Issue: March 2011
March 01, 2011
2 min read

Genetic mutations may increase susceptibility to hypothalamic amenorrhea

Caronia LM. N Engl J Med. 364:215-225.

Issue: March 2011
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Mutations in four genes associated with idiopathic hypogonadotropic hypogonadism — FGFR1, PROKR2, GNRHR and KAL1 — may predispose women to hypothalamic amenorrhea, recent data suggest.

Hypothalamic amenorrhea is related to abnormal gonadotropin-releasing hormone (GnRH) secretions. Therefore, stressors that cause energy deficits, such as weight loss, excessive exercise, eating disorders and psychological distress, can play a role in development of the condition. However, researchers remain unsure of whether genes play a role in how sensitive the hypothalamic-pituitary-gonadal axis is to these stressors and, subsequently, to hypothalamic amenorrhea.

To examine this potential connection, researchers sequenced genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea (mean age at diagnosis, 22.4 years; mean BMI, 19.4). All women completed puberty spontaneously at a mean age of 13.5 years, although 13 patients experienced delayed menarche. Four hundred twenty-two women who underwent normal puberty and had at least a 2-year history of normal menstrual cycles served as controls.

The researchers found heterozygous mutations in seven of the 55 patients with hypothalamic amenorrhea. Two mutations — GR260E and R756H — in the fibroblast growth factor receptor 1 gene FGFR1 were discovered in two women. Researchers also pinpointed two variants — R85H and L173R — in the prokineticin receptor 2 gene PROKR2 in two more patients. Another mutation — R262Q — was also located in the GnRH receptor gene GNRHR in two other patients. All variants are considered loss-of-function mutants, according to the researchers. A sixth mutation — V371I — was found in the Kallmann syndrome 1 sequence gene KAL1 in the seventh patient. Researchers, however, could not determine whether it was also a loss-of-function variant or its other characteristics.

“We speculate that such heterozygous mutations, while not sufficient to cause idiopathic hypogonadotropic hypogonadism, could set a lower threshold for functional inhibition of the hypothalamic-pituitary-gonadal axis under adverse hormonal, nutritional, or psychological conditions and thereby lead to hypothalamic amenorrhea,” the researchers wrote.

Of the seven patients, four attempted to conceive — three of whom were successful. One patient did not use assisted reproductive treatment. Two of the seven patients continued with long-term hormone therapy, according to the researchers. Five patients, however, ceased HT, but still experienced recovery of menses.

“Since patients with mutations resumed regular menses after discontinuing hormone-replacement therapy, the genetic component of hypothalamic amenorrhea predisposes one to, but is not sufficient to cause, GnRH deficiency,” the researchers wrote.

Disclosure: The researchers report no relevant financial disclosures.


This journal article gives us insight into other common diseases in women, such as type 2 diabetes and gestational diabetes. A screening test of rare variants in genes for women at risk for diabetes would be our dream come true!

–Lois Jovanovic, MD
Endocrine Today Editorial Board Member

Disclosures: Dr. Jovanovic reports no relevant financial disclosures.


While the results of this study are fascinating, at present they provide little assistance to practitioners and do not change the treatment of women affected by hypothalamic amenorrhea. In the future, such information may help us to develop new specific approaches to therapy in some affected women. More than anything else, the data emphasize the heterogeneous nature of the disorder we term 'hypothalamic amenorrhea.'

–Robert W. Rebar, MD
Endocrine Today Editorial Board Member

Disclosures: Dr.Rebar reports no relevant financial disclosures.

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