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Review
. 2015 Mar;100(3):812-24.
doi: 10.1210/jc.2014-3344. Epub 2015 Jan 12.

Neuroendocrine causes of amenorrhea--an update

Lindsay T Fourman  1 , Pouneh K Fazeli
Affiliations
Review

Neuroendocrine causes of amenorrhea--an update

Lindsay T Fourman et al. J Clin Endocrinol Metab. 2015 Mar.

Abstract

Context: Secondary amenorrhea--the absence of menses for three consecutive cycles--affects approximately 3-4% of reproductive age women, and infertility--the failure to conceive after 12 months of regular intercourse--affects approximately 6-10%. Neuroendocrine causes of amenorrhea and infertility, including functional hypothalamic amenorrhea and hyperprolactinemia, constitute a majority of these cases.

Objective: In this review, we discuss the physiologic, pathologic, and iatrogenic causes of amenorrhea and infertility arising from perturbations in the hypothalamic-pituitary-adrenal axis, including potential genetic causes. We focus extensively on the hormonal mechanisms involved in disrupting the hypothalamic-pituitary-ovarian axis.

Conclusions: A thorough understanding of the neuroendocrine causes of amenorrhea and infertility is critical for properly assessing patients presenting with these complaints. Prompt evaluation and treatment are essential to prevent loss of bone mass due to hypoestrogenemia and/or to achieve the time-sensitive treatment goal of conception.

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Figures

Figure 1.
Figure 1.
An overview of neuroendocrine causes of amenorrhea and infertility, including physiological, pathophysiological, and iatrogenic etiologies. *, Possible causes of sellar masses and lesions, including infiltrative and infectious processes, are listed in Table 1. **, In humans, high-dose glucocorticoids may also decrease the responsiveness of the pituitary to GnRH stimulation (7).
Figure 2.
Figure 2.
Potential hormonal mediators of amenorrhea and infertility. Physical, emotional, or nutritional stress may increase CRH levels, which suppress GnRH release. Cortisol levels, which increase in the setting of stress and Cushing's syndrome, also suppress GnRH release and likely decrease LH responsiveness to GnRH. Starvation results in low leptin levels and increased FGF-21 levels in animal models; the low leptin levels and increased FGF-21 levels likely suppress GnRH release by decreasing kisspeptin expression. In primary hypothyroidism, TRH levels are increased and stimulate prolactin release. Hyperprolactinemia suppresses GnRH release by decreasing kisspeptin expression, and possibly through a CRH-mediated pathway. High androgen and progesterone levels may be seen in CAH, and these hormones likely suppress GnRH release. kiss, kisspeptin.
Figure 3.
Figure 3.
A suggested diagnostic algorithm for evaluating patients with secondary amenorrhea, including non-neuroendocrine causes. Importantly, all patients presenting with secondary amenorrhea should have a history and physical examination performed and a basic laboratory evaluation consisting of serum human chorionic gonadotropin, TSH, FSH, and prolactin levels. *, Individuals who have been prescribed CTLA-4 antibody therapies (ipilimumab or tremelimumab) should have an MRI with pituitary cuts to evaluate for hypophysitis. **, Unless the cause of the hyperprolactinemia can be definitively attributed to the medication (for example, by stopping the medication and repeating the prolactin level), it is difficult to exclude the possibility of a prolactinoma or stalk disruption (due to a sellar lesion) causing the hyperprolactinemia. ***, If the lesion is small (<1 cm) and is found to be nonsecretory, we would recommend following the “No lesion and normal prolactin” pathway because this lesion is unlikely to be the cause of the amenorrhea. Abbreviations: abnl, abnormal; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; PCOS, polycystic ovary syndrome; 17-OH progesterone, 17-hydroxyprogesterone; H&P, history and physical.
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