Approach to the Patient With New-Onset Secondary Amenorrhea: Is This Primary Ovarian Insufficiency?

Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population.

Socioeconomic development predicts a weaker contraceptive effect of breastfeeding.

The contraceptive effect of breastfeeding remains essential to controlling fertility in many developing regions of the world. The extent to which this negative effect of breastfeeding on ovarian activity is sensitive to ecological conditions, notably maternal energetic status, has remained controversial. We assess the relationship between breastfeeding duration and postpartum amenorrhea (the absence of menstruation following a birth) in 17 World Fertility Surveys and 284 Demographic Health Surveys conducted between 1975 and 2019 in 84 low- and middle-income countries. We then analyze the resumption of menses in women during unsupplemented lactation. We find that a sharp weakening of the breastfeeding-postpartum amenorrhea relationship has globally occurred over the time period analyzed. The slope of the breastfeeding-postpartum amenorrhea relationship is negatively associated with development: higher values of the Human Development Index, urbanization, access to electricity, easier access to water, and education are predictive of a weaker association between breastfeeding and postpartum amenorrhea. Low parity also predicts shorter postpartum amenorrhea. The association between exclusive breastfeeding and maintenance of amenorrhea in the early postpartum period is also found in rapid decline in Asia and in moderate decline in sub-Saharan Africa. These findings indicate that the effect of breastfeeding on ovarian function is partly mediated by external factors that likely include negative maternal energy balance and support the notion that prolonged breastfeeding significantly helps control fertility only under harsh environmental conditions.

Physical Activity, Menstrual History, and Bone Microarchitecture in Female Athletes with Multiple Bone Stress Injuries.

PURPOSE: To determine differences in health and physical activity history, bone density, microarchitecture, and strength among female athletes with a history of multiple BSI, athletes with ≤1 BSI, and nonathletes. METHODS: We enrolled 101 women (age, 18-32 yr) for this cross-sectional study: nonathlete controls (n = 17) and athletes with a history of ≥3 BSIs (n = 21) or ≤1 BSI (n = 63). We collected subjects' health and training history and measured bone microarchitecture of the distal tibia via high-resolution peripheral quantitative computed tomography (HR-pQCT) and areal bone mineral density of the hip and spine by dual-energy X-ray absorptiometry. RESULTS: Groups did not differ according to age, body mass index, age at menarche, areal bone mineral density, or tibial bone microarchitecture. Women with multiple BSI had a higher prevalence of primary and secondary amenorrhea (P < 0.01) compared with other groups. Total hours of physical activity in middle school were similar across groups; however, women with multiple BSI performed more total hours of physical activity in high school (P = 0.05), more hours of uniaxial loading in both middle school and high school (P = 0.004, P = 0.02), and a smaller proportion of multiaxial loading activity compared with other groups. CONCLUSIONS: These observations suggest that participation in sports with multiaxial loading and maintaining normal menstrual status during adolescence and young adulthood may reduce the risk of multiple bone stress injuries.

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.

Complete androgen insensitivity syndrome with intra-abdominal seminoma in a phenotypic female: A rare presentation.

Androgen insensitivity syndrome (AIS) is a rare, X-linked recessive disorder which causes alterations in androgen receptor gene leading to hormone resistance, which may present clinically under three phenotypes: complete AIS (CAIS), partial AIS, or mild AIS. The symptoms range from phenotypically normal males with impaired spermatogenesis to phenotypically normal women with primary amenorrhea. We report a case of a 35-year-old woman who was diagnosed with CAIS and presented with malignant transformation of the undescended testis. The histopathology confirmed the presence of seminoma. In this case report, we reviewed the literature which describes the biochemical and endocrinological abnormalities leading to the syndrome. It also highlights the potential for malignant changes of the undescended testes, diagnosis, and therapeutic management.

Modified Vecchietti vaginoplasty using self-made single-port laparoscopy in Mayer-Rokitansky-Küster-Hauser syndrome.

