosed by two of these three criteria: hyperandrogenism, oligomenorrhea, or polycystic ovaries.

5

Oligomenorrhea and polycystic ovaries are common among adolescent women and confound the diagnosis in this age group.

2

Women with PCOS are at increased risk for infertility.

1a

Women with PCOS share many of the risk factors for endometrial cancer and may be at increased risk.

3a

Obesity is associated with increased metabolic risk and hyperandrogenism.

1a

Women with PCOS have an increased prevalence of anxiety and depression.

2a

Women with PCOS have an increased prevalence of cardiovascular risk factors, including family history of early cardiovascular disease, cigarette smoking, impaired glucose tolerance or type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, and obesity (especially increased abdominal adiposity).

2a

Despite the adverse cardiometabolic profile, there are not clear data supporting early onset or increase prevalence of cardiovascular events.

2c

Alkylating agents induce POI in 40%–50% of women.

3

Chemotherapeutic agents damage the ovary by increasing follicle loss.

2b

The most common genetic cause of POI is chromosome X abnormalities.

2b

POF1 and POF2 regions located on Xq chromosome are necessary for ovarian follicle maintenance.

2a

POI is associated with familial or personal history of autoimmune diseases in 4%–5% of patients.

3

Premutation of FRM1 gene is present in 13% of familial cases of POI.

2b

NOBOX mutation is present in 5%–7% of POI patients.

2b

More than 30 genes have been identified so far as candidate genes in human POI.

2b

CAHs influence reproduction, either as the consequence of adrenal androgen excess or as the result of a severe deficiency in the synthesis and secretion of gonadal steroids.

2a

Patients with 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and steroidogenic acute response protein/20-22 desmolase deficiencies present with female hypogonadism or male pseudohermaphroditism, and most are infertile.

3

The presentation of nonclassic CAH may be indistinguishable from functional forms of female hyperandrogenism.

2a

Infertility is common in classic CAH, and its severity parallels that of the enzymatic deficiency.

2a

Many women with classic CAH never try to conceive.

2a

Increased androgen concentrations and increased non-cycling progesterone levels in women and inhibition of gonadotropin secretion and testicular adrenal rest tumors in men may contribute to infertility.

2b

Intensification of replacement therapy in women with classic CAH results in pregnancy rates comparable to that of the normal population, yet the fertility rates are much lower.

2b

A significant number of women with classic CAH require ovulation induction or assisted reproductive technology to conceive.

2a

Fertility is not severely compromised in nonclassic CAH, and many patients conceive spontaneously.

2b

If glucocorticoid replacement is not useful in restoring ovulation in women with nonclassic CAH, clomiphene or gonadotropins can be used.

2b

Carrier frequencies for alleles causing classic 21α-hydroxylase deficiency are approximately 1:60, and the risk of a patient with classic 21α-hydroxylase deficiency of having a child with classic CAH is 1:20.

2a

Women with nonclassic 21α-hydroxylase deficiency may give birth to a fetus affected with classic 21α-hydroxylase deficiency because they frequently are compound heterozygotes for mild and severe mutations.

2b

Experimental prenatal treatment with exogenous dexamethasone may prevent virilization of affected female fetuses in approximately 80%–85% of cases.

2b

This treatment is currently being questioned because dexamethasone may have significant maternal and fetal side effects.

2a

Thyroid dysfunction is associated with menstrual disturbances.

3

Treatment of thyroid dysfunction will restore menstrual cyclicity.

2b

Ovulation induction with clomiphene citrate and tamoxifen has uncertain effects on thyroid function.

4

Ovulation induction with gonadotrophins leads to a lowering in f T4 in women with thyroid autoimmunity.

1b

Dynamic testing to evaluate hyperprolactinemia should not be applied.

1b

A single prolactin assessment for the diagnosis of hyperprolactinemia is enough.

1b

Other causes of hyperprolactinemia should be excluded.

1a

Asymptomatic hyperprolactinemia does not need any treatment.

4

Microprolactinoma that only have irregular menses can be treated with oral contraceptives or cabergoline.

4

Cessation or switch of medication causes hyperprolactinemia.^b

2b

Symptomatic micro- and macroadenomas should be treated with dopamine agonist.

1c

Cabergoline is the drug of choice because it has the highest efficacy in normalizing prolactin and tumor shrinkage.

1c

Women with prolactinomas need to discontinue dopamine agonist as soon as they know that they are pregnant.

3b

During pregnancy, prolactin assessment in prolactinoma patients is redundant.

1b

If dopamine agonists are indicated during pregnancy, bromocriptine is the drug of choice.

