• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Also Called Functional Hypothalamic amenorrhea (FHA)

• Q. What is the primary defect in this condition?

  • Inactivation of GnRH pulse generator

• Q. Is eating disorder more commonly associated with Functional hypothalamic amenorrhea?

  • Yes

• **Diagnosis and evaluation **

• Q. FHA is a diagnosis of exclusion after other causes have been ruled out, True or false?

  • True

• Q. Which are the four most common causes of Secondary amenorrhea?

  • Pregnancy
  • PCOS
  • FHA
  • Hyperprolactinemia

• Q. Which are the three important etiological causes of FHA?

  • Vigorous Exercise
  • Weight loss
  • Stress

• Q. What is the minimum amount of energy intake for menstrual functions to continue?

  • At least 30 kcal/kg/day is required for normal menstrual function
  • Below this- it leads to FHA
  • This would be around 1500 Kcal/day for a 50 Kg women

• Q. Do all women with FHA have amenorrhea?

  • No
  • There is a spectrum of disorder
  • Starting from Ovulatory eumenorrhea  to subtle defects like luteal phase defect etc. to amenorrhea

• Q. Are mood disorders associated with FHA?

  • Yes

• Q. In which women should evaluation for FHA be carried out?

  • Those having menstrual cycles > 45 days or
  • Amenorrhea for >3 months (this was six months earlier)
  • After one-year post menarche

• Q. What are the two leading theories that explain how energy imbalances cause FHA?

  • 1. Metabolic fuel hypothesis
    • Less availability of fuel is detected by peripheral system  cues to a central system to shutdown non-critical functions
  • 2. Critical body fat hypothesis
    • Certain minimal amount of body fat is required to maintain reproductive functions

• Q. What is the female athlete triad?

  • Reduce energy availability
  • Menstrual dysfunction
  • Low bone mass

• Q. What are the critical points in history to be included while dealing with a Case of FHA?

  • Exercise
  • Diet
  • Body image perceptions
  • Substance abuse
  • Eating disorder
  • Ambitions
  • High need for social approval
  • Sleep pattern
  • Stress
  • Menstrual pattern
  • Fracture
  • Rule out Pituitary causes from history

• Q. Which drugs can lead to amenorrhea?

  • Antipyschotics  reduce dopamine --> increase prolactin --> amenorrhea
  • OC pills continuously
  • Progestins
  • IUD
  • GnRH analog

• Q. What are the things to see in local gynecological examination in such a patient?

  • Red vagina- non estrogenized vagina
  • Bluish bulge- imperforate hymen

• Q. What is the first test done in women presenting with amenorrhea?

  • Beta HCG pregnancy test

• Q. What other investigations are done in a workup of FHA?

  • Beta HCG- pregnancy test
  • FSH / LH
  • Estradiol
  • Prolactin
  • Thyroid function
  • If features of hyperandrogenism–appropriate biochemical tests

• Q. What is the typical hormonal pattern seen in FHA?

  • Low LH
  • Normal FSH (higher than LH)
  • Estradiol < 50 pg/ml
  • Progesterone <1 pg/ml
  • TFT- Low T3, low normal T4, and TSH (Non-thyroidal illness type picture)

• Q. What do high FSH and LH with low estradiol suggest?

  • Impending Premature ovarian insufficiency (POI)

• Q. What does very low FSH and LH and estradiol suggest?

  • Hypogonadotropic hypogonadism

• Q. When is MRI done in the case of FHA?

  • Headache
  • Clinical / lab evidence of other anterior pituitary hormone dysfunction
  • Vomiting
  • Change in vision
  • Lateralizing neurological signs

• Q. When is BMD-DEXA performed?

  • DEXA must be performed in women having six or more months of amenorrhea
  • It may be done earlier if there is bone fragility or other nutritional deficiency

• Q. What is defective in women with FHA / eating disorder- the BMD or bone microarchitecture?

  • Both are defective
  • Pearl
  • Young women with an eating disorder have a seven-fold increased risk of fracture

• Q. What are the changes in bone turnover seen in adolescents and older women with Anorexia nervosa?

  • Adolescents- have low bone turnover
  • Older women – have uncoupling of the bone turnover- reduced formation and increased resorption

• Q. Why is bone loss more in women with FHA and AN compared to other women with POI or oophorectomy?