OBJECTIVE: To introduce the minimally invasive Vecchietti procedure based on single-port laparoscopy with self-made surgical instruments for the surgical management of Mayer-Rokitansky-Küster-Hauser syndrome (MRKH). DESIGN: Surgical video article. The approval of the Institutional Review Board and written consent from the patient were obtained. SETTING: University hospital. PATIENT(S): A 22-year-old woman presented with primary amenorrhea and inability to participate in penetrative sexual intercourse. A gynecological examination revealed a phenotypically normal vulva and absence of the vagina. A normal 46,XX karyotype was expressed. Magnetic resonance imaging and ultrasonic imaging of the abdomen and pelvis indicated that the ovaries were normal in size and there was vaginal agenesis with rudimentary uterus. No other congenital malformations were present. INTERVENTION(S): The modified Vecchietti procedure involved a transvaginal operation and laparoscopic surgery. The epidural catheter was stretched and made into two wires that were tucked into the core of the Veress needle and then folded into four strings for perineal puncture. A transverse incision of about 3 cm was made in the center of the navel, layer by layer into the abdomen, and placed in a self-made single port (made of a small wound protector and an 8-inch glove), introducing the laparoscope. Under laparoscopic surveillance, the Veress needle was inserted through the vesicorectal space guided by the index finger, which was placed in the rectum. The epidural catheter was pumped from the core into the abdominal cavity under laparoscopy. Subsequently, cystoscopy was performed to ensure that no bladder perforation occurred during the needle insertion. The ball-shaped acrylic device and the two rubber stoppers were attached to the epidural catheter of the vulva. An epidural puncture needle with wire perforated the peritoneum through McBurney's point and the opposite McBurney's point, pulling the epidural catheter out of the abdominal cavity. The epidural catheter was curled around the gauze rolls until the ball-shaped device could be accommodated into the newly created cavity at a sufficient depth. After the surgery, the top of neovagina was lifted about 1 cm every day by tightening gauze rolls to increase the traction, until a neovagina 9 cm long was achieved. MAIN OUTCOME MEASURE(S): The clinical and anatomical data such as the operative time, intraoperative bleeding, duration of hospitalization, and measurement of the final length of the newly created canal 30 days after surgery and 3 months after surgery. RESULT(S): The operative time was 30 minutes, and the intraoperative blood loss was 10 mL. The duration of hospitalization was 10 days. Before discharge, the vaginal depth was 9 cm at 5 days after the surgery, and the self-made traction system was removed. A plastic mold was then inserted using povidone-iodine. The vaginal dilator had to be worn day and night. The patient was advised to sit at the corner of a hard bed or chair from time to time to enhance the dilated effect of the vaginal mold. Three months after the surgery, it could be worn each night until regular sexual intercourse was initiated. The canal length 30 days and 3 months after the surgery was nearly 9 cm. CONCLUSION(S): The modified Vecchietti vaginoplasty is a simple, safe, cost-effective, and minimally invasive procedure, offering an anatomic and functional neovagina for MRKH patients.

Is Ovarian Reserve Impacted in Anorexia Nervosa?

STUDY OBJECTIVES: Hypothalamic amenorrhea is common in adolescents and young adults (AYAs) with anorexia nervosa (AN), and ovarian reserve is not routinely assessed. AN increases rates of fertility problems, but how or when AN negatively influences future fertility is unclear. We sought to determine whether biomarkers of ovarian reserve were impacted in AYA with AN. DESIGN: Cross-sectional study. SETTING: Tertiary care center. PARTICIPANTS: Females with AN and amenorrhea (n = 97) at the pre-intervention visit of a clinical trial, n = 19 females without an eating disorder or menstrual dysfunction. MAIN OUTCOME MEASURES: Serum anti-Müllerian hormone (AMH) concentrations. RESULTS: AMH levels were higher in AYA with AN than unaffected adolescents (4.7 vs. 3.2 ng/mL; P = .03). Neither FSH nor inhibin B differed between groups. In 19.6% of participants with AN, AMH levels were elevated above the normal range (>6.78 ng/mL). These subjects had a longer disease duration than those with normal AMH levels (9 vs. 3 mos; P = .03); age or degree of malnutrition did not differ between AN subjects with normal or elevated AMH. CONCLUSIONS: AMH levels appear to be normal or elevated in AYA with AN. Low AMH in a patient with AN should raise clinical concern regarding ovarian reserve, and should not be attributed to degree of malnutrition alone. Currently, AMH is not regularly assessed during routine AN clinical care. However, our findings suggest some clinical utility in identifying those patients with reduced ovarian reserve. Potential links between the hypothalamic amenorrhea suffered by patients with AN and PCOS should be explored.

