Obstetrics and Gynecology

Hypogonadotropic Hypogonadism

Functional hypothalamic amenorrhea (FHA), stress-induced anovulation (SIA), athletic amenorrhea, psychogenic amenorrhea, functional hypothalamic chronic anovulation (FHCA), idiopathic hypothalamic hypogonadism

1. What every clinician should know

Functional hypothalamic amenorrhea (FHA) is a type of ovulatory dysfunction that results in chronic anovulation and amenorrhea. It is a diagnosis of exclusion, and it must be distinguished from other types of ovulatory dysfunction.

The proximate cause of FHA and related syndromes is chronic anovulation due to reduced hypothalamic GnRH drive. Specifically, GnRH pulse frequency is too slow to drive sufficient pituitary LH and FSH secretion to support folliculogenesis to the point of ovulation. The term functional implies that the condition is reversible and that the cause of the reduced GnRH drive is related to potentially modifiable behaviors and other stressors.

Evidence that stress is the cause of FHA includes the demonstration that (1) cortisol levels are higher in women with FHA than in eumenorrheic ovulatory women and women with other forms of ovulatory dysfunction, and (2) that recovery from FHA results in reduction in circulating cortisol levels to cortisol levels seen in eumenorrheic ovulatory women. In practice, it may be difficult to detect hypercortisolemia because the elevation of cortisol is most evident at night and a single day time blood sample may not capture hypercortisolemia.

By definition, FHA is not attributable to organic etiologies; however, to make the diagnosis of FHA, all organic causes must be excluded. FHA may result from chronic or severe illness, such as cancer or pneumonia, but the term functional means that the hypothalamic-pituitary GnRH-gonadotropin apparatus is anatomically intact. In practice, it is often difficult to exclude insufficient GnRH drive due to genetic mutations in the genes critical to GnRH ontogeny and function, and it has been hypothesized that women with genetic mutations are more sensitive to stressors.

Reduced GnRH input reduces circulating LH and FSH to levels too low to fully support folliculogenesis to the point of ovulatory adequacy. Amenorrhea is the most clinically recognizable manifestation of reduced GnRH and occurs when there is sustained suppression of GnRH pulsatility to less than 50% of expected.

Because the suppression of GnRH exists on a spectrum, so too does the clinical presentation. More clinically occult forms due to lesser or intermittent suppression of GnRH exist that result in partial folliculogenesis and are termed luteal insufficiency and anovulatory cycling. Luteal insufficiency also exists as a spectrum ranging from preservation duration of progesterone secretion for 12 to 14 days but with a reduced amount of progesterone across the duration to shortened duration with lower progesterone levels.

In luteal insufficiency, the endometrium would not support implantation due to insufficient secretory transformation that causes developmental asynchrony between endometrium and embryo during the window of implantation. The patient may report infertility as the presenting symptom with regular cycles rather than a change in menstrual cycle duration or flow.

FHA and PCOS may co-exist and thus FHA can present in women with stigmata of hyperandrogenism or other features of PCOS including obesity. Obesity alone may suppress GnRH drive, so not all obese women who are anovulatory have PCOS. The following clinical presentations may be due to chronic or intermittent functional insufficiency of GnRH drive: complete anovulation and amenorrhea, hypermenorrhea with short menstrual intervals, oligomenorrhea with long cycle intervals, menometrorrhagia, and eumenorrheic infertility. As noted above, functional hypothalamic hypogonadism presents as a spectrum and some of the bleeding patterns reflect luteal insufficiency which by definition is not anovulatory. For this reason, the FIGO terms anovulatroy uterine bleeding (AUB) does not fully capture the spectrum of presentation of functional hypothalamic hypogonadism. Men can also develop functional hypothalamic hypogonadism due to insufficient GnRH drive that results in oligoasthenospermia with or without reduced testosterone levels.

Importantly, functional hypothalamic amenorrhea is more than an isolated disruption of GnRH drive. Functional suppression of GnRH is universally accompanied by increased cortisol secretion due to altered hypothalamic-pituitary CRH-ACTH drive and reduced thyroxine (T4) and thyroxine (T3) due to lowered hypothalamic-pituitary TRH-TSH input. At a minimum, the constellation of neuroendocrine aberrations characteristic of FHA reflects altered feedback sensitivity to estradiol, cortisol, and thyroxine.

