Functional Hypothalamic Amenorrhea: Recognition and Management of a Challenging Diagnosis.

Functional hypothalamic amenorrhea is responsible for approximately a third of the cases of secondary amenorrhea. The condition is a result of disturbances in gonadotropin-releasing hormone pulsatile secretion at the level of the hypothalamus, which in turn disrupts gonadotropin secretion. It is due to psychosocial stress, disordered eating, and/or excessive exercise. Often, however, it is a combination of more than one etiology, with a possible role for genetic or epigenetic predisposition. The dysfunctional gonadotropin-releasing hormone release leads to the cessation of ovarian function, resulting in amenorrhea, infertility, and a long-term impact on affected women's bone health, cardiovascular risk, cognition, and mental health. Functional hypothalamic amenorrhea is a diagnosis of exclusion, and treatment involves identifying and reversing the underlying cause(s). The aim of this concise review is to summarize the current knowledge of functional hypothalamic amenorrhea, review its pathophysiology and the adverse health consequences, and provide recommendations for diagnosis and management of this condition. Furthermore, this review will emphasize the gaps in research on this common condition impacting women of reproductive age all over the world.

My 28 Days - a global digital women's health initiative for evaluation and management of secondary amenorrhea: case report and literature review.

There is a need to close the gap between knowledge and action in health care. Effective care requires a convenient and reliable distribution process. As global internet and mobile communication increase capacity, innovative approaches to digital health education platforms and care delivery are feasible. We report the case of a young African woman who developed acute secondary amenorrhea at age 18. Subsequently, she experienced a 10-year delay in the diagnosis of the underlying cause. A global digital medical hub focused on women's health and secondary amenorrhea could reduce the chance of such mismanagement. Such a hub would establish more efficient information integration and exchange processes to better serve patients, family caregivers, health care providers, and investigators. Here, we show proof of concept for a global digital medical hub for women's health. First, we describe the physiological control systems that govern the normal menstrual cycle, and review the pathophysiology and management of secondary amenorrhea. The symptom may lead to broad and profound health implications for the patient and extended family members. In specific situations, there may be significant morbidity related to estradiol deficiency: (1) reduced bone mineral density, 2) cardiovascular disease, and 3) cognitive decline. Using primary ovarian insufficiency (POI) as the paradigm condition, the Mary Elizabeth Conover Foundation has been able to address the specific global educational needs of these women. The Foundation did this by creating a professionally managed Facebook group specifically for these women. POI most commonly presents with secondary amenorrhea. Here we demonstrate the feasibility of conducting a natural history study on secondary amenorrhea with international reach to be coordinated by a global digital medical hub. Such an approach takes full advantage of internet and mobile device communication systems. We refer to this global digital women's health initiative as My 28 Days®.

Menstrual disorders in adolescents and young adults with eating disorders.

Although amenorrhea is no longer a specific criterion required to make the diagnosis of anorexia nervosa (AN), the relationship between restrictive eating and menstrual status remains important in the diagnosis, treatment, and consequences for patients with eating disorders. Clinicians should understand the relationship between menstrual irregularities and malnutrition due to eating disorders, as it may be possible to intervene sooner if the diagnosis is made earlier. Treatment of AN (in those who are underweight) and atypical AN (in those who are not underweight) is aimed at cessation of restrictive thoughts and behaviors, restoration of appropriate nutrition and weight, and normal functioning of the body. While eating disorder thoughts and behaviors are helped by both therapy and nutrition, regular functioning of the body, including regular menstruation, is linked to both appropriate nutrition and weight. Patients who are not underweight based on their body mass index (BMI) may still have oligo/amenorrhea due to their caloric restriction; thus any patient who has irregular menses should have a detailed dietary evaluation as part of their workup. Timely diagnosis and treatment of patients with eating disorders and amenorrhea is important due to the impact on bone mass accrual for adolescents who have prolonged amenorrhea. Menstrual abnormalities may also be seen in patients with bulimia nervosa (BN).

Etiology and management of amenorrhea in adolescent and young adult women.

In this article, we will review the etiology and management of amenorrhea in adolescent and young adult women, beginning with the diagnostic work-up and followed by etiologies organized by system. Most cases of amenorrhea are caused by dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis, which is the major regulator of the female reproductive hormones: estrogen and progesterone.  We begin by reviewing hypothalamic etiologies, including eating disorders and relative energy deficiency in sport. Then, pituitary causes of amenorrhea are reviewed, including hyperprolactinemia, empty sella syndrome, Sheehan's syndrome and Cushing's syndrome. Next, ovarian causes of amenorrhea are reviewed, including polycystic ovarian syndrome and primary ovarian insufficiency. Finally, other etiologies of amenorrhea are discussed, including thyroid disease, adrenal disease and reproductive tract anomalies. In conclusion, there is a wide and diverse range of causes of amenorrhea in adolescents that originate from any level of the HPO axis, as well as anatomic and chromosomal etiologies.   Treatment should be focused on the underlying cause. Preservation of bone density and risk of fractures should be discussed with amenorrheic patients since many causes of amenorrhea can result in decreased bone density and may be irreversible.

