ABSTRACT
Lactation is a physiological state of hyperprolactinemia and associated amenorrhea. Despite the fact that exact mechanisms standing behind the hypothalamus-pituitary-ovarian axis during lactation are still not clear, a general overview of events leading to amenorrhea may be suggested. Suckling remains the most important stimulus maintaining suppressive effect on ovaries after pregnancy. Breastfeeding is accompanied by high levels of prolactin, which remain higher than normal until the frequency and duration of daily suckling decreases and allows normal menstrual function resumption. Hyperprolactinemia induces the suppression of hypothalamic Kiss1 neurons that directly control the pulsatile release of GnRH. Disruption in the pulsatile manner of GnRH secretion results in a strongly decreased frequency of corresponding LH pulses. Inadequate LH secretion and lack of pre-ovulatory surge inhibit the progression of the follicular phase of a menstrual cycle and result in anovulation and amenorrhea. The main consequences of lactational amenorrhea are connected with fertility issues and increased bone turnover. Provided the fulfillment of all the established conditions of its use, the lactational amenorrhea method (LAM) efficiently protects against pregnancy. Because of its accessibility and lack of additional associated costs, LAM might be especially beneficial in low-income, developing countries, where modern contraception is hard to obtain. Breastfeeding alone is not equal to the LAM method, and therefore, it is not enough to successfully protect against conception. That is why LAM promotion should primarily focus on conditions under which its use is safe and effective. More studies on larger study groups should be conducted to determine and confirm the impact of behavioral factors, like suckling parameters, on the LAM efficacy. Lactational bone loss is a physiologic mechanism that enables providing a sufficient amount of calcium to the newborn. Despite the decline in bone mass during breastfeeding, it rebuilds after weaning and is not associated with a postmenopausal decrease in BMD and osteoporosis risk. Therefore, it should be a matter of concern only for lactating women with additional risk factors or with low BMD before pregnancy. The review summarizes the effect that breastfeeding exerts on the hypothalamus-pituitary axis as well as fertility and bone turnover aspects of lactational amenorrhea. We discuss the possibility of the use of lactation as contraception, along with this method's prevalence, efficacy, and influencing factors. We also review the literature on the topic of lactational bone loss: its mechanism, severity, and persistence throughout life.
Subject(s)
Amenorrhea/metabolism , Bone Remodeling , Lactation , Neurosecretory Systems/metabolism , Contraception/methods , Female , Gonadotropin-Releasing Hormone/metabolism , Humans , Hypothalamus/metabolism , Kisspeptins/metabolism , Luteinizing Hormone/metabolism , Prolactin/metabolism , Up-RegulationABSTRACT
Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.
Subject(s)
Autocrine Communication , Bone Density , Bone and Bones/metabolism , Oxytocin/metabolism , Paracrine Communication , Sex Characteristics , Amenorrhea/metabolism , Animals , Anorexia Nervosa/metabolism , Bone and Bones/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/pathology , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Estrogens/deficiency , Estrogens/metabolism , Female , Humans , Male , Osteoporosis, Postmenopausal/metabolismABSTRACT
CONTEXT: Follicle-stimulating hormone (FSH) plays an essential role in gonadal function. Loss-of-function mutations in the follicle-stimulating hormone receptor (FSHR) are an infrequent cause of primary ovarian failure. OBJECTIVE: To analyze the molecular physiopathogenesis of a novel mutation in the FSHR identified in a woman with primary ovarian failure, employing in vitro and in silico approaches, and to compare the features of this dysfunctional receptor with those shown by the trafficking-defective D408Y FSHR mutant. METHODS: Sanger sequencing of the FSHR cDNA was applied to identify the novel mutation. FSH-stimulated cyclic adenosine monophosphate (cAMP) production, ERK1/2 phosphorylation, and desensitization were tested in HEK293 cells. Receptor expression was analyzed by immunoblotting, receptor-binding assays, and flow cytometry. Molecular dynamics simulations were performed to determine the in silico behavior of the mutant FSHRs. RESULTS: A novel missense mutation (I423T) in the second transmembrane domain of the FSHR was identified in a woman with normal pubertal development but primary amenorrhea. The I423T mutation slightly impaired plasma membrane expression of the mature form of the receptor and severely impacted on cAMP/protein kinase A signaling but much less on ß-arrestin-dependent ERK1/2 phosphorylation. Meanwhile, the D408Y mutation severely affected membrane expression, with most of the FSH receptor located intracellularly, and both signal readouts tested. Molecular dynamics simulations revealed important functional disruptions in both mutant FSHRs, mainly the loss of interhelical connectivity in the D408Y FSHR. CONCLUSIONS: Concurrently, these data indicate that conformational differences during the inactive and active states account for the distinct expression levels, differential signaling, and phenotypic expression of the I423T and D408Y mutant FSHRs.