Eating behaviours related to psychological stress are associated with functional hypothalamic amenorrhoea in exercising women.

Functional hypothalamic amenorrhoea (FHA) can occur due to the independent or combined effects of psychogenic and energetic stressors. In exercising women, research has primarily focused on energy deficiency as the cause of FHA while psychological stressors have been ignored. To assess both psychological and metabolic factors associated with FHA in exercising women, we performed across-sectional comparison of 61 exercising women (≥2 hours/week, age 18-35 years, BMI 16-25kg/m2), who were eumenorrheic or amenorrhoeic confirmed by daily urine samples assayed for reproductive hormone metabolites. Psychological factors and eating behaviours were assessed by self-report questionnaires. Exercising women with FHA had lower resting metabolic rate (p=0.023), T3 (p<0.001), T4 (p=0.013), leptin (p=0.002), higher peptide YY (p<0.001), greater drive for thinness (p=0.017), greater dietary cognitive restraint (p<0.001), and displayed dysfunctional attitudes, i.e., need for social approval (p=0.047) compared to eumenorrheic women. Amenorrhoeic women displayed asignificant positive correlation between the need for social approval and drive for thinness with indicators of stress, depression, and mood, which was not apparent in eumenorrheic women. In exercising women with FHA, eating behaviours are positively related to indicators of psychological stress and depression.

A retrospective multicenter study of bone mineral density in adolescents and adults with Turner syndrome in Japan.

Osteoporosis is one of the clinical features of women with Turner syndrome (TS). The reasons for low bone mineral density (BMD) and increased bone fragility are multifactorial, including estrogen deficiency, X-chromosome abnormalities, and environmental factors. Few, large-scale studies on bone mineral density in either adolescents or adults with TS have been done in Japan. The goal of the present study was to investigate spinal BMD in women with TS, assess its relationship with clinical parameters, especially estrogen replacement therapy, and investigate its longitudinal changes. The spinal BMD and clinical data of 149 Japanese women with TS aged 15 to 49 years who were followed at the four participating hospitals were retrospectively analyzed. The BMD Z-scores of the women with TS ranged from -5.30 to +1.89. Women with TS aged 15-39 years had lower BMD than healthy Japanese women (p < 0.01) while women with spontaneous menstruation had a significantly higher BMD Z-score than those without spontaneous menstruation (-0.73 ± 1.11 vs. -1.67 ± 1.18, p < 0.01). In women without spontaneous menstruation, BMD Z-scores correlated with the duration of their estrogen therapy (r = 0.167, p < 0.01). Women aged 15-39 years with TS had low BMD, which was associated with primary amenorrhea and short estrogen replacement therapy duration.

Female Athlete Triad Coalition cumulative risk assessment tool: proposed alternative scoring strategies.

We (i) identified alternative scoring strategies for the Female Athlete Triad Coalition cumulative risk assessment (CRA) tool to be utilized when particular risk factors (bone mineral density (BMD), oligomenorrhea/amenorrhea) cannot be determined; (ii) objectively defined dietary restriction for use in the CRA tool; and (iii) explored proxy measures of energy deficiency. This cross-sectional investigation of exercising women (n = 166) utilized an existing database derived from multiple studies designed to assess health, exercise, and menstrual function. Data from the screening/baseline period of each study included: anthropometrics, dual-energy X-ray absorptiometry, disordered eating questionnaires, descriptive data, and proxy measures of energy deficiency (total triiodothyronine (TT3) and ratio of measured-to-predicted resting metabolic rate (mRMR/pRMR)). Substituting delayed menarche for BMD was the best-fit replacement resulting in 15 (9%) participants being categorized in different clearance categories. When menstrual status cannot be assessed, such as during hormonal contraceptive use, low energy availability (EA) determined using self-report and disordered eating questionnaires was the best substitution, resulting in 34 (20%) participants being categorized in different clearance categories. Based on original clearance categorizations, the provisional group had lower TT3 (78.3 ± 2.2 ng/dL; 92.7 ± 2.7 ng/dL) and Harris-Benedict mRMR/pRMR (0.85 ± 0.01; 0.90 ± 0.01) than the full group. Until an updated risk assessment tool is developed, delayed menarche can substitute for low BMD and low EA for oligomenorrhea/amenorrhea. Novelty This investigation addresses previous limitations of the Triad CRA tool. Disordered eating questionnaires can be used to objectively identify dietary restriction for the low EA risk factor. When a risk factor cannot be assessed, delayed menarche can substitute for low BMD and low EA for oligomenorrhea/amenorrhea.

