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词条 Functional hypothalamic amenorrhea
释义

  1. Risk factors

      Stress-related    Weight-related    Exercise-related  

  2. Pathophysiology

      Hormonal    Neuroendocrine  

  3. Clinical presentation

      Reproductive    Bone    Cardiovascular    Neurological    Mental and Sexual Health  

  4. Evaluation and diagnosis

      History and physical exam    Laboratory testing    Imaging  

  5. Management

      Low bone density    Anovulatory infertility    Psychological assessment  

  6. References

Functional hypothalamic amenorrhea (FHA) is a form of amenorrhea and chronic anovulation,[1] and is one of the most common types of secondary amenorrhea[2] It is classified as hypogonadotropic hypogonadism.[3] It was previously known as "juvenile hypothalamosis syndrome," prior to the discovery that sexually mature females may also have FHA.[4] FHA has multiple risk factors, with links to stress-related, weight-related, and exercise-related factors. FHA is caused by stress-induced suppression of the hypothalamic-pituitary-ovarian (HPO) axis,[4] which results in inhibition of gonadotropin-releasing hormone (GnRH) secretion, and gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH).[3] FHA is a diagnosis of exclusion;[1][4][5][6] "functional" is used to indicate a behavioral cause, in which no anatomical or organic disease is identified, and is reversible with correction of the underlying cause.[5] Diagnostic workup includes a detailed history and physical, laboratory studies, such as a pregnancy test, and serum levels of FSH and LH, prolactin, and thyroid-stimulating hormone (TSH), and imaging.[7] Patients present with a broad range of symptoms related to severe hypoestrogenism, as well as hypercortisolemia, low serum insulin levels, low serum insulin-like growth factor 1 (IGF-1), and low total triiodothyronine (T3).[3] Treatment is primarily managing the primary cause of the FHA with behavioral modifications.[4][7] If this fails to work, secondary treatment is aimed at treating the effects of hypoestrogenism,[4][7] hypercortisolism,[5] and hypothyroidism.[5]

Risk factors

FHA is caused by a chronic energy deprivation and negative energy balance,[8] with links to three main risk factors: stress, weight, and exercise. It can occur in females of all ages, with the cause usually involving at least two out of the three factors.[3]

Stress-related

Excessive or intense psychosocial, emotional, or mental stress can lead to hypothalamic dysfunction.[7] In adolescents, this is called "adolescence crisis" and can occur during, or post, puberty. This crisis can cause young adults to develop behavioral or eating disorders (mentioned below), and, if severe and prolonged enough, can result in the menstrual irregularities seen in FHA.[7]

When the body is stressed, the hypothalamic-pituitary-adrenal (HPA) axis is activated, which suppresses the HPO axis via corticotropin-releasing hormone (CRH) inhibiting GnRH secretion in the hypothalamus.[9] CRH stimulates secretion of beta(β)-endorphins, which suppresses release of GnRH and dopamine.[7] Inhibition of dopamine allows for an increase in prolactin secretion and concentration (hyperprolactinemia), which leads to inhibition of LH, and in turn leads to anovulation.[7] Inhibition of the HPO axis also results in inhibition of the hypothalamic-pituitary-thyroid (HPT) axis and a decrease in thyroid hormones, in an attempt to minimize energy depletion.[4] This allows the body to focus on survival, rather than reproduction.[9]

High concentrations of dopamine and low concentrations of prolactin (and serotonin) can also cause FHA.[4] Females with these levels characteristically have higher levels of aggression, higher levels of testosterone, and lower levels of estrogen.[4][6]

Weight-related

FHA can affect women who are underweight, normal weight, or overweight.[4][9] Risk factors for adolescents and young women generally include eating disorders, such as anorexia nervosa or bulimia nervosa.[4] The risk of FHA due to weight-related factors increases across a series of four behaviors: 1) aesthetic dieting; 2) dieting due to obsessive ideals about diet and/or weight; 3) suppression of appetite, whether by drugs or self; 4) eating disorder, generally anorexia nervosa.[4] Patients affected by eating disorders have overactive hypothalamic-pituitary systems, causing increased cortisol release and β-endorphin concentrations, with anorexia nervosa additionally having a decrease in thyroid hormones.[4]