Subject(s)
Primary Ovarian Insufficiency/genetics , Receptors, FSH/genetics , Adult , Amenorrhea/genetics , Amenorrhea/metabolism , Amino Acid Substitution , Family , Female , Follicle Stimulating Hormone/pharmacology , HEK293 Cells , Humans , Isoleucine/genetics , Loss of Function Mutation/genetics , Models, Molecular , Mutation, Missense , Pedigree , Primary Ovarian Insufficiency/metabolism , Receptors, FSH/agonists , Receptors, FSH/chemistry , Receptors, FSH/metabolism , Threonine/geneticsABSTRACT
Background/Purpose: A prolactinoma is the most common pituitary adenoma, but it is relatively rare in childhood and adolescence. There is only limited research about the clinical spectrum, treatment, and outcomes of prolactinomas in childhood and adolescence. In this single-center cohort study, we assessed the clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of children and adolescents with prolactinomas. Methods: This retrospective cohort study included 25 patients with prolactinomas diagnosed before 19 years of age, who presented at Samsung Medical Center during a 15-year period (March 2005 to August 2019). Results: The median age at diagnosis was 16.9 (range 10.1-18.5) years, and 80% of the patients were female. The common clinical manifestations at diagnosis were galactorrhea (10/20, 50%) and amenorrhea (9/20, 45%) among females and visual field defects (3/5, 60%) and headaches (2/5, 40%) among males. In our cohort, macroadenomas accounted for 56% of cases, and the rate of overall responsiveness to dopamine agonists (DAs) was 56% (10/18). Male gender, the prolactin (PRL) level at diagnosis, and the presence of panhypopituitarism were positively correlated with maximum tumor diameter (r = 0.443, P = 0.026; r = 0.710, P < 0.001; and r = 0.623, P = 0.001, respectively). After the trans-sphenoidal approach (TSA), 53% (8/15) of patients showed normalization of the PRL level. Three patients, who underwent gamma knife surgery (GKS) owing to either resistance or intolerance to DAs or recurrence after the TSA, achieved a normal PRL level accompanied with marked tumor reduction and symptom remission. Conclusions: A macroprolactinoma is more prevalent than a microprolactinoma in children and adolescents than in adults. Male gender, increased PRL levels, and the presence of panhypopituitarism at diagnosis are closely related to macroprolactinomas in children and adolescents.
Subject(s)
Adenoma/pathology , Amenorrhea/pathology , Bromocriptine/therapeutic use , Galactorrhea/pathology , Pituitary Neoplasms/pathology , Prolactinoma/pathology , Vision Disorders/pathology , Adenoma/diagnostic imaging , Adenoma/drug therapy , Adenoma/metabolism , Adolescent , Adult , Amenorrhea/diagnostic imaging , Amenorrhea/drug therapy , Amenorrhea/metabolism , Child , Dopamine Agonists/therapeutic use , Female , Follow-Up Studies , Galactorrhea/diagnostic imaging , Galactorrhea/drug therapy , Galactorrhea/metabolism , Humans , Male , Pituitary Neoplasms/diagnostic imaging , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/metabolism , Prolactin/metabolism , Prolactinoma/diagnostic imaging , Prolactinoma/drug therapy , Prolactinoma/metabolism , Retrospective Studies , Treatment Outcome , Vision Disorders/diagnostic imaging , Vision Disorders/drug therapy , Vision Disorders/metabolism , Young AdultABSTRACT
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.
