Confronting amenorrhea as a gynecologist can be confusing and difficult. Understanding why a woman is not getting her period beyond the possibility of pregnancy or menopause can take us back to the textbook and still remain a puzzle. One possible reason for a young woman to be anovulatory could be polycystic ovarian syndrome and another less common diagnosis is hypothalamic amenorrhea.

Hypothalamic amenorrhea, or hypothalamic hypogonadism, (“HYPO HYPO”) is defined as the absence or cessation of menses caused by a deficiency in the GnRH pulsatile secretion below a critical range (Stedman, Berga). Typically this results in very low levels of FSH, LH and estrogen. The prevalence of amenorrhea, excluding some of the most common causes- pregnancy, menopause, and lactation, is about 3-5% of the population (Pettersson). In the infertile population as a subgroup, it is much more common than this. Specific hypothalamic causes, which consist of one-third of amenorrheic women (Reindollar), include Anovulation polycystic ovary (to be further discussed in a future topic letter), stress, weight loss, anorexia, bulimia, malnutrition, excess exercise, hypothalamic suppression, hypothyroidism, drug use, idiopathic, postpill use, and more rarely inherited genetic defects- Kallmann’s syndrome and adrenal hypoplasia. Since hypothalmaic amenorrhea is often a diagnosis of exclusion, this condition is suspected by demonstrating low or normal gonadotropins and failed withdrawal bleed. It is also important to confirm normalProlactin and thyroid stimulating Hormone levels. Imaging of the brain and/or the sella turcica (Speroff) is also advised.

Evaluation:

  • History and Physical
    • Recent weight loss/ gain? Eating disorders? BMI < 20kg/m2 ?
    • Exercise Patterns: Regular vigorous exercise?
    • Diet- Reduced caloric intake?
    • Stress?
    • Recent discontinuation of contraceptive pill?
  • Labs to consider: β-HCG, FSH (decreased or normal), LH, estrogen, TSH, Prolactin, and Testosterone Level.
  • Ultrasound: to check ovarian size, antral Follicle count, endometrial thickness
  • Consider brain imaging if gonadotropins are normal or low and the diagnosis is uncertain.

Differential Diagnosis:

  • Low GnRH Secretion- Dysfunctional Hypothalamus
  • Pituitary Tumor- Prolactin Secreting
  • Empty Sella Syndrome
  • Sheehan Syndrome
  • Premature Ovarian Failure
  • Hyperandrogemism/ Polycystic Ovary
  • Asherman Syndrome (Intrauterine Adhesions)
  • Rare Causes: Abnormalities of Hypothalamus- lymphoma, histiocytosis X, sarcoidosis, and hypothalamic cysts

Treatment

First, reverse underlying causes of hypothalamic amenorrhea through behavior modification- reduce stress levels, decrease intensity of exercise, and increasing weight and BMI. Simple discussions about increasing caloric intake and decreasing energy expenditure may be all that is necessary to treat amenorrhea, and consequently, ovulatory menses should resume (Warren-Perlroth). LH secretion may be hindered by inadequate caloric intake and/or increase in energy expenditure (Loucks, Loucks-Thuma) and improvement may be related to increases in BMI (Falsetti). On the other hand, behavior changes may be difficult in some patients; other patients may not find that these changes improve their condition. Enrolling the help of other health care professionals such as nutritionist and psychologist can be very helpful to properly counsel the patient.

Second, women with hypothalamic amenorrhea are at risk for developing complications of estrogen deficiency. The “female athlete triad” describes an amenorrheic woman who also has an eating disorder and osteoporosis even though they are aggressively exercising (Warren, Brunet). Bone density in women is dependent on appropriate endogenous levels of estrogen and Progesterone, and the decreased density of hypoestrogenic bones cannot be reversed by strenuous exercise (Drinkwater-Chestnut, Drinkwater-Ott, Myerson, Warren). Thus, patients should be treated with exogenous cyclic estrogen/ progestin therapy or a contraceptive pill to prevent excessive bone loss (Davies, Grinspoon). Supplementation of vitamin D (400 IU/day) and calcium (1,200 to 1,500 mg/day) should be added to treatment to slow decline of bone density.

Third, psychological support to these women is imperative and it may be beneficial to include professional help as well as include their family in these conversations.

For those with an eating disorder, weight gain may be critical to their health and as you know, they struggle with this for a lifetime. Whether they are attempting pregnancy or not, addressing some of the emotional components to this disorder is part of treatment.