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.

Low Bone Mineral Density in Elite Female Athletes With a History of Secondary Amenorrhea in Their Teens.

OBJECTIVE: To determine whether secondary amenorrhea during teenage years influences bone mineral density (BMD) in female athletes in their 20s. DESIGN: Original research. SETTING: Japan Institute of Sports Sciences. PARTICIPANTS: Two hundred ten elite female athletes older than 20 years were included in the study. MAIN OUTCOME MEASURES: Information on the participants' past (ie, during their teenage years) and current menstrual cycle, training time, history of stress fractures, and blood tests for hormones received was obtained. Bone mineral density of the lumbar spine was evaluated by dual-energy x-ray absorptiometry; low BMD was defined as a Z-score ≤-1. We investigated the correlation factors for low BMD in athletes in their 20s by univariable and multivariable logistic regression analysis. RESULTS: A total of 39 (18.6%) female athletes had low BMD. Secondary amenorrhea in their teens [odds ratio (OR), 7.11, 95% confidence interval (CI), 2.38-21.24; P < 0.001] and present body mass index (BMI) (OR, 0.56, 95% CI, 0.42-0.73; P < 0.001) were independent correlation factors for low BMD in the multivariable logistic regression analysis. The average Z-score for those with secondary amenorrhea in their teens and 20s, secondary amenorrhea in their 20s only, and regular menstruation was -1.56 ± 1.00, -0.45 ± 1.21, and 0.82 ± 1.11 g/cm, respectively. CONCLUSIONS: Secondary amenorrhea for at least 1 year during teenage years in female athletes and BMI at present was strongly associated with low BMD in their 20s.

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.

Discriminating hypothalamic oligomenorrhea/amenorrhea from hyperandrogenic oligomenorrhea/amenorrhea in exercising women.

The mechanism underlying oligo/amenorrhea in exercising women is often presumed as hypothalamic inhibition secondary to energy deficiency; however, hyperandrogenism may provide an alternative mechanism in some exercising women. Our purpose was to compare reproductive, metabolic, and androgen profiles of exercising women with eumenorrheic, ovulatory menstrual cycles (n = 91), oligo/amenorrhea without evidence of hyperandrogenism (Oligo/Amen; n = 83), and oligo/amenorrhea with evidence of hyperandrogenism (Oligo/Amen-HA; n = 17), and determine the prevalence of oligo/amenorrhea with evidence of hyperandrogenism in exercising women. Self-reported menstrual history and quantification of daily estrogen and progesterone urinary metabolites determined reproductive status. Resting energy expenditure, body composition, and metabolic hormone concentrations determined metabolic status. Serum androgens and calculated free androgen index (FAI) determined androgen status. Groups were similar in age (22.4 ± 0.3 years), height (165.1 ± 0.5 cm), resting energy expenditure (1198.4 ± 12.0 kcal/day), and total triiodothyronine (85.0 ± 1.5 ng/dL) concentration. Oligo/Amen-HA had greater weight (60.0 ± 1.6, 56.1 ± 0.7 kg), body mass index (22.3 ± 0.4, 20.6 ± 0.2 kg/m2), percentage body fat (27.3% ± 1.4%, 24.4% ± 0.6%), fat mass (16.2 ± 1.0, 13.8 ± 0.4 kg), insulin (5.8 ± 0.7, 4.2 ± 0.3 µIU/mL), leptin (12.2 ± 2.3, 6.6 ± 0.7 ng/mL), FAI (6.1 ± 0.3, 1.7 ± 0.1), and luteinizing hormone/follicle-stimulating hormone (1.9 ± 0.3, 1.3 ± 0.2) compared with Oligo/Amen, respectively. In our sample, 17% of those with oligo/amenorrhea had concurrent hyperandrogenism. This study supports that oligo/amenorrhea in some exercising women is related to hyperandrogenism. Novelty Caution must be utilized when discriminating hypothalamic oligo/amenorrhea from hyperandrogenic oligo/amenorrhea. In our sample, 17% of those with presumed hypothalamic oligo/amenorrhea had concurrent hyperandrogenism. Exercise and/or mild energy deficiency may be protective against developing severe hyperandrogenic symptoms.