Other feedback sensitivities may be altered, including leptin and ghrelin signaling. Increased circulating and CSF cortisol levels are specific to FHA. Many of the clinical consequences of FHA such as osteoporosis reflect the clinical impact of the full constellation of neuroendocrine aberrations that accompany FHA.

Risk factors for the development and persistence of FHA include any factors that chronically activate the HPA axis and commonly include greater energy expenditure than intake, excessive exercise, nutritional restriction of protein and fats, unrealistic expectations of self and others, attitudes that increase reactivity to common and uncommon stressors including perfectionism, high need for social approval, and conditional love. Stressors are synergistic rather than additive. Recovery from FHA results when cortisol levels are restored; restoration of eucortisolism permits secondary resumption of GnRH and TRH drive and restoration of eumetabolism independent of weight gain.

2. Diagnosis and differential diagnosis

The causes differ for primary and secondary presentations of amenorrhea. The differential diagnosis includes: (1) müellerian anomalies, congenital and acquired, that block the outflow tract, including vaginal agenesis, imperforate hymen, and Asherman syndrome; (2) ovarian causes of anovulation, such as gonadal agenesis, Turner syndrome (45, XO), polycystic ovary syndrome, and premature ovarian insufficiency (premature menopause); (3) other endocrine conditions, such as primary hyperthyroidism and hypothyroidism, and Cushing syndrome and disease; (4) pituitary causes, such as pituitary adenomas and hyperprolactinemia; and (5) organic central causes, such as meningioma and Kallman syndrome and variants. The causes to be investigated can be categorized as vaginal, cervical, uterine, ovarian, adrenal, thyroidal, pituitary, hypothalamic, and central.

Defining reproductive tract anatomy is always the first step in excluding anatomic causes of amenorrhea and doing so is especially important in primary amenorrhea. Outflow tract anomalies often present as primary amenorrhea and require a physical examination and often imaging with ultrasound or MRI to exclude and/or define anatomic anomalies.

Asherman syndrome from intrauterine synechiae, adhesions, or unintended endometrial ablation may present as secondary amenorrhea. A history of a postpartum D&C or pelvic infection may raise the index of suspicion for endometrial injury, but hysteroscopy is typically needed to establish the diagnosis of Asherman syndrome. Polymenorrhea may be due to intrauterine polyps or intramural fibroids rather than functional hypothalamic hypogonadism.

A karyotype is needed to evaluate the possibility of gonadal dysgenesis and Turner syndrome, although typically there are physical stigmata. Amenorrhea in the setting of a 46,XY karyotype may reflect müellerian agenesis and either (1) 5-alpha reductase deficiency causing insufficient production of dihydrotestosterone (DHT) from testosterone or (2) androgen insensitivity syndromes (AIS) due to variable androgen receptor sensitivity. In both of these conditions, the uterus regressed during development and the gonad is a testes, but its location may be inguinal or pelvic. If the karyotype is 46,XY, a testosterone level will be in the male range in 5-alpha reductase deficiency and AIS, and very low in gonadal dysgenesis (Swyer syndrome).

In the setting of secondary amenorrhea, history is important, and physical examination often shows normal reproductive anatomy and external genitalia. Thus it is critical to obtain screening clinical chemistry studies to establish the diagnosis.

In amenorrhea, the timing of the blood sampling is not important. A panel that includes LH, FSH, estradiol (E2), progesterone, TSH, free thyroxine, prolactin, and androstenedione detects most important causes if properly interpreted. The pattern of hormone levels is more critical than absolute values. In FHA, FSH will be in the normal range and typically it will be slightly higher than LH, which will also be in the normal or low normal range, with estradiol less than 50 pg/ml and progesterone less than 1 ng/ml. Very low LH and FSH levels suggest organic HA due to genetic mutations affecting GnRH ontogeny and function or central causes such as brain or pituitary tumors.

