Ed: This condition suppresses the hypothalamic-pituitary-ovarian axis. Dysregulation of hormones result.
Next to pregnancy, PCOS and Functional Hypothalamic Amenorrhea (FHA) are the most common causes of secondary amenorrhea.
FHA is a chronic form of anovulation and is a diagnosis of exclusion. It is part of the WHO group 1 ovulation disorders and is commonly seen in women who experience significant weight loss, excessive exercise or a high degree of physical or psychosocial stress.
FHA occurs as a result of the interaction of the metabolic, nervous and hormonal systems leading to a suppression of hypothalamic-pituitary-ovarian (HPO) axis.
Patients with FHA will have a typical laboratory picture of low LH and normal FSH, along with undetectable levels of estradiol and progesterone. Androgen level (testosterone and DHEAS) will also be low. They will also often have prolactin, TSH and T4 levels that are low or low-normal. Due to the activation of the nervous and metabolic systems these patients will often have hypercortisolemia.
Women with FHA will have altered bone metabolism with a reduced BMD and an increased incidence of osteoporosis and fracture risk. This is due to a combination of being hypoestrogenic and having nutritional deficiencies – which speaks to the complex nature of this presentation. Hypercortisolism can further supress bone metabolism.
As a result of the dysfunctional or absent signally from FSH and LH, women will have poor ovarian follicle development and oocyte maturation which results in poor estradiol secretion from the follicles and ultimately a poor luteal phase which effects embryo implantation. This leads to infertility, an increased risk of fetal loss and small for gestational age babies.
Women with FHA also have a higher prevalence of disordered eating and food attitudes along with anxiety and stress intolerance.
There are five principles to the management of women with FHA.
1. Correct the energy imbalance
It is important to assess the dietary energy intake versus the exercise energy expenditure. Engaging the services of a dietitian skilled in this area is of value and the action taken depends on the deficit. For example, weight gain through refeeding in patients with anorexia nervosa or exercise modification and increased dietary energy for athletes. Few studies have examined the precise weight gain needed for resumption of the HPO axis. One study has suggested a weight gain of at least 2kg above the weight at which the cycle ceased and at least 6-12 months of weight stabilisation is required before resumption of menses.
2. Correct the psychosocial issues with CBT
Women with FHA have greater difficult in coping with daily stressors and greater prevalence of psychiatric and mood disorders. Significant ovulatory recovery through cognitive behavioural therapy (CBT) has been seen in a small RCT of FHA women without other significant history. In this study there was also improvement in metabolic factors such as cortisol, leptin and TSH with CBT.
3. Prescription of HRT over COCP
In FHA it is not recommended that the combined oral contraceptive pill (COCP) be used for the sole purpose of regaining menses or for bone protection. It is beneficial to counsel patients that the COCP may indeed mask recovery of the HPO axis.
It is suggested that clinicians consider short term combined hormone replacement therapy (HRT) and ideally after only 6-12 months of corrective interventions, as the long term bone health parameters may be compromised if left longer.
4. Bone health
Multiple studies have confirmed that the COCP has limited to no benefit on BMD. Transdermal 17B-estradiol along with a cyclical oral progestin (e.g. medroxyprogesterone acetate 2.5mg BD) has been demonstrated to have a positive effect on BMD and the best bioavailability. Bisphosphonates and denosumab are not recommended in this population.
5. Fertility management
Ovulation induction is recommended after correction of energy imbalance and psychological factors. Patients benefit from a complete fertility workup – including the partner. Firstline management is pulsatile recombinant GnRH via a pump, however this is not available in Australia. Combined recombinant FSH and LH is standard treatment, given in slowly increasing rFSH doses with the intention of mono-ovulation. This is best performed in a fertility centre setting with monitoring. Treatment often takes weeks, even months, and the treatment burden is difficult for patients. Treating patients with a BMI <18.5 kg/m2 is not recommended due to the increased risk of fetal loss, intrauterine growth retardation and pre term birth.
References available on request.
Questions? Contact the editor.
Author competing interests: nil relevant disclosures.
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