Both significant weight loss and weight gain can cause FHA through insulin.[9] Significant weight loss, as in eating disorders and chronic malnutrition, is characterized by low insulin levels. Significant weight gain can lead to obesity and insulin resistance, which mimics low insulin levels via functional hypoinsulinaemia.[9] As insulin assists in regulating the HPO axis, these low, or functionally low, levels of insulin can cause FHA.[9]

Exercise-related

Exercise-related factors generally affect athletes who participate in sports that require intensive training and a low body weight, causing a net energy deficiency.[4][6] FHA in female athletes is commonly part of the female athlete triad, which has been renamed to Relative energy deficiency in sport (RED-S), as the triad is also seen in males, with hypogonadotropic hypogonadism replacing the FHA component.[10] Up to 69% of female athletes practicing these sports (e.g. long-distance runners, gymnasts, ballet dancers, swimmers) can be affected by FHA, as disordered eating is also often a component.[4]

Some studies suggest female athletes with FHA may also be affected by hyperandrogenism in addition to hypoestrogenism, and it is the hyperandrogenism (as seen in polycystic ovary syndrome) that causes the menstrual irregularity, rather than chronic low energy availability and low estrogen levels.[6] However, further studies and analysis is needed in this area.[6]

Pathophysiology

Hormonal

FHA results from a functional reduction in GnRH.[3][11] Reduced levels of gonadotropins LH and FSH are insufficient to maintain full folliculogenesis and ovulatory ovarian function and results in profound hypoestrogenism.[3][11] Additionally, external stress factors activate the HPA axis; increased corticotropin-releasing hormone (CRH) secretion results in increased secretion of ACTH from the pituitary gland, and thus increased secretion of cortisol from the adrenal glands.[3] FHA patients have been found to have higher 24-hour mean plasma cortisol levels.[5][9][11] The increase in glucocorticoids inhibits the release of GnRH and gonadotropins and contributes to the pathophysiology of stress-related FHA.[3][5][9] The hypothalamic-pituitary-thyroid axis is also altered in FHA; TSH levels are low-to-normal and there is an increase in reverse triiodothyronine and low level of triiodothyronine.[3] Other hormonal changes in FHA include increased levels of nighttime serum growth hormone (GH), decreased levels of 24 hour prolactin, low serum insulin and IGF-1, and increased insulin sensitivity.[3]

Neuroendocrine

The complex mechanisms of FHA are unclear, though it is known that many neuromodulatory signals are involved in the regulation of pulsatile GnRH secretion.[3] Some notable substances include kisspeptin, neuropeptide Y (NPY), ghrelin, leptin, CRH, β-endorphin, and allopregnanolone.[3] Kisspeptin and its G-protein coupled receptor, GPR54, activate the HPO axis to directly stimulate GnRH secretion from the hypothalamus.[3] NPY regulates energy balance and affects feeding behavior and appetite.[3] If estradiol (E2) levels are sufficient, NPY induces GnRH secretion.[3] Ghrelin stimulates appetite and inhibits the HPO axis; it is found to be elevated in patients with FHA.[3] Conversely, leptin is reduced in patients with FHA and this may suppress GnRH through a kisspeptin-mediated pathway.[3][9]

Clinical presentation

FHA can be caused by chronic stress,[5] whether it be from psychosocial/emotional/mental factors, weight-related factors, or exercise-induced factors. As such, the clinical manifestations of the disorder are the result of this chronic stress caused by the above three factors. The "classic" description was previously a "thin woman who undereats and overexercises,"[5] but recent studies are finding FHA can also present as a "high-achieving individual"[5] with poor stress-management behaviors that include under- or over-eating and overexercising.[5]