  • This is because bone loss is not due to estrogen alone. It is a combination of factors that include
    • High cortisol
    • Reduced T3/T4
    • Low E2
    • Nutrition

• Q. What is the role of the progesterone challenge test in these women?

  • After ruling out progesterone challenge test is done in these women
  • Typical Medroxyprogesterone is given in a dose of 10 mg for ten days (5-10 mg for 5-10 days)
  • Other progesterone may also be used

• Q. What does absent bleed after progesterone challenge suggest?

  • outflow tract obstruction
  • Low endometrial estrogen exposure

• Treatment of Functional hypothalamic amenorrhea

• Q. Which patients with FHA require indoor admission?

  • Those with
  • Bradycardia
  • Orthostasis
  • Hypotension
  • Electrolyte imbalance

• Q. What is the critical aspect of managing FHA?

  • Improving energy balance
  • Increase of caloric intake and reduction of exercise

• Q. How much weight gain is required for the resumption of menses?

  • At least 2 kg above the weight which caused loss of menses

• Q. How much time would it take to resume menses after weight gain?

  • About 6-12 months

• Q. Can FHA and PCOS coexist?

  • Yes

• Q., which psychological technique is helpful in women with FHA?

  • Cognitive-behavioral therapy

• Q. Should OC pills be used in FHA women for resumption of menses and protection of bone?

  • The guidelines are against the use of OC pills in FHA

• Q. Do OCP have a protective effect on the bone?

  • No
  • They do not protect the bone based on the available evidence
  • This is based on the meta-analysis done by the Endocrine society

• #Clinicalpearl

  • Remember, bone loss in FHA is not due to estrogen-deficient alone, and there are other players like cortisol
  • Hence OCP is not a solution for the bone in women with FHA

• Q. OCP is not used, but how about the use of Estrogen and progesterone separately?

  • The guidelines suggest the use of estrogen and cyclic progesterone in adolescents who do not have a resumption of menses 6-12 months after regaining the weight
  • Transdermal estrogen is better in this regard

• Q. Does transdermal estrogen protect the bone?

  • Yes
  • However, the estrogen will have a more negligible effect if nutritional factors are not corrected

• Q. So why does transdermal estrogen protect the bone while OC pills do not?

  • OC pills tend to reduce IGF1 in the bone, while transdermal estrogen does not
  • Have OC pills may have no benefit/detrimental effect on the bones

• Q. Should osteoporosis drugs like bone resorptive agents be used in women with FHA having low BMD?

  • Guidelines are against the use of osteoporosis medication in this setting

• Q. Why are they not recommending the use of bone resorptive agents?

  • There are no studies that have shown the benefit of the use of Bisphosphonates in FHA women
  • Whatever studies are available- are mainly known for Anorexia nervosa, which has shown some benefit
  • Remember these are young women with potential for pregnancy in the near future- bisphosphonates may have potential teratogenicity

• Q. What does the guideline say on the use of Recombinant leptin (metreleptin in these women )?

  • Preliminary studies have shown metreleptin showing a positive effect on LH pulsatility and endocrine effects
  • However, interestingly, as expected, leptin reduces appetite and causes further weight loss !!

• Q. What about the effect of leptin on the bone?

  • Studies have shown a positive effect of leptin on bone
  • However, more evidence is needed

• Q. Can teriparatide be used in these cases?

  • The guidelines recommend the use of teriparatide in FHA women with poor fracture healing and very low BMD for a short period

• Q. How will you manage an FHA patient with infertility?

  • Pulsatile GnRH is the first-line therapy. Gonadotropins may be used if GnRH is not available
  • Clomiphene may be used if estradiol levels are fine

• Q. What care must be taken before ovulation induction in these women?

  • The BMI Should be at least >18.5 kg/m2 before ovulation induction- else increased risk of pregnancy complications

• Q. What is the cardiovascular risk status in women with FHA?

  • They have a higher CV Risk than normal women
  • They tend to have dyslipidemia
  • Also, women with Anorexia nervosa rehabilitated have higher visceral fat probably due to lack of estrogen
  • Also, stress contributes to increasing CV risk