Causes of Anovulation: WHO Class 1

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Causes of Anovulation: WHO Class 1

Camille Grysole and Didier Dewailly


WHO class 1 anovulation harbors the different anovulatory patients with a central origin (hypothalamic/pituitary) of their ovulatory dysfunction. After having easily eliminated hyperprolactinemia (HPRL) and before discussing a congenital hypogonadotropic hypogonadism (CHH), it is essential to keep in mind the other etiologies that can be either functional or organic.

According to the WHO classification, class 1 anovulation is characterized by low levels of serum estra-diol and gonadotropins. However, there is an important clinical variability, and the hormonal picture is not always typical, making this diagnosis not always as easy as it seems.

Overview of Existing Evidence

The WHO class 1 anovulation results from gonadotropic insufficiency. The hormonal features of WHO class 1 anovulation include low serum estradiol levels (i.e., <30 pg/ml with the most commonly used assays) associated with low or normal serum LH and FSH levels (i.e., <2 and <4 IU/L with the most commonly used assays, respectively). Congenital and acquired causes can be distinguished (LOE 4):

→  Congenital HH (CHH):

•  Kallmann syndrome

•  Normosmic CHH

→  Acquired HH:


•  Functional hypothalamic amenorrhea (FHA)

•  Other causes:

Sheehan syndrome


History of cerebral radiotherapy


Lymphocytic hypophysitis

Head trauma

Subarachnoid hemorrhage

Cushing syndrome


Iatrogenic HH (opiates, corticosteroids)


The prevalence of CHH, estimated between 1/10,000 and 1/14,000 in men, is considered to be two to five times lower in women. However, this frequency is underestimated due to the non-recognition of forms with partial pubertal development (LOE 4). CHH is characterized by partial or total absence of pubertal development due to inadequate secretion of pituitary gonadotropins (LH and FSH) from genetic origin in the absence of anatomic abnormalities of the hypothalamic–pituitary region and with a normal reserve of remaining pituitary hormones (1). The literature reports an increasing number of genes whose mutations are responsible for CHH. Based on the presence or absence of olfactory dysfunction, CHH is divided into two groups: CHH with olfactory impairment (called Kallmann syndrome, corresponding to abnormal migration of Gn-RH neurons with aplasia or hypoplasia of the olfactory bulbs), whose leading mutated genes are KAL1 and KAL2, and idiopathic CHH with normal olfaction (normosmic), whose most frequent mutations are in the Gn-RH-Receptor gene (1).

The diagnosis of CHH is made during the second decade of life when patients present with delayed puberty, primary or secondary amenorrhea, or during the third decade of life because of infertility. In more than 90% of cases, CHH is revealed by primary amenorrhea. The development of thelarche and adrenarche varies. It is usually present but only partially. In Kallmann syndrome, besides anosmia/hyposmia, patients can show craniofacial anomalies (cleft lip and palate, arched palate, dental agenesis, hypertelorism), neurosensorial deafness, neurological disorders (cerebellar ataxia, oculomotor disturbances, synkinesia), and digital anomalies (clinodactyly, syndactyly, camptodactyly) (1).

In CHH, it is important to exclude a HPRL by a serum prolactin measurement. It is also mandatory to evaluate all pituitary functions to eliminate an anterior hypopituitarism. Serum assays of thyroid stimulating hormone (TSH) and tetraiodothyronine (T4) allow exploring of the thyroid function. Serum insulin-like growth factor-1 (IGF-1) assesses the somatotropic axis, and morning serum cortisol and adrenocorticotropic hormone (ACTH) assays evaluate the corticotroph axis (LOE 4). Any unexplained anterior hypopituitarism requires a hypothalamic–pituitary MRI in order to detect a tumor of the hypothalamic–pituitary region. MRI with specific sections of the olfactory tract is useful in the diagnosis of Kallmann syndrome because the presence of hypoplasia or agenesis (unilateral or bilateral) of olfactory bulbs and hypoplasia of the anterior pituitary is pathognomonic of this syndrome. The genetic study must be the last step in the investigation of CHH: In the presence of hyposmia/anosmia, mutations in FGFR1, FGF8, PROK2, and PROKR2 genes must be searched first, and in case of normosmic CHH, the mutations in GN-RH1/Gn-RH receptor, KISS1R (GPR54), and TAC3/TACR3 genes are to be assessed (1). However, so far, mutations are found in only 30% of cases.

Acquired HH


In HPRL, the partial gonadotropic insufficiency results from impaired secretion of gonadotropin-releasing hormone (Gn-RH), making it a WHO class 1 anovulation. HPRL is addressed in Chapter 7.

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