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.