Reproductive

FHA can have long and short term consequences in a patient's reproductive development and fertility. Anovulation and amenorrhea is the characteristic feature of FHA.[3] If hypoestrogenism and impaired HPO axis occurs during puberty, primary amenorrhea occurs.[4] If the impairment occurs after puberty, secondary amenorrhea occurs, which is more common.[4]

On physical exam, FHA presents with delayed development, with patients halted in the secondary and tertiary sex characteristics of the pubertal stage before they developed FHA.[4] The severity of the symptoms depends on the duration and severity of hypoestrogenism.[4]

In adolescents, FHA presents with delayed menarche and non-specific development of pubertal stages, and underdevelopment of secondary and tertiary sex characteristics.[3] In adult women, FHA can lead to atrophic changes, such as lack of cervical mucus, thinning of vaginal epithelium, and uterine muscle atrophy (hypoplasia), which can lead to painful intercourse (dyspareunia).[3][4]

Because anovulation is a characteristic feature, patients often suffer from infertility. Patients with a history of, or who currently have, FHA, who become pregnant, require extra care and monitoring during pregnancy to avoid the increased risks of inadequate weight gain, intrauterine fetal growth restrictions, miscarriage, and/or preterm labor.[3]

Bone

The majority of people reach their peak bone mass (PBM) around 30 years of age, however, 40-50% of that mass is formed during puberty.[3] In women, estrogens are the main component in proper bone formation.[3] Because FHA causes hypoestrogenism, women with FHA may lack age-appropriate bone density [5]and have an increased risk of skeletal fragility, stress fractures, osteopenia, and osteoporosis.[3] Additionally, women with FHA may have improper diets or malnutrition, leading to low calcium and vitamin D intake, and may have a tendency to overexercise, which further increases the risk for osteopenia.[3] This improper dieting and tendency to overexercise, leading to low bone density, is also seen in RED-S.[10] Unlike in males diagnosed with RED-S, females are at an increased risk for the consequences of decreased bone density, since females have a PBM 25-30% lower than males.[3] Although this decreased bone density is also seen in anorexia nervosa, the severity of peak bone density loss is less in FHA patients.[3]

Cardiovascular

Cardiovascular disease (CVD) is the leading cause of death in women in developed countries, and it is well studied that hypoestrogenism has many regulatory functions in the cardiovascular system.[3] Estradiol (E2), an estrogen steroid hormone and the major female sex hormone, has a cardio-protective effect.[3] As such, hypoestrogenism caused by FHA causes significant impairment in the endothelial and vascular function.[3][12] Although hypoestrogenism is the main cause of impaired cardiovascular health in FHA, patients also suffer from metabolic disturbances and an overall negative energy balance that further increases the risk of CVD.[3] Women with FHA caused by exercised-induced factors tend to have a higher lipid profile[13] and an increased frequency of diabetes mellitus,[3] with women who have both FHA and diabetes mellitus having a higher risk for CVD than women who have only diabetes mellitus.[12]

Neurological

High levels of cortisol caused by FHA is seen not just in peripheral tissues, but also in the cerebrospinal fluid (CSF), where it is unbound and therefore more biologically available.[5] FHA accelerates the onset of aging syndromes, such as osteoporosis and vaginal atrophy.[3][4] Because of the high levels of cortisol in the CSF, it is suggested that the chronic stress that causes FHA may alter not just the endocrinological secretory patterns, but also the neurological secretory patterns. This altering can impact brain health, and can lead to an increased risk in neurological aging syndromes, such as dementia and Alzheimer's Disease (AD).[5]

The low levels of estrogen seen in FHA may also contribute to the increased neurodegenerative risk.[5] Microglia are the main immune cells of the central nervous system (CNS) and protect the brain Estrogen is a significant regulator of microglia, and limits the inflammation that occurs when the brain is stressed (e.g. due to bacteria, viruses, hypoxia).[5] In FHA, the lack of adequate estrogen levels, combined with the chronic stress that caused FHA, promotes a neuroinflammatory state that can cause impaired neuron formation and neuronal stem cell survival, and promote neurodegenerative diseases.[5] However, more research is needed to find a direct link between FHA and its long term effects on neurological health.