Idiopathic hyperprolactinemia - A challenge for primary care.

Hyperprolactinemia is a condition of elevated serum prolactin, which usually occurs in women as compared to men. Most patients present to primary care clinics with a history of galactorrhoea, oligomenorrhea, amenorrhoea or infertility. Literature search reveals that there were few idiopathic causes of hyperprolactinemia, which resolved by itself without specific pharmacological or surgical treatment. This case is of a 39-year-old woman presented with amenorrhea for four months after Implanon removal and concomitantly noted to have galactorrhoea for four years without any medical attention. The condition persisted after cessation of breastfeeding. After undergoing several investigations including imaging studies, the underlying cause of hyperprolactinemia was noted to be idiopathic. Due to the unclear cause of its aetiology, this case caused various challenges to the primary care. Exhaustive physiological and pathological causes of hyperprolactinemia have been ruled out. Nevertheless, with adequate treatment, she gained her normal menstrual and resolved galactorrhoea symptoms.

Aetiology And Management Of Primary Amenorrhoea.

BACKGROUND: Amenorrhoea is absence of menstruation. It could be primary, if menstruation has not occurred by the age of 16 years in the presence of normal growth and secondary sexual characters or by the age of 14 years in the absence of secondary sexual characters. It is secondary if periods have not occurred for six months. This study was done with the objective to determine the frequency of etiologic causes of primary amenorrhoea. STUDY DESIGN: Cross-sectional descriptive study. METHODS: The study was conducted in the department of Obstetrics and Gynaecology Sheikh Khalifha Bin Zyed Al Nahyan /Combined Military Hospital Muzaffarabad Azad Jammu Kashmir (SKBZ/CMH MZD AJK) from December 2014 to November 2017. Women with primary amenorrhoea reported and managed in the hospital are included in the study. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, hormonal profile, pelvic ultrasound, magnetic resonance imaging and cytogenetic study including karyotyping.. RESULTS: Three most common causes of primary amenorrhoea were Mullerian anomalies (36.7%) followed by gonadal dysgenesis (33.3%), hypothalamic causes (23.3%) and Pituitary causes (6.7%). There were 03 cases of polycystic ovarian syndrome and 02 cases of hyperprolactinemia. CONCLUSIONS: The most common etiological factor leading to primary amenorrhoea is Mullerian anomalies followed by gonadal dysgenesis. Genetic and environmental factors could also play role in the causes of primary amenorrhoea.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary amenorrhea and female delayed puberty.

Puberty is the period of transition from childhood to adulthood characterized by the attainment of adult height and body composition, accrual of bone strength and the acquisition of secondary sexual characteristics, psychosocial maturation and reproductive capacity. In girls, menarche is a late marker of puberty. Primary amenorrhea is defined as the absence of menarche in ≥ 15-year-old females with developed secondary sexual characteristics and normal growth or in ≥13-year-old females without signs of pubertal development. Furthermore, evaluation for primary amenorrhea should be considered in the absence of menarche 3 years after thelarche (start of breast development) or 5 years after thelarche, if that occurred before the age of 10 years. A variety of disorders in the hypothalamus-pituitary-ovarian axis can lead to primary amenorrhea with delayed, arrested or normal pubertal development. Etiologies can be categorized as hypothalamic or pituitary disorders causing hypogonadotropic hypogonadism, gonadal disorders causing hypergonadotropic hypogonadism, disorders of other endocrine glands, and congenital utero-vaginal anomalies. This article gives a comprehensive review of the etiologies, diagnostics and management of primary amenorrhea from the perspective of pediatric endocrinologists and gynecologists. The goals of treatment vary depending on both the etiology and the patient; with timely etiological diagnostics fertility may be attained even in those situations where no curable treatment exists.

Fifteen-minute consultation: a structured approach to the child with primary amenorrhea.

Puberty is a life-changing time in the life of a young person, with physical, psychological and social considerations. Amenorrhea is derived from Latin: a-'not', men-'month' and rhein-'flow', meaning absence of monthly flow. In medical terms, it is a symptom describing absence of menstruation. It can be classified as either primary or secondary. This article will focus solely on primary amenorrhea. Primary amenorrhea can induce great anxiety in both the patient and the family and often presents to the general paediatrician. A thorough history and examination and judicious use of investigations is crucial to ensure timely diagnosis and management.