Finally, treatment of Infertility can be done with either pulsatile GnRH (Kesrouabi) or exogenous gonadotropins. Clomiphene citrate typically does not work well to stimulate Ovulation so injectable gonadotropins that include FSH and LH are a consideration. However, the concern with injectables is risk of hyperstimulation, as well as the risk of high-order multiple birth. In face of these risks, in vitro Fertilization with a transfer of a low number of embryos/elective single Embryo transfer may also be a consideration. Lowering the risk of a multiple birth is a significant benefit to this type of patient. Behavior modification should still be a part of the first line treatment since nutritional intake is important during pregnancy to promote normal fetal growth and development.

Future Considerations/ Recommendations

A recent study has suggested that leptin administration in patients with hypothalamic amenorrhea may improve reproductive function and bone formation, and normalize thyroid and growth hormones. Future studies are still needed to discover the therapeutic implications and specific parameters necessary for optimal intervention (Welt).

This is a brief review of an uncommon, but often difficult-to-diagnosis problem. Treatment in summary should include hormone replacement such as ocps if pregnancy is not desired; if pregnancy is the goal, she may potentially require more aggressive methods of Ovulation Induction or advanced reproductive technologies.

References

1. Stedman’s Medical Dictionary. 27ed. Philadelphia: Lippincott Williams & Wilkins 2000;56.

2.  Berga SL. Behaviorally induced reproductive compromise in women and men. Seminars Reprod Endocrinol 1997; 15:47.

3. Speroff L, Fritz MA. Amenorrhea. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Philadelphia: Lippincott Williams & Wilkins 2005; 438,418.

4. Pettersson F, Fries H, Nillius SJ. Epidemiology of secondary amenorrhea. I. Incidence and prevalence rates. Am J Obstet Gynecol 1973; 117: 80-6.

5. Kesrouani A, Abdallah MA, Attieh E, Abboud J, Atallah D et al.  Luteinizing Hormone-releasing hormone for infertility in women with primary hypothalamic amenorrhea. Towards a motr-interventional approach. J  Reprod Med. 2001; 46:23-8.

6. Davies MC, Hall ML, Jacobs HS. Bone mineral loss in young women with amenorrhea. BMJ. 1990; 301: 790-3.

7. Drinkwater BL, Nilson K, Chestnut CH, Bremmer WJ, Shainholz S, et al. Bone mineral content of amenorrheic and eumenorrheic athletes. New Engl J Med 1984; 311: 277.

8. Drinkwater BL, Nilson K, Ott S, Chestnut III CH. Bone mineral density after resumption of menses in amenoeehic athletes. JAMA. 1986; 256:380.

9. Myerson M, Gutin B, Warren MP, Wang J Lichtman S, Pierson RN Jr. Total bone density in amenorrhic runners. Obstet Gynecol 1992; 79:9730.

10. Warren MP, Brooks-Gunn J, Fox RP, Holderness CC, Hyle EP, Hamilton WG. Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study. J Clin Endocrinol Metab. 2002; 87:3162.

11. Grinspoon SK, Friedman AJ, Miller KK, Lippman J, Olson WH, et al. Effect of a triphasic combination oral contraceptive containing norgestimate/ ethinyl estradiol on biochemical markers of bone metabolism  in young women with osteopenia secondary to hypothalamic amenorrhea. J Clin Endocrinol Metab. 2003; 88:3651-6.

12. Reindollar RH, Novak M, Tho SP, McDonough PG. Adult-onset amenorrhea: a study of 262 patients. Am J Obstet Gynecol 1986; 155: 531.

13. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol 2001; 170: 3.

14. Loucks AB, Verdun M, Health EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol 1998; 84: 37.

15. Loucks AB, Thuma JR,. Luteinizing Hormone; pulsatility is disrupted at a threshold of energy  availability in regularly menstruating women. J Clin Endocrinol Metab 2003; 88: 297.

16. Falsetti L, Gambera A, Barbetti L, Specchia C. Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors. J Clin Endocrinol Metab 2002; 87: 500.

17. Brunet M. Female Athlete Triad. Clin Sports Med. 2005; 24: 623-636.

18. Welt CK, Chan JL, Bullen J, Murphy R, Smith P et al. Recombinant human leptin in women with hypothalamic amenorrhea. New Engl J Med 2004; 351: 987-97.