Mental and Sexual Health

While it is known that mental and sexual health is related to estrogen levels in women, there are limited studies concerning FHA and mental and sexual health.[3] The increased cortisol release caused by FHA can contribute to fluctuating moods, difficulty coping with common life events and stresses, and disordered eating,[3] as serum cortisol levels correlate with the Hamilton Rating Scale for Depression (HAM-D) and Anxiety (HAM-A).[14] Studies have shown similarities between women affected with FHA and women affected with anorexia nervosa, including a tendency towards depression and an obsession with dieting and weight.[3]

Women with FHA tend to have more sexual problems, contributing to the mental health issues and hormonal imbalances associated with FHA.[3][15] However, more studies are needed to determine the effects of FHA on sexual health.[3]

Evaluation and diagnosis

Females who have menstrual cycles lasting longer than 45 days and/or amenorrhea for three or more months should be evaluated for FHA.[11] Differentiating FHA from the irregular menstrual patterns seen in adolescents during the initial years after menarche due to immaturity of the HPO axis can be challenging.[4][11] However, studies have shown that even during this period, the length of a menstrual cycle does not exceed 45 days.[4][11] Furthermore, healthy girls with normal BMI (18.5-25 kg/m2) should develop regular menstrual cycles (every 28 +/- 3-5 days) within 1-2 years after menarche.[4][11] FHA is a diagnosis of exclusion, and thus the evaluation should be used to rule out organic causes of amenorrhea (e.g., pregnancy, thyroid disorders, inflammatory bowel disease, etc.)[4][11] Evaluation for FHA may include a thorough history and physical exam, laboratory testing, and imaging if appropriate. The Endocrine Society Clinical Practice Guidelines on Functional Hypothalamic Amenorrhea (FHA) suggests obtaining a baseline bone mineral density measurement by DEXA scan from any patient with 6 or more months of amenorrhea.[11]

History and physical exam

To evaluate for FHA, a thorough personal history should be obtained. The patient should be asked about weight loss, level of physical activity, diet, low-weight eating disorders, significant stressors, menstrual pattern, bone fractures, and substance abuse.[11] A full physical exam, external gynecological and bimanual exam can be performed to assess for organic causes of amenorrhea.[11] FHA may present with weight loss, bradycardia, mottled, cool extremities, and/or yellowing of the skin.[11]

Laboratory testing

In all cases of amenorrhea, pregnancy should be excluded.[7] This can be done by obtaining serum B-hCG levels. In cases of suspected FHA, screening laboratory tests include a complete blood count (CBC), electrolytes, glucose, bicarbonate, blood urea nitrogen (BUN), creatinine, liver panel, and when appropriate, sedimentation rate and/or C-reactive protein levels.[11] The initial endocrine evaluation includes testing for levels of TSH and free T4, prolactin, LH, FSH, estradiol (E2), and anti-Mullerian hormone (AMH).[11] If clinical hyperandrogenism is evident, total testosterone and DHEA-S levels may also be obtained.[11] 17α-hydroxyprogesteone levels should be evaluated if late-onset congenital adrenal hyperplasia (CAH) is suspected.[11] A progestin challenge can also be conducted to evaluate levels of estrogen and the anatomic integrity of the outflow tract.[11][4] Withdrawal bleeding following the progestin challenge indicates sufficient levels of estradiol (E2) for endometrial thickening, and that the amenorrhea is a result of anovulation and progesterone deficiency.[4]

Imaging

A transvaginal ultrasound (TVUS) can be used to rule out any anatomic Mullerian tract abnormalities that may result in primary amenorrhea.[11] A brain MRI showing the sella turcica should be obtained in cases of unexplained hypogonadotropic hypogonadism, or when patients show evidence of central nervous system (CNS) symptoms such as severe or persistent headaches, persistent vomiting, changes in vision, thirst, or urination with no attributable cause.[11]

