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Hypothalamic amenorrhea (HA) is associated with dysfunction of the hypothalamic-pituitary-peripheral endocrine axes, leading to infertility and bone loss, and usually is caused by chronic energy deficiency secondary to strenuous exercise and/or decreased food intake. Energy deficiency also leads to hypoleptinemia, which has been proposed, on the basis of observational studies as well as an open-label study, to mediate the neuroendocrine abnormalities associated with this condition. To prove definitively a causal role of leptin in the pathogenesis of HA, we performed a randomized, double-blinded, placebo-controlled trial of human recombinant leptin (metreleptin) in replacement doses over 36 wk in women with HA. We assessed its effects on reproductive outcomes, neuroendocrine function, and bone metabolism. Leptin replacement resulted in recovery of menstruation and corrected the abnormalities in the gonadal, thyroid, growth hormone, and adrenal axes. We also demonstrated changes in markers of bone metabolism suggestive of bone formation, but no changes in bone mineral density were detected over the short duration of this study. If these data are confirmed, metreleptin administration in replacement doses to normalize circulating leptin levels may prove to be a safe and effective therapy for women with HA.

Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in patients with hypopituitarism and hypothalamic damage (HHD), that might be associated with neuropsychological deficits and sexual dysfunction, leading to worse quality of life (QoL). Therefore, identifying a provocative test to diagnose an OXT-D will be important. Corticotropin-releasing hormone (CRH) is a candidate for such a test as it increases oxytocin secretion in animal models. This study aimed to examine the effects of CRH on oxytocin release in HHD compared to healthy controls (HC) and to describe the psychopathology, sexual function and QoL and their associations with oxytocin. This is a single-blind, randomized, placebo-controlled, proof-of-concept study (NCT 04902235) with crossover assignment (CRH vs. placebo). Nineteen HHD patients (10 females) and 20 HC (11 females) completed two visits, receiving CRH or placebo in random order and completed validated questionnaires to assess psychopathology, sexual function and QoL. Samples were collected over 120 min to assess oxytocin. Linear mixed-effects regression model evaluated the change in oxytocin after CRH/placebo in HHD vs. HC. CRH administration did not impact oxytocin concentrations across groups over time (p = 0.97). HHD had greater psychopathology (most ps < 0.05), sexual dysfunction (p < 0.03) and worse QoL (p < 0.001) compared to HC, nevertheless, baseline oxytocin concentrations and area under the curve of oxytocin were not significantly associated with psychopathology, sexual function or QoL, neither in HHD or HC. In conclusion, CRH administration does not appear to be a suitable provocative test for diagnosing OXT-D in HHD. Identifying a reliable diagnostic test for OXT-D remains crucial. Alternative provocative tests or biomarkers should be explored.

Abstract Context Different phenotypical features of women with hypothalamic hypogonadism (HH), also known as World Health Organization-1 anovulation, including ovarian morphology, have been scarcely described in large cohorts. Some studies have reported increased levels of anti-Müllerian hormone (AMH) in women with HH. Objective To assess whether women with HH, compared with healthy controls, have increased serum levels of AMH and what proportion of these women erroneously meet the Rotterdam Criteria for Polycystic Ovarian Syndrome (PCOS). Design, Setting and Participants Retrospective cohort study in a Dutch academic medical center including 83 women with neither anovulation nor menstrual cycle disorders (healthy controls), 159 women with HH and 3640 women with PCOS. Age matching was used between the HH and PCOS group (1:2 ratio) to create a second group consisting of 318 age-matched women with PCOS. Intervention None. Main outcome measures AMH levels and ovarian morphology. Results Median AMH serum levels for the HH group were 3.8 (<0.1–19.8), compared with 7.5 (<0.1–81.0) in the PCOS group and 1.9 (<0.1–21.5) in the control group (P < 0.001). In the HH group, 58 (36%) erroneously met the Rotterdam Criteria for PCOS (meeting 2 of 3 criteria). Conclusions AMH levels are increased in women with HH. We hypothesize that this increase, although there was no increase in follicle count, may be explained by the presence of a relatively large pool of antral follicles smaller than 2 mm in diameter, that are undetectable by transvaginal ultrasound. This study highlights the importance of measuring gonadotropins and estradiol before diagnosing a patient with PCOS.

Objectives To determine metabolic and hormonal profiles in women with functional hypothalamic amenorrhea (FHA) with normal body mass index (BMI). Methods In FHA ( n  = 69) and controls ( n  = 69), matched for age and BMI lipid, fasting plasma glucose (FPG) and insulin (Ins) levels along with hormonal profile were determined. Results FHA showed slightly lower FPG (− 8.2%, p  = 0.001) contrary to the controls with no differences in lipid profile. In the FHA group, BMI was positively correlated with Ins ( r  = 0.57, p  < 0.001) and negatively with high-density lipoprotein cholesterol (HDL-C; r  = − 0.58, p  < 0.001). Regarding hormonal profile, FHA showed higher prolactin (PRL; + 61.6%) and thyroid-stimulating hormone (TSH; + 4.0%) levels compared to the controls (all p  < 0.05). FHA had higher androgen levels reflected by higher total testosterone (TT; + 22.2%) and 17-hydroxyprogesterone (17-OHP; + 88.9%) levels (all p  < 0.05) in contrary to the remainder. Conclusion FHA women with normal BMI present unfavorably altered hormonal profile reflected by hyperandrogenemia and slightly lower, but significant, FPG level. The findings confirm the importance of assessing both metabolic and hormonal panels in FHA women despite normal BMI.

Background Almost half of patients with functional hypothalamic amenorrhea (FHA) show polycystic ovarian morphology (PCOM) on the ultrasound, which leads to a diagnostic confusion. Although FHA and polycystic ovarian syndrome (PCOS) have been thought to co-exist and some FHA-patients seem to have had PCOS before developing FHA, respectively, once hypothalamic inhibition proceeds, the FHA phenotype predominates over the PCOS features, except from PCOM. This connection has never been shown longitudinally. Furthermore, it is still not clear if FHA-PCOM is actually related to preexisting PCOS or if these women constitute their very own heterogeneous subgroup. Thus, the aims of this study were to evaluate changes in hormonal parameters and PCOM after remission and to provide further insight into pathophysiological processes of PCOM in FHA. Methods Monocentric retrospective cohort study. Sixty women with FHA in remission were included. While anti-mullerian hormone (AMH) was the main outcome parameter, we also analyzed total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), sex hormone-binding globulin (SHBG) and dehydroepiandrosterone sulfate (DHEAS). PCOM was diagnosed using ultrasound. Results At baseline, FHA-PCOM patients revealed higher baseline prolactin ( p  = 0.029) and AMH levels ( p  < 0.001). At follow-up, compared to women without PCOM, these women had higher PCOM prevalence (48.1% versus 0%, p  < 0.001), higher AMH levels (median 6.49 ng/mL, IQR 4.74–7.95 versus median 2.25 ng/mL, IQR 2.0-2.71; p  < 0.001) and higher PCOS prevalence (22.2% versus 0%, p  = 0.006). While overall median AMH levels increased significantly, FHA-PCOM patients revealed a significant median decrease in AMH levels (median AMH dynamics − 0.82 ng/mL, IQR – 2.30 - -0.16; p  < 0.001). Conclusions Our data support the hypothesis that relative FSH deficiency in hypothalamic dysfunction can lead to lower AMH levels. In contrast, the decline in AMH levels and the resolution of PCOM in the FHA-PCOM group may indicate a reversible state of ovarian hyperactivation during FHA. Trial registration Not applicable.

APS (autoimmune polyglandular syndrome) is defined as the coexistence of at least two kinds of endocrine autoimmune diseases. APS type 3 comprises autoimmune thyroid diseases and other autoimmune diseases but does not involve autoimmune Addison’s disease. So far, APS-3 combined with isolated gonadotropin-releasing hormone (GnRH) reduction caused by the suspected autoimmune hypothalamic disease has not been reported. We recently received a 43-year-old woman with a one-year history of Graves’ disease (GD) and a four-month history of type 1 diabetes presented with hyperthyroidism and hyperglycemia. After the GnRH stimulation test, she was diagnosed with secondary amenorrhea attributed to suspected autoimmune Hypothalamitis and APS type 3 associated with Graves’ disease and Latent Autoimmune Diabetes (LADA). According to this case, the hypothalamus cannot be spared from the general autoimmune process. It is recommended to carry out the GnRH stimulation test when encountering APS patients combined with secondary amenorrhea.

Hypothalamic amenorrhea in anorexia nervosa often precedes weight loss and may persist after re-feeding and restoration of a stable normal weight. To assess the rate of persistent amenorrhea in anorexia nervosa (AN) after re-feeding and the relations of this condition with body composition changes and other endocrine parameters. A cohort of 250 female outpatients was studied to assess persistent amenorrhea prevalence after stable weight recovery. Among these, we selected 20 AN female patients (age 16.5-35), 10 with amenorrhea (group 1) and 10 with normal menses (group 2). We collected data such as age, age at menarche, age at onset of AN, actual body mass index (BMI) and at onset of AN, duration of disease. Physical activity has been evaluated as minute per day. The following data were obtained: prolactin, growth hormone, estradiol, luteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, free urinary cortisol, serum calcium and phosphates, urinary calcium, phosphaturia and alkaline phosphatase. Body composition was assessed with a dual energy x-ray absorptiometry (DEXA). Thirty-five patients (14%) over a cohort of 250 where still amenorrhoic after stable weight recovery. No significance was found in the evaluation of blood biochemical tests of the 2 groups. Free urinary cortisol was significantly higher in amenorrhoic patients (58.14+/-0.4 vs 15.91+/-9.5), p=0.02. The analysis of body composition has shown a percentage of fat of 22.23+/-5.32% in group 1 and of 26.03%+/-9.1% in group 2, respectively, showing no significant differences. Amenorrhoic patients carried on doing a significantly heavier physical activity than eumenorrhoic patients. An adequate body composition and a well represented fat mass are certainly a necessary but not sufficient condition for the return of the menstrual cycle. Such menstrual cycle recovery would probably need other conditions at present being studied and evaluated to occur, such as secretory patterns of leptin and its correlations with adrenal function.

The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was −0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.

We studied, by means of TSH nocturnal secretion and TRH test, 42 children (4.2-19.9 years) with hypothalamic pituitary disorders and 24 healthy euthyroid children (5.7-15.4 years) as control group. Patients were divided according to their serum values of FT4 in group 1 (n = 27) with FT4 >/=10.3 pmol/l and group 2 (n = 15) with FT4 <10.3 pmol/l. TSH was measured by immunoradiometric assay. TSH nadir, TSH peak and TSH surge were calculated. Both groups differed significantly from control group in TSH surge values: group 1 (p < 0. 05), group 2 (p < 0.01). TRH test was abnormal in 11/27 patients of group 1 and 10/15 patients of group 2. In group 1, 7 patients had normal tests, 2 had abnormalities in both tests, 9 had only TSH nocturnal surge altered and 9 showed only TRH alterations. All patients of group 2 presented thyroid axis abnormalities. In conclusion, in patients with hypothalamic pituitary disorders with low FT4, no further investigation is required to demonstrate thyroid axis alterations, however in patients with normal FT4, nocturnal TSH secretion and TRH test may be required to evidence thyroid abnormalities.

A case is presented of 14 year old female with hypothalamic obesity due to hydrocephalus caused by aqueductal stenosis. Evidence of hypothalamic obesity included 1) acute hyperphagia and weight gain, 2) neuroradiology showed hydrocephalus with focal enlargement of the third ventricle, 3) endocrinological studies revealed hyperinsulinaemia and impaired growth hormone (GH) response to arginine, but normal GH response to growth hormone-releasing factor (GRF) and 4) Torkildsen's ventriculo-cisternal shunting resulted in improvement in hyperphagia and obesity.