Indices of Resting Metabolic Rate Accurately Reflect Energy Deficiency in Exercising Women.

Energy deficiency in exercising women can lead to physiological consequences. No gold standard exists to accurately estimate energy deficiency, but measured-to-predicted resting metabolic rate (RMR) ratio has been used to categorize women as energy deficient. The purpose of the study was to (a) evaluate the accuracy of RMR prediction methods, (b) determine the relationships with physiological consequences of energy deficiency, and (c) evaluate ratio thresholds in a cross-sectional comparison of ovulatory, amenorrheic, or subclinical menstrual disturbances in exercising women (n = 217). Dual-energy X-ray absorptiometry (DXA) and indirect calorimetry provided data on anthropometrics and energy expenditure. Harris-Benedict, DXA, and Cunningham (1980 and 1991) equations were used to estimate RMR and RMR ratio. Group differences were assessed (analysis of variance and Kruskal-Wallis tests); logistic regression and Spearman correlations related ratios with consequences of energy deficiency (i.e., low total triiodothyronine; TT3). Sensitivity and specificity calculations evaluated ratio thresholds. Amenorrheic women had lower RMR (p < .05), DXA ratio (p < .01), Cunningham1980 (p < .05) and Cunningham1991 (p < .05) ratio, and TT3 (p < .01) compared with the ovulatory group. Each prediction equation overestimated measured RMR (p < .001), but predicted (p < .001) and positively correlated with TT3 (r = .329-.453). A 0.90 ratio threshold yielded highest sensitivity for Cunningham1980 (0.90) and Harris-Benedict (0.87) methods, but a higher ratio threshold was best for DXA (0.94) and Cunningham1991 (0.92) methods to yield a sensitivity of 0.80. In conclusion, each ratio predicted and correlated with TT3, supporting the use of RMR ratio as an alternative assessment of energetic status in exercising women. However, a 0.90 ratio cutoff is not universal across RMR estimation methods.

A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features.

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

Opioids and reproduction.

More than 40years ago, the endogenous opioids were first described. Their role as important neuromodulators of pain and their influence on a variety of neuroendocrine control systems within the central nervous system has been recognized. More recently, endogenous opioids and their receptor have been identified in a variety of reproductive and non-reproductive tissues outside the central nervous system. What role the opioid system plays in these peripheral tissues and organs is not completely understood and thus the subjects of current research. In the central nervous system, endogenous opioids inhibit pulsatile Gonadotropin Releasing Hormone (GnRH) release, affecting the release of gonadotropins from the pituitary, and thus mediating stress response within the central nervous-pituitary-gonadal axes in both women and men-Peripherally, endogenous opioids have been demonstrated to be present-among other organs-in the pancreas and in the ovary, where they are produced by granulosa cells and may influence oocyte maturation. In men, endogenous opioids play a role in sperm production within the testis. Opioid antagonists such as naltrexone have been used to restore cyclicity in women through improvement in insulin resistance, GnRH-pulsatility and hyperandrogenemia stemming from specific pathophysiological conditions such as hypothalamic amenorrhea, polycystic ovarian syndrome, hyperinsulinemia, ovarian hyperstimulation syndrome. Opioid antagonists have also been used to treat male sexual disorders and male infertility. In summary, endogenous opioids exert a variety of actions within the reproductive system which are reviewed in this chapter.

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.