Anosmia indicates Kallman syndrome, which is failure of GnRH neurons to migrate from the olfactory placode to the hypothalamus. Androstenedione (or testosterone) will be in the lower range of normal, both TSH and free thyroxine will be in the lower range of normal (hypothalamic hypothyroidism or sick euthyroid syndrome), and prolactin will be in the low normal range.

In contrast, elevated LH and FSH with low E2 (< 50 pg/mL) and progesterone (< 1 ng/mL) indicate low or absent ovarian reserve consistent with complete or impending premature menopause. High LH and FSH with E2 >150 pg/ml and progesterone less than 2 ng/ml indicates the midcycle gonadotropin surge. If TSH is low and free thyroxine is high, then one must consider the possibility of autoimmune hyperthyroidism (Graves disease). Similarly, if TSH is in the upper limit of normal while free thyroxine is in the lower range of normal, then autoimmune thyroiditis and hypothyroidism must be considered and the next step would be to measure antithyroid antibodies, such as thyroid peroxidase and thyroid stimulating immunoglobulin.

If frank hyperprolactinemia is found, additional evaluation is needed and is beyond the scope of this chapter. Prolactin levels are elevated by food, sleep, exercise, coitus, nipple stimulation, physical examination, lactation, and many medications. Acromegaly may present with oligomenorrhea or amenorrhea and an elevated somatomedin-C (IGF-1). Diabetes may present as oligomenorrhea or amenorrhea. As with Cushing syndrome and disease, the cause is reduced GnRH drive.

While the cause of FHA is stress, the increase in cortisol secretion in FHA is less than that seen with Cushing syndrome, and disease and the circadian pattern is preserved; so the cortisol increase is highest overnight and in the early morning hours. If Cushing is suspected, a 24-hour urinary free cortisol (UFC) is a reasonable screening test. Rarely secondary adrenal insufficiency presents as fatigue and anovulation. Serum dehydroandrosterone sulfate (DHEAS) will be in the lower range for age.

The differential diagnosis of low normal DHEAS includes Sheehan syndrome with partial or complete pituitary apoplexy. Referral to a reproductive endocrinologist or endocrinologist is strongly recommended. Provocative stimulation testing helps to establish pituitary hypofunction due to injury, tumor, autoimmune hypophysitis or other CNS conditions. History is essential for elaborating the differential diagnosis and guiding the evaluation.

MRI of the pituitary and the brain will exclude (or confirm) serious CNS conditions. A history of trauma should raise the index of suspicion to include pituitary stalk damage. The differential diagnosis of central lesions and conditions is extensive. A high index of suspicion and a low threshold for obtaining a MRI is recommended.

Certain medications and drugs of abuse suppress GnRH drive or cause other endocrine perturbations. Chronic drug use is often a marker of stress and undernutrition. An evaluation for syndromal psychiatric conditions, such as eating disorders, depression, and personality disorders, is critical. Formal psychiatric evaluation may be indicated. Psychiatric conditions are associated with activation of the hypothalamic-pituitary-adrenal axis and appropriate treatment may reverse the functional suppression of GnRH drive.

3. Management

Functional hypothalamic amenorrhea will theoretically reverse when stress is reduced or is managed such that hypercortisolism is reduced. Assuming that stress has been identified as the probable cause and that all other conditions have been evaluated and excluded, stress management is indicated. The goal of treatment is to identify and reduce the neuroendocrine impact of stressors.

Some stressors can be removed or avoided, but stress is a component of living, so psychoeducation about how to manage typical stressors is more practical than trying to eradicate or remove stressors. Typically in FHA, the stressors are multiple and seemingly minor. When assessing stress, the goal is to define the total burden or what is termed “allostatic load.”

For practical purposes, stressors are often categorized as metabolic stressors or behaviors in which energy expenditure exceeds energy intake and psychogenic stressors. Psychogenic stressors can be internally imposed and are often unrealistic demands or attitudes that compromise coping with more common daily demands that are to some extent externally imposed.

Typically, individuals with FHA report a mix metabolic and psychogenic variables that synergistically interact, and they display greater neurobiologic reactivity to stressors than individuals who apparently are more stress-resilient. Metabolic stressors, such as exercise and nutritional restriction, are often undertaken to reduce psychological stress and yet havethe potential to serve independently as metabolic or even psychogenic stressors.