3a

Hypogonadotropic hypogonadism is characterized by low levels of FSH, and LH along with low levels of estradiol; it is classified as WHO class 1 anovulation.

2

In HH (WHO class 1) patients, anosmia or hyposmia is suggestive for Kallmann syndrome.

2

Normogonadotropic normo-estrogenic anovulation is characterized by normal levels of FSH, LH, and estradiol; it is classified as WHO class 2 anovulation. The majority of these women also suffer from polycystic ovary syndrome (PCOS).

2

PCOS should be diagnosed according to the Rotterdam consensus.

3

According to the Rotterdam consensus, the diagnosis of PCOS should be made if two of the three following criteria are met: androgen excess, ovulatory dysfunction, or polycystic ovarian morphology (PCOM).

2

A normal bleeding interval is between 21 and 35 days.

3

Hirsutism is defined as a Ferriman-Gallwey score of 8 or higher. Biochemical hyperandrogenism is defined as an elevated testosterone level or an elevated free androgen index (FAI) [T × 100/SHBG].

3

PCOM is defined as an increased number of follicles per ovary. The cutoff depends on the frequency of the transducer used. In case a FNPO is not assessable, ovarian volume might be used.

2

Cutoff values for clinical and biochemical hyperandrogenism are laboratory and age as well as ethnicity dependent.

2

Other causes of anovulation (thyroid disease or hyperpolactinemia) or HA (classical and nonclassical forms of congenital adrenal hyperplasia, adrenal tumors, and Cushing’s disease) should be ruled out before the diagnosis of PCOS can be made.

2

Hypergonadotropic hypogonadism is characterized by elevated levels of FSH and LH along with low levels of estradiol; it is classified as WHO class III anovulation. The monotropic rise in FSH is pathognomonic in these patients.

2

Patients with POI typically present with primary or secondary amenorrhea.

2

POI is often accompanied by complaints, such as hot flashes, night sweats, neurocognitive complaints as well as sexual problems such as loss of libido and dyspareunia.

2

Assessment of AMH levels or AFC measurements might aid the diagnosis of anovulatory infertility.

3

Ovulation induction and controlled ovarian hyperstimulation are two different treatment options and should not be mixed up.

GPP

Controlled ovarian hyperstimulation in non-IVF should aim at achieving two to three follicles.

1a

COH-IUI should be a first-line treatment option in couples with mild male and unexplained subfertility when spontaneous chances of pregnancy are low.

1b

It remains unclear whether luteal support clearly improves cost-effectiveness of COH-IUI cycles.

1a

There is insufficient evidence to define which monitoring methods are the most safe and costeffective. US monitoring is the most advisable method for monitoring in OI.

4

The pregnancy-related diameter of the leading follicle in CC cycles varies between 18 and 22 mm.

3

The pregnancy-related diameter of the leading follicle in gonadotropin cycles varies between 17 and 21 mm.

3

There is insufficient evidence about a pregnancy related cutoff point for endometrium thickness in OI cycles.

3

There is insufficient evidence that US monitoring in CC cycles improves pregnancy rates. There is no sufficient evidence to suggest that US monitoring in CC cycles reduces multiple pregnancy rates.

1a

US monitoring in gonadotropin cycles is mandatory.

4

One relatively small comparative nonrandomized study showed a nonsignificant higher cumulative conception rate with the pulsatile GnRH and a nonsignificantly lower rate of multiple pregnancies.

3

Case studies show ovulation rate/cycle of 70%–100% and 38%–97% with pulsatile GnRH and gonadotropins, respectively.

3

Case studies show pregnancy rates/cycle of 9%–30% and 20%–93% with pulsatile GnRH and gonadotropins, respectively.

3

Case studies show multiple pregnancy rates of 0%–17% and 15%–38% with pulsatile GnRH and gonadotropins, respectively.

3

Pulsatile GnRH does not require hormonal luteal support treatment.

4

Pulsatile GnRH treatment requires simple once-a-month monitoring for verification of ovulation, resulting in less burden for the patient.

4

Ovarian hyperstimulation is a very rare if not absent side effect of pulsatile GnRH treatment.

4

Most reported side effect is local inflammation at injection site.

4

CC used for hypothalamic–pituitary dysfunction—WHO Group 2, mainly PCOS, increases ovulation and pregnancy rates compared with placebo.

1a

Clomiphene plus dexamethasone treatment is effective in increasing pregnancy rate compared to clomiphene alone.

1a

The routine addition of hCG in a CC cycle does not improve conception rates.

1a

CC is superior to metformin in achieving live birth in infertile women with PCOS.

1b

Letrozole produces higher live birth and pregnancy rates in subfertile women with anovulatory PCOS, compared to CC.

1a

No evidence of a difference in effect was found between clomiphene versus tamoxifen.

1a

Pregnancies and live births are achieved more effectively and faster after low-dose FSH versus CC for first-line treatment.

1b

There is no convincing evidence of an increase in the risk of ovarian tumors following CC treatment.

1a

Ovulation induction for PCOS patients with letrozole compared to clomiphene citrate (followed by timed intercourse) results in a significantly higher live birth rate for letrozole treatment.

1a

In a clomiphene citrate–resistant PCOS population, letrozole results in a comparable live birth rate to ovarian drilling.

1a

After a clomiphene failure in more than one cycle, for the purpose of ovulation induction, pregnancy rates are equivalent for letrozole versus gonadotropin injections.

1b

Higher pregnancy rates are achieved when the leading follicles are in the 23 to 28 mm range for letrozole ovulation induction cycles.

3

Compared to timed intercourse, IUI does not seem to increase the pregnancy rate in couples with PCOS and normal semen analysis treated with letrozole for ovulation induction.

3

Vaginal progesterone luteal support after letrozole ovulation induction may result in a higher clinical pregnancy rate in women with PCOS.

3

Metformin should not be first-line therapy for ovulation induction and should not be commenced until intensive lifestyle modification has been attempted.

1b

LEO is not superior to CC as a first-line treatment in anovulatory PCOS women.

1b

LEO and gonadotrophins are equally effective in inducing ovulation and generating pregnancies in CC-resistant PCOS women.

1a

LEO is associated with lower risks of multiple pregnancy compared to gonadotrophins.

1a

Four punctures (7–8 mm deep) per ovary with a power setting of 30–40 watts for 5 seconds per puncture seem to be the optimum dose of monopolar ovarian electrocautery.

2

Approximately, 50% of PCOS women continue to benefit from LEO for many years.

2

Both bipolar and monopolar techniques of LEO have proven long-term safety.

2

In women with WHO 2 anovulation as the main cause of infertility, the use of step-up protocols significantly reduces the risk of multiple pregnancies.

1a

The starting dose of gonadotropins and the risk of over-response can be assessed by prediction models.

1a

A frequent monitoring every 5–7 days using ultrasound assessment and hormonal determination is able to prevent the risk of over-response.

1b

The safety of low-dose and chronic low-dose protocols is higher than the conventional one.

1b

Small FSH dose increments of 50% of the initial or previous FSH dose are less likely to result in excessive stimulation.

1b

When more than three growing follicles are observed on ultrasound in young women, the risk of multiple pregnancies is increased.

1b

The concomitant use of a GnRH agonist and gonadotropins does not improve pregnancy rates and is associated with an increased risk of OHSS.

1a

The introduction of GnRH antagonist during stimulation for WHO 2 anovulation is not absolutely required except in presence of premature progesterone elevation.

1b

Modest weight loss achieved by lifestyle modification in overweight/obese women with WHO 2 anovulation contributes to resumption of ovulation.

2a

Limiting weight gain in women who are overweight or obese by means of lifestyle modification during pregnancy improves obstetric outcomes.

1a

Lifestyle modification for weight loss should include a healthy diet (reduced calorie intake) and increased exercise in combination with behavior modification.

1a

Ovulation rates can reach up to 42% following ovulation induction.

1b

GnRH agonist pretreatment does not improve the results of ovulation induction.

1b

Estrogen therapy increased ovulation rate in a randomized trial, but this result is contradicted by smaller studies with a lower evidence level.

1b

Corticosteroid treatment may improve ovulation or pregnancy rates, but further research is required to substantiate this conclusion.

1b

Dehydroepiandrosterone does not improve the chances of ovulation or endocrine conditions in the ovary.

1b

Oocyte donation is more effective than ovulation induction for achieving pregnancy, but pregnancies following ovulation induction are more at risk for complications.

3

Success of ovulation induction has multiple dimensions and depends on the stage and strategy of treatment.

2a

For cost-effectiveness analysis, fertility treatments are more difficult than for other types of medical care.

4

The definition of success of ovulation induction in clinical research can differ from the definition of success in daily practice.

4

The purpose of ovulation induction is monofollicular growth and ovulation.

3

Multiple follicular development is associated with increased chances of (multiple) pregnancy.

1a

During ovulation induction, the chance of multiple follicle development is reduced by frequent monitoring and strict cancellation criteria.

3/4

Ultrasound as well as serum estradiol measurement can be utilized for monitoring follicle development during ovulation induction.