Management

The term "functional" in functional hypothalamic amenorrhea implies that the ovulatory ovarian dysfunction is reversible with correction of the underlying cause.[11] Correcting energy deficits to improve function of the HPO axis often includes lifestyle changes such as increasing caloric intake and reducing the level of physical activity with resultant weight gain for normalization of BMI.[11] Menstruation typically resumes after correction of the underlying energy deficit.[7] Avoidance of chronic stressors and modification of the stress-response with cognitive behavioral therapy (CBT) may also help in cases of FHA associated with significant stress.[4] A multi-disciplinary team approach in management that includes a medical doctor, dietitian, and a psychiatrist or psychologist to provide psychological support is recommended.[11]

If menstruation does not resume spontaneously following lifestyle changes, the patient should be monitored for thyroid function, HPO axis function, and concentrations of ACTH, cortisol, and prolactin every 4-5 months.[4]

Low bone density

Bone loss is best treated by correction of the underlying cause.[7] Patients should undergo evaluation of bone marrow density using a DEXA scan and started on Vitamin D and calcium supplementation.[7] If menstruation does not resume after 6 months with reasonable trial of non-pharmaceutical management, loss of bone mass becomes the main concern and hormonal therapy should be implemented.[4] Short-term use of transdermal estradiol E2 with cyclic oral progestin may be used for estrogen replacement.[4] Care must be taken to exclude risks for thromboembolic disease prior to implementation of hormonal therapy given the associated increase in risk for venous thromboembolism.[16] The Endocrine Society Clinical Practice Guidelines on Functional Hypothalamic Amenorrhea (FHA) recommend against oral contraceptives, bisphosphonates, denosumab, testosterone, and leptin for the improvement of bone mass density in FHA.[11] Oral contraceptives may mask the return of spontaneous menstruation while loss of bone mass continues.[11][7]

Anovulatory infertility

Following a complete fertility workup, the first line of treatment for anovulatory infertility secondary to FHA is pulsatile exogenous GnRH followed by gonadotropin therapy and induction of ovulation when GnRH is unavailable.[11][17] Ovulation can be induced with clomiphene citrate.[11] However, this therapy should be restricted to patients with a BMI >18.5 kg/m2 due to the increased risks associated with lower BMI including fetal loss, small for gestational age (SGA) babies, preterm labor, and delivery by Cesarean section.[11][3]

Psychological assessment

Patients with FHA should be screened for psychological stressors and referred to appropriate psychiatric care where they can receive psychological support, such as CBT.[11] Psychological disorders (e.g. anorexia nervosa) may be linked to amenorrhea through associated behaviors like hyperexercise and restrictive eating.[11]  

References

1. ^1 {{cite journal | vauthors = Nader S | title = Functional hypothalamic amenorrhea: case presentations and overview of literature | journal = Hormones | date = April 2018 | pmid = 29858842 | doi = 10.1007/s42000-018-0025-5 }}
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9. ^1 2 3 4 5 6 7 8 {{cite journal | vauthors = Fourman LT, Fazeli PK | title = Neuroendocrine causes of amenorrhea--an update | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 3 | pages = 812–24 | date = March 2015 | pmid = 25581597 | pmc = 4333037 | doi = 10.1210/jc.2014-3344 }}
10. ^1 {{Cite journal|last=Ljungqvist|first=Arne|last2=Budgett|first2=Richard|last3=Steffen|first3=Kathrin|last4=Sherman|first4=Roberta|last5=Meyer|first5=Nanna|last6=Lebrun|first6=Constance|last7=Constantini|first7=Naama|last8=Carter|first8=Susan|last9=Burke|first9=Louise|date=2014-04-01|title=The IOC consensus statement: beyond the Female Athlete Triad—Relative Energy Deficiency in Sport (RED-S)|url=https://bjsm.bmj.com/content/48/7/491|journal=Br J Sports Med|language=en|volume=48|issue=7|pages=491–497|doi=10.1136/bjsports-2014-093502|issn=1473-0480|pmid=24620037}}
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