Identifying the attitudes and behaviors, and teaching better attitudes and coping styles, has been shown to reduce the neuroendocrine impact of stressors and may result in a decrease in cortisol, particularly during sleep; an increase in leptin independent of weight gain; and an increase in TSH. In a small pilot study, Berga et al showed that 75% of women with FHA randomized to cognitive behavior therapy (CBT) regained ovulatory ovarian function, whereas only 25% of those randomized to observation showed return of ovarian function.

Stress management can be undertaken before or concurrently with other interventions, including infertility therapy. One form of stress management that has been documented to restore ovulatory ovarian function and reduce hypercortisolemia is CBT. Clomiphene citrate is less effective in eliciting an increase in FSH release when GnRH drive is suppressed and feedback sensitivity is deranged. The efficacy of aromatase inhibitors has not been studied in the context of FHA. While antidepressants reduce hypercortisolemia in those with depression and PTSD, their use for treatment of FHA has not been studied.

It is not uncommon for patients with FHA to undergo gonadotropin therapy and assisted reproductive therapies (ART) to treat the infertility associated with FHA. The pros and cons of this approach are open to debate. Potential maternal and fetal consequences of maternal stress include preterm labor, intrauterine growth restriction, and fetal neurodevelopmental disorders such as learning disabilities and autism spectrum disorders. ART is likely to increase rather than decrease metabolic and psychogenic stress. ART may amplify the neuroendocrine consequence of pre-existing stress, exposing oocytes, the mother, and the fetus to persistent neuroendocrine aberrations, including lower thyroxine and higher cortisol.

Since the mother is the sole source of thyroxine in the first trimester and since thyroxine is critical for fetal neuronal migration and differentiation, fetal neurodevelopment may be compromised. Even intermittent hypercortisolemia may accelerate placental aging and induce epigenetic changes in fetal DNA. Ultimately, the consequences of these exposures may be to potentiate the fetal origins of adult disease.

Health conditions that accrue from chronic FHA putatively include osteoporosis, syndromal psychiatric conditions, and infertility. Longer term health consequences may include an increased risk of cardiovascular diseases and neurodegenerative diseases due to persistent stress and hypercortisolism. Treatment of osteoporosis with bisphosphonates in women intending to become pregnant is discouraged because the bisphosphonates incorporate into maternal bone and then are mobilized during pregnancy and incorporated into fetal bone. Hormone replacement regimens also have limitations and may not permit full bone accretion because glucocorticoids abrogate the impact of estrogens by competing for transcriptional co-activators or alternatively by interfering with estrogen action by competitively blocking DNA binding to the cis consensus site known as AP-1. There is no reason to assume that chronic stress is benign or that hormone replacement regimens can fully counteract the clinical impact of chronic stress or the constellation of neuroendocrine aberrations that accompany FHA.

4. Complications

Contraceptive agents may be used in FHA for contraceptive purposes. However, doing so will mask recovery from FHA and will make it impossible to track the impact of CBT upon resumption of ovarian function. Indeed, what was once termed postpill amenorrhea may simply represent FHA that developed while taking a contraceptive formulation.

There is no evidence that hormone use is otherwise harmful in women with FHA, but it may not confer the same theoretical benefits such as bone accretion or reduced CVD risk that are touted for eumetabolic women. Hormone use would not be expected to reverse the metabolic impact of stress and hypercortisolism. Said another way, cortisol elevations outside the relatively narrow range seen in eumetabolic and eumenorrheic women are likely to elicit metabolic and immunologic changes, the consequences of which may not be benign, and may abrogate the customary benefits of endogenous or exogenous sex steroid exposures.

As noted above, the use of bisphosphonates to improve bone density is discouraged in women who might subsequently become pregnant. The use of agents such as clomiphene citrate and aromatase inhibitors to induce ovulation may not have the same efficacy as they do in eumetabolic women. There are likely to be additional or increased maternal and fetal risk when ART is performed in patients with functional hypothalamic hypogonadism.

5. Prognosis and outcome

The reversibility of FHA by CBT has been demonstrated in a pilot study only. The long-term impact of other interventions, such as hormone replacement therapies or antidepressants remains to be established. Fertility treatments may carry additional risks to mother and fetus due to the neuroendocrine alterations in cortisol and thyroxine. Stress is very likely to pose long-term health consequences and to the extent possible interventions to mitigate stress should be initiated.

6. What is the evidence for specific management and treatment recommendations

Berga, SL. "Stress and reproduction: a tale of false dichotomy?". Endocrinology. vol. 149. 2008. pp. 867-8.

(This reference discusses why metabolic stressors are also psychogenic stressors and vice versa.)

Berga, SL, Daniels, TL, Giles, DE. "Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations". Fertil Steril. vol. 67. 1997. pp. 1024-30.

(This reference showed that elevated cortisol levels are found only in women with FHA and not in women with other forms of anovulation such as PCOS.)

Berga, SL, Loucks-Daniels, TL, Adler, LJ. "Cerebrospinal fluid levels of corticotropin-releasing hormone in women with functional hypothalamic amenorrhea". Am J Obstet Gynecol. vol. 182. 2000. pp. 776-81.

(This manuscript demonstrated that CRH levels are not elevated in the CSF of women with FHA despite the fact that they have elevated cortisol levels and then discusses the significance of this finding in terms of set point and allostasis.)

Berga, SL, Marcus, MD, Loucks, TL, Hlastala, S, Ringham, R, Krohn, MA. "Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy". Fertil Steril. vol. 80. 2003. pp. 976-81.

(The first manuscript to show that one effect of CBT in women with FHA is restoration of ovulatory ovarian activity.)

Berga, SL, Mortola, JF, Girton, L. "Neuroendocrine aberrations in women with functional hypothalamic amenorrhea". J Clin Endocrinol Metab. vol. 68. 1989. pp. 301-8.

(A paradigm shift in the conceptualization of FHA, this manuscript was the first to show that FHA involved a constellation of neuroendocrine aberrations and not just a suppression of GnRH drive or an elevation of circulatory cortisol.)

Brundu, B, Loucks, TL, Adler, LJ, Cameron, JL, Berga, SL. "Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea". J Clin Endocrinol Metab. vol. 91. 2006. pp. 1561-5.

(This manuscript demonstrated for the first time that women with FHA display a greater relative elevation of cortisol in the CSF as contrasted with the circulation and discussed this finding in the context of allostasis.)

Caronia, LM. "A genetic basis for FHA". NEJM. vol. 364. 2011. pp. 215.

(A review articile about the multiple genetic polymorphisms found in women with organic hypothalamic amenorrhea.)

Giles, DE, Berga, SL. "Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison". Fertil Steril. vol. 60. 1993. pp. 486-92.

(This reference shows that women with FHA have attitudes and coping mechanisms that predispose to stressful reactions to everyday events.)

Marcus, MD, Loucks, TL, Berga, SL. "Psychological correlates of functional hypothalamic amenorrhea". Fertil Steril. vol. 76. 2001. pp. 310-6.

(The manuscript extends our previous studies on the psychological profiles of women with FHA.)

Michopoulos, V, Mancini, F, Loucks, TL, Berga, SL. "Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial". Fertil Steril. vol. 99. 2013. pp. 2084-91.

(This landmark manuscript shows that the recovery of ovulatory function that follows CBT is accompanied by a change in cortisol levels, especially at night, when subjects were sleeping.)

Whirledge, S, Cidlowski, JA. "A role for glucocorticoids in stress-impaired reproduction: beyond the hypothalamus and pituitary". Endocrinology. vol. 154. 2013. pp. 4450-68.

(This review discusses the molecular mechanisms by which glucocorticoids counteract the effects of estradiol at the cellular level.)

Williams, NI, Berga, SL, Cameron, JL. "Synergism between psychosocial and metabolic stressors: impact on reproductive function in cynomolgus monkeys". Am J Physiol Endocrinol Metab. vol. 293. 2007. pp. E270-6.

(This landmark article shows that there is profound interaction between stressors and reproductive compromise and demonstrates how allostatic load represents more than the additive effects of stressors.)
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