Osteoporosis in Premenopausal Women: A Clinical Narrative Review by the ECTS and the IOF.

CONTEXT: Consensus regarding diagnosis and management of osteoporosis in premenopausal women (PW) is still lacking due to few studies carried out in this population. DESIGN: The European Calcified Tissue Society and the International Osteoporosis Foundation convened a working group to produce an updated review of literature published after 2017 on this topic. RESULTS: Fragility fractures in PW are rare and mostly due to secondary osteoporosis (ie, in presence of an underlying disease such as hormonal, inflammatory, or digestive disorders). In absence of another disorder, low bone mineral density (BMD) together with fragility fractures qualifies as idiopathic osteoporosis. In contrast, low BMD alone does not necessarily represent osteoporosis in absence of bone microarchitectural abnormalities. BMD increases in PW with osteoporosis when the underlying disease is treated. For example, in celiac disease, an increase of 9% in radius trabecular volumetric density was achieved after 1 year of gluten-free diet, while anti-tumor necrosis factor alpha improved BMD in PW with inflammatory bowel diseases. In amenorrhea, including anorexia nervosa, appropriately delivered estrogen replacement therapy can also improve BMD. Alternatively, antiresorptive or anabolic therapy has been shown to improve BMD in a variety of conditions, the range of improvement (3%-16%) depending on skeletal site and the nature of the secondary cause. No studies were powered to demonstrate fracture reduction. The effects of bisphosphonates in childbearing women have been scantly studied and caution is needed. CONCLUSION: The majority of PW with osteoporosis have an underlying disease. Specific therapy of these diseases, as well as antiresorptive and anabolic drugs, improve BMD, but without evidence of fracture reduction.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea in adolescent girls. It is often seen in the setting of stress, weight loss, or excessive exercise. FHA is a diagnosis of exclusion. Patients with primary or secondary amenorrhea should be evaluated for other causes of amenorrhea before a diagnosis of FHA can be made. The evaluation typically consists of a thorough history and physical examination as well as endocrinological and radiological investigations. FHA, if prolonged, can have significant impacts on metabolic, bone, cardiovascular, mental, and reproductive health. Management often involves a multidisciplinary approach, with a focus on lifestyle modification. Depending on the severity, pharmacologic therapy may also be considered. The aim of this paper is to present a review on the pathophysiology, clinical findings, diagnosis, and management approaches of FHA in adolescent girls.

Return of Menses in Previously Overweight Patients with Eating Disorders.

STUDY OBJECTIVE: Adolescents with eating disorders and a history of overweight present with higher weights, longer duration of disease, but equally severe symptomatology compared with previously normal weight patients. To better delineate treatment goals for this understudied population, we compared weight at menses resumption with premorbid maximum weight among previously overweight and normal weight patients. DESIGN: Retrospective cohort study. SETTING: Outpatient adolescent medicine clinic at an eating disorder referral center. PARTICIPANTS: Postmenarchal patients meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition eating disorders. History of overweight was defined as a body mass index (BMI) greater than or equal to the 85th percentile or 25 or more. INTERVENTIONS AND MAIN OUTCOME MEASURES: Weight characteristics at presentation and menses resumption (BMI, BMI z-score, change from maximum weight to presentation weight) RESULTS: Previously overweight patients presented with greater mean weight, longer duration of disease, and higher BMI than previously normal weight patients. No difference was found in rates of amenorrhea at presentation or menses resumption. Previously overweight patients resumed menses at a younger age and higher BMI z-scores. The difference between weight at menses resumption and premorbid maximum weight was greater for previously overweight patients. CONCLUSION: Previously overweight patients with eating disorders present differently than their normal-weight peers, so reliance on weight status as a screening criterion might result in underdiagnosis. Although BMI z-scores associated with menses resumption are higher for previously overweight patients, there is no difference in weight gain between presentation and menses resumption and time to menses resumption compared with previously normal-weight patients. Moreover, menses resumption occurred at weights significantly lower than premorbid maximum weight for previously overweight patients, so restoration to highest premorbid weight is not necessary.

The efficacy of using acupuncture in managing polycystic ovarian syndrome.