Subject(s)
Amenorrhea/metabolism , Amenorrhea/psychology , Exercise/psychology , Feeding Behavior/psychology , Feeding and Eating Disorders/metabolism , Feeding and Eating Disorders/psychology , Stress, Psychological , Adolescent , Adult , Amenorrhea/physiopathology , Basal Metabolism , Body Mass Index , Cross-Sectional Studies , Depression/psychology , Diet , Exercise/physiology , Feeding and Eating Disorders/physiopathology , Female , Humans , Hypothalamus/physiology , Menstrual Cycle , Thinness/psychology , Young AdultABSTRACT
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.
Subject(s)
Amenorrhea/diagnosis , Exercise/physiology , Hyperandrogenism/diagnosis , Hypothalamic Diseases/diagnosis , Oligomenorrhea/diagnosis , Adult , Amenorrhea/metabolism , Amenorrhea/physiopathology , Diagnosis, Differential , Female , Humans , Hyperandrogenism/metabolism , Hyperandrogenism/physiopathology , Hypothalamic Diseases/metabolism , Hypothalamic Diseases/physiopathology , Oligomenorrhea/metabolism , Oligomenorrhea/physiopathology , Young AdultABSTRACT
Decreased mineral density is one of the major complications of anorexia nervosa. The phenomenon is even more pronounced when the disease occurs during adolescence and when the duration of amenorrhoea is long. The mechanisms underlying bone loss in anorexia are complex. Oestrogen deficiency has long been considered as the main factor, but cannot explain the phenomenon on its own. The essential role of nutrition-related factors-especially leptin and adiponectin-has been reported in recent studies. Therapeutic strategies to mitigate bone involvement in anorexia are still a matter for debate. Although resumption of menses and weight recovery appear to be essential, they are not always accompanied by a total reversal of bone loss. There are no studies in the literature demonstrating that oestrogen treatment is effective, and the best results seem to have been obtained with agents that induce bone formation-such as IGF-1-especially when associated with oestrogen. As such, bone management in anorexia remains difficult, hence, the importance of early detection and multidisciplinary follow-up.
Subject(s)
Amenorrhea/complications , Anorexia Nervosa/complications , Bone Density/physiology , Osteoporosis/therapy , Absorptiometry, Photon , Adiponectin/administration & dosage , Adiponectin/deficiency , Amenorrhea/metabolism , Anorexia Nervosa/diagnosis , Anorexia Nervosa/metabolism , Anorexia Nervosa/rehabilitation , Bone Density/drug effects , Bone Density Conservation Agents/administration & dosage , Drug Therapy, Combination , Estrogens/administration & dosage , Estrogens/metabolism , Exercise/physiology , Female , Humans , Insulin-Like Growth Factor I/administration & dosage , Leptin/administration & dosage , Leptin/deficiency , Lipolysis/drug effects , Osteoporosis/diagnosis , Osteoporosis/etiology , Osteoporosis/metabolism , Recombinant Proteins/administration & dosage , Treatment Outcome , Weight Gain/physiologyABSTRACT
PURPOSE: A clinical case presenting secondary amenorrhea accompanied by an adrenal adenoma and hyperprogesteronemia is described in this study. METHODS: Selective catheterization and sampling of adrenal and ovarian veins were performed. RESULTS: The source of hyperprogesteronemia was located in the right adrenal gland. A progesterone-producing tumor in the right adrenal gland was diagnosed and removed. Twenty-six days after tumor resection, menstruation occurred. CONCLUSIONS: Progesterone-producing tumors should be considered with the presence of an adrenal mass and hyperprogesteronemia. Combined adrenal and ovarian venous sampling may help to identify the source of progesterone secretion.
Subject(s)
Adrenal Cortex Neoplasms/complications , Adrenal Cortex Neoplasms/metabolism , Adrenal Glands/blood supply , Adrenocortical Adenoma/complications , Amenorrhea/etiology , Blood Specimen Collection/methods , Ovary/blood supply , Progesterone/blood , Adrenal Cortex Neoplasms/pathology , Adrenal Cortex Neoplasms/surgery , Adrenal Glands/pathology , Adrenal Glands/surgery , Adrenocortical Adenoma/metabolism , Adrenocortical Adenoma/pathology , Adrenocortical Adenoma/surgery , Adult , Amenorrhea/metabolism , Amenorrhea/pathology , Amenorrhea/surgery , Female , Humans , Treatment OutcomeABSTRACT
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.
Subject(s)
Amenorrhea/therapy , Athletes , Cardiovascular Diseases/prevention & control , Energy Metabolism/drug effects , Estrogen Replacement Therapy , Estrogens/deficiency , Amenorrhea/epidemiology , Amenorrhea/metabolism , Amenorrhea/physiopathology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Female , Follicle Stimulating Hormone, Human/metabolism , Humans , Inflammation Mediators/metabolism , Luteinizing Hormone/metabolism , Risk Assessment , Risk FactorsABSTRACT
PURPOSE: Ovarian function is important for optimizing endocrine treatment in patients with hormone receptor-positive (HR+) early breast cancer (eBC). The aim of the study was to determine whether patients' pretreatment levels of anti-Mullerian hormone (AMH) were associated with menses status after chemotherapy and to build a predictive nomogram model for amenorrhea in women with HR+ eBC. METHODS: Between August 2013 and December 2014, 120 premenopausal patients with HR+ eBC were included retrospectively. The associations among age, prechemotherapy levels of AMH, follicle-stimulating hormone (FSH),and estradiol (E2) and the 2-year postchemotherapy menses status were analyzed. We determined the cutoff values of hormone levels by using the biostatistical tool (Cutoff Finder). A novel nomogram was established to predict the 2-year amenorrhea status based on the logistic analysis. Concordance index (C-index) was used to validate the capacity. RESULTS: One hundred nine women (90.8%) experienced amenorrhea after chemotherapy. AMH < 0.965 ng/ml predicted amenorrhea at 2 years (AUC 0.84, sensitivity 74% and specificity 81.8%), independent of age. The predictive nomogram based on age and pretreatment AMH and FSH levels was developed to predict the probability of 2-year postchemotherapy amenorrhea with a C-index of 0.88 (95% CI 0.84-0.91). CONCLUSIONS: In premenopausal patients with HR+ eBC, prechemotherapy AMH concentration was associated with the patient's 2-year amenorrhea status, independent of age. The nomogram model based on age and pretreatment AMH and FSH levels accurately predicted the 2-year amenorrhea status.
Subject(s)
Amenorrhea/metabolism , Anti-Mullerian Hormone/blood , Biomarkers, Tumor , Breast Neoplasms/metabolism , Menstrual Cycle/metabolism , Premenopause , Adult , Amenorrhea/blood , Amenorrhea/diagnosis , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/blood , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Staging , Nomograms , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Young AdultABSTRACT
Context: Mutations in the kisspeptin receptor (KISS1R) gene have been reported in a few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110). Objectives: To describe a female patient with nCHH and a novel homozygous KISS1R mutation and to assess the role of kisspeptin pathway to induce an ovulation by GnRH pulse therapy. Design, Setting, and Intervention: Observational study of a patient including genetic and kisspeptin receptor functions and treatment efficiency using a GnRH pump. Main Outcome Measure: Response to pulsatile GnRH therapy. Results: A partial isolated gonadotropic deficiency was diagnosed in a 28-year-old woman with primary amenorrhea and no breast development. A novel homozygous c.953T>C variant was identified in KISS1R. This mutation led to substitution of leucine 318 for proline (p.Leu318Pro) in the seventh transmembrane domain of KISS1R. Signaling via the mutated receptor was profoundly impaired in HEK293-transfected cells. The mutated receptor was not detected on the membrane of HEK293-transfected cells. After several pulsatile GnRH therapy cycles, an LH surge with ovulation and pregnancy was obtained. Conclusion: GnRH pulsatile therapy can induce an LH surge in a woman with a mutated KISS1R, which was previously thought to be completely inactivated in vivo.
Subject(s)
Amenorrhea/drug therapy , Gonadotropin-Releasing Hormone/administration & dosage , Hypogonadism/drug therapy , Luteinizing Hormone/metabolism , Receptors, Kisspeptin-1/genetics , Adult , Amenorrhea/genetics , Amenorrhea/metabolism , Female , HEK293 Cells , Homozygote , Humans , Hypogonadism/genetics , Hypogonadism/metabolism , Kisspeptins/metabolism , Loss of Function Mutation , Ovulation/drug effects , Ovulation/metabolism , Pregnancy , Pulse Therapy, Drug , Receptors, Kisspeptin-1/deficiency , Signal Transduction/genetics , Treatment OutcomeABSTRACT
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.
Subject(s)
Amenorrhea , Sports , Adolescent , Algorithms , Amenorrhea/diagnosis , Amenorrhea/etiology , Amenorrhea/metabolism , Amenorrhea/therapy , Female , Hormones/physiology , Humans , Sports/physiologyABSTRACT
PURPOSE: Aim of this study is focusing on bone metabolism in AN patients with amenorrhoea and related estrogen deficiency effects. METHODS: AN patients were compared both with healthy females and with postmenopausal women (reference model for estrogen deficiency). The study sample included 81 females with AN. Laboratory tests [25-OH vitamin D, bone turnover markers, intact parathyroid hormone, sclerostin (SOST) and dickkopf-related protein (DKK1)] and dual energy X-ray absorptiometry (DXA) were taken into account. RESULTS: AN patients had higher levels of C-terminal telopeptide of type I collagen (CTX) than both control groups. AN adolescents had CTX higher than AN young adults. In postmenopausal women, intact N-propeptide of type I collagen was higher if compared with each other group. In AN groups, Dickkopf-related protein 1 was significantly lower than the two control groups. No differences were found in sclerostin except in adolescents. In AN adolescents, DXA values at femoral sites were higher than in AN young adults and a positive correlation was found with body weight (p < 0.01) and with fat mass evaluated using DXA (p < 0.01). CONCLUSIONS: AN women with amenorrhoea have an increased bone resorption like postmenopausal women but bone formation is depressed. The consequent remodeling uncoupling is considerably more severe than that occurring after menopause.
Subject(s)
Amenorrhea/metabolism , Anorexia Nervosa/metabolism , Bone and Bones/metabolism , Collagen Type I/blood , Parathyroid Hormone/blood , Vitamin D/analogs & derivatives , Adolescent , Adult , Amenorrhea/etiology , Anorexia Nervosa/complications , Biomarkers/blood , Body Composition/physiology , Body Weight/physiology , Bone Density/physiology , Female , Humans , Phosphopeptides/blood , Procollagen/blood , Vitamin D/blood , Young AdultABSTRACT
Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous-pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study.
Subject(s)
Amenorrhea/metabolism , Analgesics, Opioid/metabolism , Gonadal Steroid Hormones/metabolism , Ovarian Hyperstimulation Syndrome/metabolism , Ovary/metabolism , Pregnancy/metabolism , Reproduction/physiology , Animals , Female , Humans , Models, BiologicalABSTRACT
OBJECTIVE: To determine the threshold of total body and trunk fat mass required for menstrual recovery and to assess the impact of body composition in psychopathology of adolescents with Anorexia Nervosa (AN). METHODS: Prospective study of 60 adolescents presented with secondary amenorrhea and diagnosed with AN. Anthropometrics, body composition by dual-energy X-ray absorptiometry, hormonal studies and responses to mental health screens (EAT-26), were obtained at the beginning and at complete weight restoration, in all adolescents, independently of menstrual recovery (Group A) or not (Group B). RESULTS: At weight restoration, Group A total body fat mass, trunk fat mass, and trunk/extremities fat ratio were significantly higher (p < .001) than Group B. Menstruation was expected in 20% of total body fat mass and 20% of trunk fat mass (% of total trunk tissue). At time of menstrual recovery, total body fat mass (%) and trunk fat mass (%) were significantly negatively correlated with EAT-26 (r = -0.363, p = .032) and (r = -0.416, p = .013), respectively, while an increase of 0.40% of trunk fat mass (%) lowers EAT-26 by one unit. DISCUSSION: Trunk fat mass distribution can positively influence psychopathology of adolescents with AN.
Subject(s)
Adipose Tissue/pathology , Anorexia Nervosa/etiology , Anorexia Nervosa/metabolism , Anorexia Nervosa/psychology , Body Fat Distribution , Hormones/blood , Menstrual Cycle/physiology , Adolescent , Amenorrhea/diagnosis , Amenorrhea/etiology , Amenorrhea/metabolism , Amenorrhea/psychology , Body Composition/physiology , Child , Female , Humans , Psychology, Adolescent , Psychopathology , Recovery of Function , Thorax , Young AdultABSTRACT
Exercising women with menstrual disturbances frequently display a low resting metabolic rate (RMR) when RMR is expressed relative to body size or lean mass. However, normalizing RMR for body size or lean mass does not account for potential differences in the size of tissue compartments with varying metabolic activities. To explore whether the apparent RMR suppression in women with exercise-associated amenorrhea is a consequence of a lower proportion of highly active metabolic tissue compartments or the result of metabolic adaptations related to energy conservation at the tissue level, RMR and metabolic tissue compartments were compared among exercising women with amenorrhea (AMEN; n = 42) and exercising women with eumenorrheic, ovulatory menstrual cycles (OV; n = 37). RMR was measured using indirect calorimetry and predicted from the size of metabolic tissue compartments as measured by dual-energy X-ray absorptiometry (DEXA). Measured RMR was lower than DEXA-predicted RMR in AMEN (1,215 ± 31 vs. 1,327 ± 18 kcal/day, P < 0.001) but not in OV (1,284 ± 24 vs. 1,252 ± 17, P = 0.16), resulting in a lower ratio of measured to DEXA-predicted RMR in AMEN (91 ± 2%) vs. OV (103 ± 2%, P < 0.001). AMEN displayed proportionally more residual mass (P < 0.001) and less adipose tissue (P = 0.003) compared with OV. A lower ratio of measured to DXA-predicted RMR was associated with lower serum total triiodothyronine (ρ = 0.38, P < 0.001) and leptin (ρ = 0.32, P = 0.004). Our findings suggest that RMR suppression in this population is not the result of a reduced size of highly active metabolic tissue compartments but is due to metabolic and endocrine adaptations at the tissue level that are indicative of energy conservation.
Subject(s)
Adipose Tissue/metabolism , Amenorrhea/metabolism , Basal Metabolism , Body Composition , Bone and Bones/metabolism , Brain/metabolism , Exercise , Muscle, Skeletal/metabolism , Absorptiometry, Photon , Adaptation, Physiological , Adult , Amenorrhea/etiology , Calorimetry, Indirect , Case-Control Studies , Cross-Sectional Studies , Energy Metabolism , Female , Humans , Leptin/metabolism , Triiodothyronine/metabolism , Young AdultABSTRACT
INTRODUCTION: Kisspeptins are a family of neuropeptides whose identification has become one of the biggest discoveries in reproductive endocrinology during the past decade. Kisspeptins act upstream of GnRH as high-level mediators of the reproductive axis. AREAS COVERED: The authors performed a search of all publications on kisspeptin since its discovery in 1996. A full appraisal of the expanding literature concerning kisspeptin is beyond the scope of this review. This article therefore aims to cover the principle human studies outlining kisspeptin action in human physiology and to discuss the key findings, describing kisspeptin's potential as a therapeutic target in human reproduction. EXPERT OPINION: The identification of the kisspeptin signaling pathway has greatly advanced the study of reproductive endocrinology. Building on a large body of animal data, a growing number of human studies have shown that exogenous kisspeptin can stimulate physiological gonadotropin responses in both healthy subjects and those with disorders of reproduction. There is an increasing appreciation that kisspeptin may act as a signal transmitter between metabolic status and reproductive function. Future work is likely to involve investigation of novel kisspeptin analogs and further exploration of role of neurokinin B and dynorphin on the kisspeptin-GnRH axis.
Subject(s)
Kisspeptins/metabolism , Reproduction/physiology , Amenorrhea/drug therapy , Amenorrhea/metabolism , Animals , Female , Humans , Hypogonadism/drug therapy , Hypogonadism/metabolism , Menopause/metabolism , Ovulation/metabolismABSTRACT
We report on a 31-year old female who presented at genetic counseling for a small uterus, secondary amenorrhea and sterility. Gonadotropic hormone levels were low, suggesting a Hypogonadotropic Hypogonadism (HH) condition. Cytogenetic analysis demonstrated the presence of Trisomy X associated to an interstitial deletion of chromosome 4q13.2, resulting in the complete loss of a copy of the GNRHR gene. As GNRHR is known to be responsible for an autosomal recessive form of HH, we checked the status of the undeleted allele and we found the Q106R substitution. In conclusion, the results of our cytogenetic and molecular analyses have allowed us to clarify the etiology of the patient's condition.
