Hypercarotenemia in hypothalamic amenorrhea.

Six patients are described with hypothalamic amenorrhea and associated hypercarotenemia. The commencement of the hypothalamic amenorrhea followed weight reduction or stress in each case. The subjects were otherwise healthy and had none of the associated stigmata of anorexia nervosa. None of the subjects had ingested excessive quantities of vegetables or fruits rich in carotene. Although all six patients had elevated serum carotene levels, only three had clinically apparent yellow pigmentation of the skin. The exact mechanism responsible for hypercarotenemia in patients with hypothalamic amenorrhea is not apparent. Mobilization of lipid stores and catabolic changes occurring with weight-loss states appear to be related in some undefined way to the elevated carotene levels.     

Gonadotropin-releasing hormone for infertility in women with primary hypothalamic amenorrhea. Toward a more-interventional approach

OBJECTIVE: To assess the effectiveness of a protocol of pulsatile gonadotropin releasing-hormone (GnRH) in treating infertility in women with primary hypothalamic amenorrhea. STUDY DESIGN: Retrospective analysis of 44 cycles treated at an infertility center. Twenty-four patients with primary hypothalamic amenorrhea were treated intravenously with pulsatile GnRH using 5 micrograms per bolus every 90 minutes. Ultrasound monitoring and cervical assessment by Insler's scoring system allowed timed injection of human chorionic gonadotropin (hCG) and intrauterine insemination if needed. Luteal support was provided with hCG. RESULTS: The ovulation rate was 95% with the 5-microgram dose. A single follicle was produced in 91% of cycles. The overall pregnancy rate per ovulatory cycle was 45%, and the pregnancy rate per patient was 83%. In patients treated previously with exogenous gonadotropins, poor results were observed. Only one case of mild overstimulation was reported. CONCLUSION: Pulsatile GnRH is an effective and safe method of treating infertility in women with primary hypothalamic amenorrhea, thus simulating normal ovulation; however, more-interventional management, including the qualitative estrogenic response, may lead to optimal results and increase the pregnancy rate.     

Autonomic and neuroendocrine responses to stress in patients with functional hypothalamic secondary amenorrhea

OBJECTIVE: To evaluate the ability of women affected by functional hypothalamic secondary amenorrhea (FHSA) or polycystic ovary syndrome (PCOS) to adapt to stress. DESIGN: Controlled clinical study. Setting: University hospital. PATIENT(s): Thirty-one patients affected by FHSA, 29 patients with PCOS, and 30 eumenorrheic women. INTERVENTION(s): The subjects took the Stroop Color Word (Stroop CW) test and underwent blood sampling. MAIN OUTCOME MEASURE(s): Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum cortisol levels. RESULT(s): The healthy controls had better Stroop CW scores than patients with FHSA. Serum cortisol levels significantly increased during Stroop CW with respect to the baseline in patients with FHSA or PCOS but not in the healthy controls. The SBP, DBP, and HR of the controls as well as SBP and DBP of patients with PCOS were significantly higher than those measured in patients with FHSA both at the baseline and during Stroop CW. CONCLUSION(s): Patients with FHSA do not cope as well as healthy patients, and their autonomic response to stress is worse than both controls and patients with PCOS.     

Treatment of functional hypothalamic amenorrhea with hypnotherapy

OBJECTIVE: To determine the effects of hypnotherapy on resumption of menstruation in patients with functional hypothalamic amenorrhea (FHA). DESIGN: Uncontrolled clinical study. SETTING: Academic clinical care center. PATIENT(S): Twelve consecutive women with FHA were selected. INTERVENTION(S): A single 45- to 70-minute session of hypnotherapy was administered, and patients were observed for 12 weeks. MAIN OUTCOME MEASURE(S): Patients were asked whether or not menstruation resumed and whether or not well-being and self-confidence changed. RESULT(S): Within 12 weeks, 9 out of 12 patients (75%) resumed menstruation. All of the patients, including those who did not menstruate, reported several beneficial side effects such as increased general well-being and increased self-confidence. CONCLUSION(S): Hypnotherapy could be an efficacious and time-saving treatment option that also avoids the pitfalls of pharmacological modalities for women with FHA.     

The etiology in 77 primary amenorrhea patients

This study is based upon an analysis of 77 cases of primary amenorrhea. The work-up included a complete endocrinological study, cytogenetics, laparoscopy, and gonadal biopsy. Of the total number of patients, 31 had a completely developed female phenotype, 22 had an insufficiently developed one, and the remaining 24 patients were characterized by infantilism. A positive sex chromatin was obtained in 59 patients, and negative in 18. Out of 77 patients, 25 had an abnormal karyotype or one corresponding to the opposite sex. In six patients, the existence of a Y chromosome in the karyotype was found in spite of the female phenotype. Five patients had the testicular feminisation syndrome.     

Osteopenia in women with hypothalamic amenorrhea: a prospective study

Hypothalamic amenorrhea, a common disorder associated with abnormalities in gonadotropin pulsatility and subsequent estrogen deficiency, is usually transient, and treatment indications are unclear unless fertility is desired. To determine whether this disorder is associated with progressive bone loss, we studied 24 women with primary or secondary amenorrhea related to stress or simple weight loss, compared with 31 normal women of the same age. Amenorrheic women had significantly lower (P = .01) body fat (26.4 +/- 7.3 versus 30.6 +/- 4.7%) and higher (P = .0001) urine free cortisol levels (250 +/- 100 versus 140 +/- 50 nmol/day) than normals. Trabecular bone density in women with hypothalamic amenorrhea as assessed by spinal computed tomography was significantly (P = .001) lower than in normals (140.2 +/- 27.3 versus 175.1 +/- 24.6 mg K2HPO4/mL, respectively). Twenty of the 24 amenorrheic women had initial spinal bone density below the mean in normals, and in eight it was 2 standard deviations or more below the normal mean. Initial bone density correlated negatively with duration of amenorrhea (r = -0.489, P = .02) and positively with serum free testosterone levels (r = 0.517, P = .02). Prospective evaluation showed a decline in spinal bone density in those who were amenorrheic for fewer than 5 years. The slope of change in bone density correlated with initial weight, percent ideal body weight, and percent body fat (R2 = 0.597, P = .0003; R2 = 0.549, P = .0007; and R2 = 0.618, P = .0002, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Psychological correlates of functional hypothalamic amenorrhea

OBJECTIVE: To determine whether mood, attitudes, or symptoms of disordered eating discriminated women with functional hypothalamic amenorrhea (FHA) from those with organic causes of amenorrhea and eumenorrhea. DESIGN: Cross-sectional comparison of women with FHA, women with organic amenorrhea, and eumenorrheic control women. SETTING: Clinical research center in an academic medical institution. PATIENT(S): Seventy-seven women > or =18 years old with time since menarche > or =5 and < or =25 years were recruited by advertisement. INTERVENTION(S): Ovulation was confirmed in eumenorrheic control women. Causes of anovulation were carefully documented in amenorrheic participants and LH pulse profiles were obtained to document the diagnosis of FHA. All participants were interviewed and completed questionnaires. MAIN OUTCOME MEASURE(S): Self-report measures of dysfunctional attitudes, coping styles, and symptoms of depression and eating disorders. RESULT(S): Women with FHA reported more depressive symptoms and dysfunctional attitudes than did eumenorrheic women, but not significantly more than women with organic amenorrhea. However, women with FHA reported significantly more symptoms of disordered eating than did either anovulatory or ovulatory women. CONCLUSION(S): The findings are consistent with the hypothesis that FHA is precipitated by a combination of psychosocial stressors and metabolic challenge.     

Endocrine dynamics during pulsatile GnRH administration in patients with hypothalamic amenorrhea and polycystic ovarian disease

The LH secretory patterns and ovarian endocrine responses have been determined during pulsatile gonadotropin-releasing hormone (GnRH) administration for induction of ovulation in patients with hypothalamic amenorrhea (HA). However, until now these endocrine dynamics during GnRH therapy have not been thoroughly investigated in patients with polycystic ovarian disease (PCOD). Seven patients with HA and 4 patients with PCOD have therefore been studied to determine changes in LH pulsatile activity and in serum sex steroid levels in response to chronic intermittent GnRH stimulation. GnRH was administered intravenously (5-10 micrograms/90 minutes) by means of a portable infusion pump. Blood samples were obtained at 15-minute intervals for 4 hours on the day before the start of GnRH stimulation (control day) and on treatment days 5, 10 and 15. LH was determined in all samples and FSH, serum androgens and estrogens were measured in baseline samples by RIA. While 8 (62%) ovulations and 5 conceptions were observed in 13 treatment cycles in patients with HA, no ovulations were achieved during 9 treatment cycles in patients with PCOD. On the control day significantly (p less than 0.05) higher basal LH and testosterone (T) levels and significantly (p less than 0.05) lower FSH levels were found in the PCOD patients. The LH pulsatile profiles of the PCOD patients showed significantly (p less than 0.05) higher pulse amplitudes and areas under the curve (integrated responses). Pulsatile GnRH administration induced a significant (p less than 0.05) increase in LH pulse amplitudes in both HA and PCOD patients, and also increased (p less than 0.05) the integrated responses in patients with HA. During the GnRH stimulation, the LH interpulse intervals of both HA and PCOD patients were found to be similar to the frequency in which exogenous GnRH was administered. FSH levels rose continuously (p less than 0.001) during stimulation in patients with HA, but remained unchanged in patients with PCOD. In HA patients, T, androstenedione (AD) and estrone (E1) did not change during the GnRH treatment, but estradiol (E2) rose so that the ratios of aromatized estrogens to non-aromatized androgens (E1/AD, E2/T) increased. In contrast, T and AD increased significantly (p less than 0.05 or less) and E2 remained unchanged during stimulations in PCOD patients, which resulted in decreasing ratios of estrogens to androgens. These observations confirm that pulsatile GnRH administration can successfully induce ovulation in patients with HA by restoring the ovarian physiology. The data also demonstrate that pulsatile GnRH administration can influence the LH secretory patterns in PCOD patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA)

Objective: To evaluate the influence of short-term estriol administration (10 d) on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA).

Study design: Controlled clinical study on patients with FHA (n?=?12) in a clinical research environment.

Intervention(s): Hormonal determinations and gonadotropin (luteinizing hormone [LH] and FSH) response to a gonadotropin-releasing hormone (GnRH) bolus (10?μg) at baseline condition and after 10 d of therapy with 2?mg/d of estriol per os.

Main outcome measure(s): Measurements of plasma LH, FSH, prolactin, estradiol, androstenedione, 17α-hydroxyprogesterone, insulin, cortisol, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine.

Result(s): After treatment, the FHA patients showed a statistically significant increase of both LH and FSH plasma levels and the significant increase of their responses to the GnRH bolus.

Conclusion(s): Estriol short-term therapy modulates within 10 d of administration the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of both gonadotropins synthesis and secretion in hypogonadotropic patients with FHA.     

下丘脑性闭经的诊治

下丘脑性闭经是闭经的常见类型,需在排除垂体、卵巢或子宫性闭经之后才能作出诊断.下丘脑性闭经分为功能性下丘脑性闭经(functional hypothalamic amenorrhea,FHA)和器质性下丘脑性闭经[1].     

Induction of ovulation with clomiphene citrate in combination with metoclopramide in patients with amenorrhea of hypothalamic origin.

Literature data have demonstrated that the chronic use of metoclopramide (MCP), a dopamine antagonist, causes increased gonadotropin secretion in patients with hypothalamic amenorrhea but without triggering ovulation. It has also been observed that women with hypothalamic amenorrhea respond poorly to ovulation induction with clomiphene citrate (CC). On this basis, the objective of the present study was to determine the effect of MCP on the response to CC in patients with hypothalamic amenorrhea in order to evaluate the validity of the simultaneous use of these drugs as ovulation inducers in this type of chronic anovulation. Twenty-two patients with amenorrhea of hypothalamic origin were submitted to a randomized double blind study in which one tablet of 5 mg MCP or placebo was administered every 8 hours for 2 months. After the 30th day of medication (MCP or placebo), CC, 100 mg orally, was additionally administered to both groups for 5 days. Blood samples were collected on days 1, 15 and 30 during the first month of the study and on days 7, 14 and 21 after the last CC tablet during the second month, for later measurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol and progesterone by radioimmunoassay. The group that received MCP showed a significant increase in LH and FSH during the first month of the study, as well as a slighter increase in estradiol. Prolactin increased only during the second stage of treatment. No significant increases in gonadotropins, prolactin or estradiol occurred in the placebo group. In the group treated with MCP, 40% of the patients ovulated after CC, with menstruation occurring in 60% of them. In the placebo group, 33.3% of the women ovulated after CC and 44.4% menstruated at the end of the study. We conclude that MCP increases the circulating levels of LH, FSH, estradiol and prolactin in patients with hypothalamic amenorrhea and low estrogen levels, supporting the hypothesis that an increase in hypothalamic dopaminergic tonus occurs in these patients. On the other hand, the combination of MCP and CC does not improve the rate of ovulation compared to placebo.     

Induction of ovulation and pregnancy in twenty-six patients with primary hypogonadotropic amenorrhea

The methods and results of treatment with human menopausal gonadotropins (hMG) and chorionic gonadotropin (hCG) in 26 patients (mean age 24 years, range 22-35 years) with hypogonadotropic primary amenorrhea and without chromosomal abnormalities are reported. The usual dose of hMG was 225 IU daily until the karyopycnotic index rose to 40% or more and the other clinical parameters revealed sufficient follicular maturation. A dose of hCG was then administered at the rate of 10,000 IU daily for 4 days. In 60 courses of treatment, we obtained 17 pregnancies (28.3%) in 13 patients (i.e., including some second pregnancies), 35 ovulations without pregnancy (58.3%), and seven patients did not respond (11.6%). Three patients who did not respond and who continued the treatment ovulated and became pregnant. Clinical hyperstimulation occurred in three patients on the first course of treatment. Two of them again presented this complication on repetition of treatment despite the precautions taken. Urinary estrogen and pregnanediol measurements on the 7th-11th day after hCG administration revealed considerable hormonal hypersecretion in 19 of 27 courses of treatment. In eight patients the high output of pregnanediol continued during the first 1-2 months of pregnancy and decreased thereafter. The rate of pregnancies seemed to be higher in patients with hypersecretion whereas clinical hyperstimulation did not correlate with the degree of the hormonal output. Pregnancies were all single and uneventful except for one abortion in a patient who was found to have mycoplasma infection. All patients gave birth to normal children and lactated normally. The increased dosage of hCG used in this series is considered to be a decisive factor in the induction of ovulation and the maintenance of pregnancies through the abundant steroid production it induced.     

Decreased plasma concentrations of brain-derived neurotrophic factor (BDNF) in patients with functional hypothalamic amenorrhea

Abstract

Introduction: Functional hypothalamic amenorrhea (FHA) is a non organic, secondary amenorrhea related to gonadotropin-releasing hormone pulsatile secretion impairment. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays an important role in the growth, development, maintenance and function of several neuronal systems.

Aim of the study: The aim of the study was the evaluation of plasma BDNF concentrations in patients with the diagnosis of FHA.

Material and methods. We studied 85 subjects diagnosed with FHA who were compared with 10 healthy, eumenorrheic controls with normal body mass index. Plasma BDNF and serum luteinizing hormone, follicle-stimulating hormone and estradiol (E2) concentrations were measured by immunoenzymatic method (enzyme-linked immunosorbent assay).

Results: Significantly lower concentration of plasma BDNF was found in FHA patients (196.31?±?35.26?pg/ml) in comparison to healthy controls (407.20?±?25.71?pg/ml; p?<?0.0001). In the control group, there was a strong positive correlation between plasma BDNF and serum E2 concentrations (r?=?0.92, p?=?0.0001) but in FHA group it was not found.

Conclusions: Role of BDNF in FHA is not yet fully understood. There could be found studies concerning plasma BDNF concentrations in humans and animals in the literature. However, our study is one of the first projects which describes decreased plasma BDNF concentration in patients with diagnosed FHA. Therefore, further studies on BDNF in FHA should clarify the role of this peptide.