PURPOSE OF REVIEW: Polycystic ovarian syndrome (PCOS) is a common reproductive disorder, which significantly impairs the fertility of 3-10% of women at reproductive age. It is getting very popular for women with PCOS to seek alternative therapies to treat PCOS, for example, acupuncture. This review examines the currently available evidence from the randomized controlled trial to guide future recommendation on using acupuncture to assist the treatment of PCOS. RECENT FINDINGS: PCOS is manifested by oligo-amenorrhoea, infertility, and hirsutism. The standard treatment of PCOS includes oral pharmacological agents, lifestyle changes, and surgical modalities. Pharmacologically based therapies are only effective in 60% of the patients, which are also associated with different side-effects. As such, acupuncture offered an alternative option. Acupuncture can affect ß-endorphin production, which may, in turn, affect gonadotropin-releasing hormone secretion and affecting ovulation and menstrual cycle. Therefore, it is postulated that acupuncture may induce ovulation and restore menstrual cycle via increasing ß-endorphin production. SUMMARY: Although modern medical science has discovered the action mechanisms underlying how acupuncture may manage the symptoms of PCOS, majority of the trials are small in sample size and lack of consistency in the choice of acupoints. Larger scale trials are needed to provide standardized protocols.

Treatment of postpill amenorrhea with abdominal obesity by traditional Korean medicine treatment focused on pharmacopuncture and moxibustion: A case report.

RATIONALE: Hormone imbalance and menstrual irregularities are normal for postpill women. Pharmacopuncture and moxibustion can stimulate acupoints with herbal extract and heat, respectively, to regulate the function of qi and blood, expel pathogens, and support health. PATIENT CONCERNS: A 39-year-old female patient presented with amenorrhea, >6 months after she had stopped taking the oral contraceptive pill, which she had taken for more than 10 years, and possible associated infertility. Additionally, she reported sudden weight gain of approximately 12 kg in 1 year. DIAGNOSES: In this study, we examined the amenorrhea lasted more than 6 months for postpill patient. INTERVENTIONS: She refused a strong acupuncture stimulus; she underwent lower abdomen pharmacopuncture with wild ginseng complex (WGC) and moxibustion at CV4, 5 times during 1 month. As a secondary treatment, 1 g Geoseub-hwan pills were prescribed for overeating and during social events. After 5 weekly primary treatments, Geoseub-hwan was prescribed intermittently. OUTCOME: After 3 primary treatments, she began menstruation without menstrual cramps or discomfort. After 5 treatments, she exhibited improvement of body weight and body composition. At 1- and 3-month follow-up examinations, she confirmed regular menstruation without discomfort. LESSONS: Pharmacopuncture with WGC and moxibustion may be effective for the treatment of postpill amenorrhea with abdominal obesity and can be used for patients with fear of a strong acupuncture stimulus.

Amenorrhea: A Systematic Approach to Diagnosis and Management.

Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if menarche has not occurred by 15 years of age or three years post-thelarche. Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a pregnancy test and assessment of serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, should be individualized. Patients with primary ovarian insufficiency can maintain unpredictable ovary function and may require hormone replacement therapy, contraception, or infertility services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and endometrial cancer risk. Amenorrhea can be associated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support.

Can improvement in hormonal and energy balance reverse cardiovascular risk factors in athletes with amenorrhea?

Female athletes display a high prevalence of hypothalamic amenorrhea as a result of energy imbalance. In these athletes with amenorrhea, decreased luteinizing hormone/follicule-stimulating hormone secretion leads to deficiency in endogenous estrogen. The severe estrogen deficiency in these athletes may increase cardiovascular risk similar to that in postmenopausal women. This review discusses the potential cardiovascular risk factors in athletes with amenorrhea as a result of hypoestrogenism, which include endothelial dysfunction and unfavorable lipid profiles. We also consider the potential to reverse the cardiovascular risk by restoring energy or hormonal imbalance along the reproductive axis in athletes with amenorrhea.

Amenorrhoea in adolescent female athletes.

Female athletes often experience amenorrhoea at various times during training, but this should not be considered normal. Low energy availability is a common cause of menstrual dysfunction, and amenorrhoea can serve as a warning sign of some of the health and performance consequences associated with inadequate energy, including poor bone accrual and low bone mineral density. Adolescence is an important time for bone accrual, growth, and development, making delayed menarche and secondary amenorrhoea particularly concerning in young athletes. The development of disordered eating and eating disorder behaviours also peaks during adolescence. Thus, screening for low energy availability, establishing the various causes of amenorrhoea, and treating amenorrhoea and low energy availability with an interdisciplinary team is most effective.

Etiology and management of primary amenorrhoea: A study of 102 cases at tertiary centre.

OBJECTIVE: To determine the prevalence of etiologic causes of primary amenorrhea in Indian population. MATERIALS AND METHODS: A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo-sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype. RESULTS: The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis. CONCLUSIONS: The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea.