Causes of Anovulation: WHO Class 1

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Causes of Anovulation: WHO Class 1

Camille Grysole and Didier Dewailly

Introduction

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:

•  HPRL

•  Functional hypothalamic amenorrhea (FHA)

•  Other causes:

Sheehan syndrome

Haemochromatosis

History of cerebral radiotherapy

Sarcoidosis

Lymphocytic hypophysitis

Head trauma

Subarachnoid hemorrhage

Cushing syndrome

Acromegaly

Iatrogenic HH (opiates, corticosteroids)

CHH

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

HPRL

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.

FHA

FHA represents 15% of the causes of secondary amenorrhea. It is the second leading cause of gonado-tropic insufficiency after HPRL (LOE 4). FHA is a reversible form of Gn-RH deficiency due to a negative energy balance, which may result from dietary restriction and/or excessive physical activity (2). It is characterized by the suppression of Gn-RH pulsatility, resulting in a decreased secretion of pituitary gonadotropins, causing anovulation. Disturbances of the hypothalamic gonadal axis are associated with low leptin levels, an adipose tissue protein whose levels are proportional to fat mass and depend on calorie intake. A randomized study demonstrated that administration of recombinant human leptin allowed a recovery of menstrual cycles in these patients (LOE 2a) (3). Ghrelin, a peptide secreted by the stomach but also by the pituitary and hypothalamus, has a role in FHA: Indeed, high ghrelin levels were found in patients with FHA. Other neuropeptides are likely involved as well.

In FHA, amenorrhea usually more than 6 months, primary (for teenagers) or secondary, and is resistant to the progesterone withdrawal test. The clinical picture usually coincides with extreme weight loss, eating disorders, intensive physical practice, and psychosocial stress. Other signs can be found evoking hypo-estrogenism (vaginal dryness, libido disorders), hypometabolism (cyanosis of extremities, nervousness, lanugo hair, bradycardia, hypotension), and chronic vomiting (loss of tooth enamel, gingival abrasions, parotid gland enlargement). However, FHA is a diagnosis of exclusion (LOE 4). It is therefore necessary to look for symptoms of other causes of amenorrhea: galactorrhea, headache, visual disturbances (suggesting a central organic cause), hyperandrogenism (suggesting polycystic ovary syndrome, PCOS), premature ovarian insufficiency (POI), virilization signs such as male pattern baldness, or a clitoromegaly (suggesting adrenal hyperplasia or androgen-secreting tumor).

In FHA, the hypo-insulinemia causes an increase of sex hormone binding globulin (SHBG) and a decrease of triiodothyronine (T3), which are signs of peripheral hypometabolism (LOE 4). A minimal workup is necessary to rule out any organic cause of anovulation, such as PCOS (abnormally high serum androgens and anti-Müllerian hormone (AMH) levels, polycystic ovaries at ultrasound), POI (low AMH and estrogens, high FSH), 21-hydroxylase deficiency (abnormal high 17-hydroxyprogesterone), HPRL (abnormal high prolactin), and pituitary tumor (abnormal hypothalamic/pituitary MRI) (LOE 4).

Other Causes of Acquired HH

HH may be secondary to Sheehan syndrome, a postpartum complication related to ischemic necrosis of the anterior pituitary occurring during a postpartum hemorrhage. This syndrome has become rare with the progress of obstetrics, but it can occur in a partial form, is difficult to diagnose, and is revealed only by postpartum amenorrhea. The prevalence of pituitary deficits after brain irradiation is of the order of 80% and may occur up to 10 years after irradiation. Hypogonadism is one of the two most frequent endocrine complications of hemochromatosis with diabetes. According to the available studies in the literature, the frequency of hypogonadism is 40%–50%. Despite treatment with bloodlettings, normalization of pituitary function is exceptional. The infiltrative and inflammatory diseases of the pituitary gland can result in a gonadotropin deficit, frequently associated with other pituitary deficits. Sarcoidosis affects the central nervous system in 10% of cases, including the hypothalamic–pituitary axis in one-third of cases. Lymphocytic hypophysitis, with a prevalence of 1.9 million, mainly occurs during pregnancy or postpartum. A gonadotropic deficiency after a head injury or subarachnoid hemorrhage is present in 10%–30% of cases with no correlation to the severity of the trauma. HH may also occur in Cushing syndrome and acromegaly but can also be iatrogenic, caused by opiates or high-dose and long-term corticosteroids.

Discussion

There are diagnostic difficulties regarding WHO class 1 anovulation.

Although widely used, the diagnostic value of the Gn-RH test in CHH has been questioned because of its poor profitability. The Gn-RH test is classically positive (with preserved response of gonadotropins) in FHA, although it would be negative in CHH. Actually, it provides no additional information compared to baseline FSH and LH levels (LOE 4). Its response is variable and depends on the severity of the gonadotropin deficiency, which can be better assessed by clinical features (such as the degree of breast development), the baseline LH and FSH assays using ultrasensitive techniques, and pelvic ultrasound that allows measuring the uterus height, which is <45 mm in case of severe and long-lasting gonadotropin deficiency (LOE 4).

A hypothalamic/pituitary MRI must be performed systematically in FHA to eliminate an organic cause (essentially a pituitary or supra-pituitary tumor) (LOE 4). The existence of persistent or severe headache, non-induced vomiting, or visual disorders are late symptoms.

CHH is often underdiagnosed in patients with partial forms of the disease and who have normal breast and hair development and only chronic oligomenorrhea. Differentiating a partial form of normosmic CHH without identified mutation from FHA is sometimes challenging. Indeed, caloric restriction, related to an eating disorder, is not always revealed by the nutrition survey. A psychiatric evaluation can be helpful. In addition, both states may coexist, which could explain why all women do not have the same sensitivity to energy deficit. Indeed, some genetic mutations involved in CHH are also found in a simple heterozygous state in patients with FHA (LOE 4) (4). This is an additional difficulty in differentiating FHA from CHH.

In 30%–50% of FHA patients, a polycystic ovarian morphology can be found without real PCOS (LOE 4) (5). This can lead to erroneously diagnose PCOS and to underdiagnose FHA. In this situation, careful analysis of energy balance and serum LH assay (low to normal in FHA, normal to high in PCOS) can help.

Conclusion

WHO class 1 anovulation is a common cause of infertility, and each cause should be assessed because it requires specific treatments. For ovulation induction, the specific treatment is pulsatile administration of Gn-RH that is relatively easy, providing appropriate devices are used (see Chapter 14).

However, these diseases are often underdiagnosed. Indeed, the clinical presentation as well as the hormonal picture shows considerable variation. This variability must be known not to underestimate their diagnosis.

Nevertheless, research to improve their identification is constantly evolving, especially in the field of genetics.

TABLE 3.1

Level of Evidence of Statements

TABLE 3.2

Grade of Strength for Recommendations

REFERENCES

1. Silveira LF, Latronico AC. Approach of the patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013; 98(5):1781–8.

2. Catherine M, Gordon MD. 2010. Clinical practice. Functional Hypothalamic Amenorrhea. N Engl J Med. 2010, July; (363):365–71.

3. Welt CK, Chan JL, Bullen J. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004; (351):987–97.

4. Caronia LM, Martin C, Welt CK. 2011. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med. 2011; (364):215–25.

5. Robin G, Gallo C, Catteau-Jonard S, Lefebvre-Maunoury C, Pigny P, Duhamel A, Dewailly D. Polycystic ovary-like abnormalities (PCO-L) in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 2012; 97(11):4236–43.

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