3

Low-dose gonadotropin protocols in ovulation induction decrease risk of multiple follicle development.

3

It is more difficult to accomplish monofollicular development in a patient with a more explicit PCOS phenotype.

3

Changes in endocrine milieu can decrease chances of multiple follicle development in ovulation induction.

1b

Using frequent monitoring and strict cancellation criteria during a low-dose step-up gonadotropin stimulation protocol results in 70%–80% monofollicular development.

3

OHSS with ovulation induction is a rare complication.

2b

Women with PCOS or previous OHSS can be identified as women at risk of developing OHSS with ovulation induction.

4

Prevent OHSS by using a step-up protocol for ovulation induction with gonodotrophin.

2b

u-hCG versus rec-hCG trigger does not increase OHSS for ovulation induction combined with IUI.

2a

Trigger with GnRH analog reduced OHSS compared to hCG.

2a

HES 6% infusion during the time of IUI when ultrasound free fluid is present can prevent OHSS symptoms.

4

Rescue IVF is a valid option in case of over-response to prevent the development of OHSS.

3

Dopamine agonists might be useful for reducing OHSS symptoms, but the evidence is limited.

2b

Pregnancy is more likely to occur with two follicles than with one in COS cycles (9).

1a

The risk of multiple pregnancies for two follicles as compared to one follicle increases by 6% (9).

1a

There is no difference in the risk of multiple pregnancies between anti-estrogens and gonadotropins in IUI programs (11).

1a

Long-lasting underexposure to estrogens may lead, in these circumstances, to osteoporosis (i.e., decreased bone mineral density [BMD]), mood and cognitive disturbances, and sexual dysfunction as well as accelerated cardiovascular aging and subsequent cardiovascular disease and, if left untreated, a reduced life span.

2

WHO 2 anovulation and especially PCOS are associated with obesity, insulin resistance, and metabolic syndrome; these women also have an increased risk to develop type 2 diabetes, hypertension, and probably cardiovascular disease.

2

WHO 1 anovulation is associated with osteopenia, osteoporosis, endothelial dysfunction, and dyslipidemia compared to healthy ovulatory women.

2

Women with HH present with significantly higher depression and anxiety and also sexual problems compared to healthy subjects.

2

HH women have lowered PBM because of their hypo-estrogenic state along with other factors, such as low calcium and vitamin D3 intake, undernutrition, and excessive exercise.

2

HH is associated with significant coronary artery disease and endothelial dysfunction.

2

WHO 1 patients present a particular susceptibility to common life events, restrictive disordered eating, depressive traits, and psychosomatic disorders.

2

Increased adiposity, particularly abdominal, is associated with HA and increased metabolic risk.

Women with PCOS are at an increased risk for developing impaired glucose tolerance and type 2 diabetes.

2

Weight loss is likely beneficial for both reproductive and metabolic dysfunction in this setting. Weight loss is likely insufficient as a treatment for PCOS in normal-weight women.

2

Women with PCOS suffer more often from psychological and behavioral disorders and reduced quality of life.

2

Women with PCOS share many of the risk factors associated with the development of endometrial cancer, including obesity, hyperinsulinism, type 2 diabetes, and abnormal uterine bleeding. Hence, they do have an increased lifelong risk for developing endometrial cancer.

2

Early menopause has been associated with increased CVD risk.

2

Women with early menopause are at higher risk of angina after myocardial infarction (MI), independent of comorbidities, severity and quality of care.

2

Bilateral oophorectomy leads to an increase in CVD as well as to an increase in neurological or mental diseases.

2

Women with POI experience more sexual dysfunction compared to healthy controls.

2

Women with POI are at risk for cognitive impairment.

2

Life expectancy in POI is about 2 years less than those who have menopause over 55 years, and this is thought to be due to an excess of deaths due to CVD, osteoporosis, and neurocognitive decline.

2

Nonhormonal therapies, such as SSRIs, serotonin and norepinephrine reuptake inhibitors, or gabapentin may have a role in the management of vasomotor symptoms in women who decline HRT or in whom HRT is contraindicated.

3

There is no evidence for the use of complementary or herbal preparations in POI.

2

Body mass index and hyperandrogenemia seem the predominant predictors for ovulation after CC treatment.

2a

Age and cycle history seem the predominant predictors pregnancy rate after CC treatment.

2a

Metformin might be effective as an adjuvant to CC in CRA patients.

2a

Patients with hyperandrogenism (T and FAI) and elevated BMI had decreased chances of conceive after LEO.

2a

Presence of the FSH receptor polymorphism might predict clomiphene resistance.

2a