Subject(s)
Amenorrhea/genetics , Hypogonadism/genetics , Infertility, Female/genetics , Receptors, LHRH/genetics , Sex Chromosome Disorders of Sex Development/genetics , Trisomy/genetics , Uterus/abnormalities , Adult , Amenorrhea/metabolism , Amenorrhea/physiopathology , Chromosomes, Human, Pair 4/genetics , Chromosomes, Human, X/genetics , Chromosomes, Human, X/metabolism , Female , Gene Deletion , Genotype , Gonadotropins/metabolism , Humans , Hypogonadism/metabolism , Hypogonadism/physiopathology , Infertility, Female/metabolism , Infertility, Female/physiopathology , Karyotype , Phenotype , Sequence Analysis, DNA , Sex Chromosome Aberrations , Sex Chromosome Disorders of Sex Development/metabolism , Sex Chromosome Disorders of Sex Development/physiopathology , Trisomy/physiopathologyABSTRACT
BACKGROUND/AIMS: Splicing CYP19 gene variants causing aromatase deficiency in 46,XX disorder of sexual development (DSD) patients have been reported in a few cases. A misbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast development but an incomplete sex maturation progress. The aim of this study was to functionally characterize a novel CYP19A1 intronic homozygote mutation (IVS9+5G>A) in a 46,XX DSD girl presenting spontaneous breast development and primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. METHODS: Genomic DNA analysis, splicing prediction programs, splicing assays, and in vitro protein expression and enzyme activity analyses were carried out. CYP19A1 mRNA expression in human steroidogenic tissues was also studied. RESULTS: A novel IVS9+5G>A homozygote mutation was found. In silico analysis predicts the disappearance of the splicing donor site in intron 9, confirmed by patient peripheral leukocyte cP450arom and in vitro studies. Protein analysis showed a shorter and inactive protein. The intron 9 transcript variant was also found in human steroidogenic tissues. CONCLUSIONS: The mutation IVS9+5G>A generates a splicing variant that includes intron 9 which is also present in normal human steroidogenic tissues, suggesting that a misbalance between normal and aberrant splicing variants might occur in target tissues, explaining the clinical phenotype in the affected patient.
Subject(s)
Amenorrhea/genetics , Aromatase/deficiency , Adolescent , Adrenal Glands/metabolism , Amenorrhea/metabolism , Animals , Aromatase/genetics , Aromatase/metabolism , COS Cells , Cell Line , Chlorocebus aethiops , Female , Humans , Male , Mice , Mutation , Phenotype , Placenta/metabolism , Pregnancy , Protein Splicing , Testis/metabolismABSTRACT
OBJECTIVE: To determine if reducing the frequency of urinary sample collection from daily to 5, 3, or 2 days per week during a menstrual cycle or 28-day amenorrheic monitoring period provide accurate representations of the reproductive hormone metabolites estrone-1-glucuronide (E1G) and pregnanediol glucuronide (PdG) exposure and mean concentrations. METHODS: Exercising women presenting with eumenorrhea or exercise-associated menstrual disturbances collected daily urine samples for the assessment of E1G and PdG concentrations. After enzyme immunoassay analysis of the daily samples, E1G and PdG data were systematically removed from each menstrual cycle or amenorrheic monitoring period to mimic three reduced collection frequencies, representing 5, 3, and 2 days per week. Exposure and mean concentration were calculated for both hormones and all four urinary collection frequencies. RESULTS: E1G and PdG exposure and mean cycle concentrations derived from reduced collection frequencies were not different from daily collection (P > 0.05), independent of whether menstrual cycles and monitoring periods were analyzed together or separately. Bland-Altman analysis indicated acceptable agreement between each reduced collection frequency and daily collection. CONCLUSIONS: Compared with daily urinary collection, a reduced collection frequency of 5, 3, or 2 days each week provides accurate E1G and PdG profiles of collection periods of various lengths and types of menstrual function. Reduction of urinary sample collection frequency may enable researchers to reduce participant burden and costs, increase compliance, and study a wider range of study populations.