New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea.

OBJECTIVE: To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. DESIGN: This was an open-label study. PATIENTS: Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. MAIN OUTCOME MEASURES: Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. RESULTS: Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. CONCLUSIONS: The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.     

Utilization of the biochemical response to clomiphene citrate for the selection of women with hypothalamic amenorrhea who require further investigation

Clomiphene citrate (CC) 100 mg daily for 5 days was given to 41 women with hypothalamic amenorrhea. CC also was given to 6 similar women with known organic suprasellar disease and to 8 normal women in the early follicular phase. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) were measured both before the first tablet of CC and again on the fifth day. Biochemical evidence of ovulation occurred in 12 of the 41 women. The remaining 29 women included 14 with a significant rise in one or more of serum LH, FSH, and E2 similar to the normal group. The 15 women without rise in any hormonal parameter were investigated further because their response was similar to the organic suprasellar disease group. Serious organic sellar/suprasellar disease was initially found in 4 women, while 2 of the remaining 11 subsequently developed previously unrecognized organic disease over the ensuing year. The authors conclude that the biochemical response to CC is useful to indicate which women with hypothalamic amenorrhea--without any other obvious clinical stigmata--should be further investigated for underlying organic disease.     

Addition of human chorionic gonadotropin to clomiphene citrate ovulation induction therapy does not improve pregnancy outcomes and luteal function

In a randomized prospective study, 125 women with World Health Organization class II anovulation received 50 mg of clomiphene citrate alone (group A, n = 65) or 50 mg of clomiphene citrate plus hCG (group B, n = 60) in a total of 125 cycles during natural intercourse-advised cycles. There were no statistically significant differences between groups regarding pregnancy outcomes and midluteal P levels, but luteal phase length was longer in group A.     

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.     

A longitudinal study of disturbances of the hypothalamic-pituitary-adrenal axis in women with progestin-negative functional hypothalamic amenorrhea

OBJECTIVE: To longitudinally evaluate disturbances of the hypothalamic-pituitary-adrenal (HPA) axis in women with secondary progestin-negative hypothalamic amenorrhea. DESIGN: Retrospective cohort study. SETTING: Yokohama City University, Yokohama, Japan. PATIENT(S): Twenty-four women with progestin-negative hypothalamic amenorrhea. INTERVENTION(S): Administration of human corticotropin-releasing hormone (hCRH) and treatment with a combination of estrogen and progesterone. MAIN OUTCOME MEASURE(S): Plasma cortisol and ACTH concentrations and period required for recovery from amenorrhea. RESULT(S): Plasma ACTH concentrations 30 and 60 minutes after injection of hCRH and the percent maximum increment (%Cmax) of ACTH were significantly lower in the amenorrheic patients compared with the control group patients. The basal cortisol was significantly higher, and the %Cmax of cortisol was significantly lower. In the 16 patients who recovered from amenorrhea, there was a significant positive correlation (Y = 1.93X-10.8, r = 0.629) between the basal cortisol concentrations (X) and the period for recovery (Y). The serum E2 gradually increased before recovery, and this E2 increase was preceded by changes in the plasma cortisol concentration and the %Cmax values of cortisol and ACTH. CONCLUSION(S): The CRH test might be useful for evaluating the roles of stress and for estimating the period required for recovery in hypothalamic amenorrhea.     

Clomiphene citrate does not improve spermatozoal fertilizing capacity in idiopathic oligospermia

Clomiphene citrate (CC) was given to 24 men with idiopathic oligospermia at a daily dose of 25 mg (10 subjects) or 50 mg (14 subjects). Sperm concentration increased slightly after CC treatment in both groups. Sperm motility and morphology remained unchanged. Spermatozoal fertilizing capacity as assessed by the zona-free hamster ova penetration test showed no significant change throughout the treatment period. Two pregnancies occurred in the partners of the subjects treated with 50 mg CC/day, but none occurred in the other group. We conclude that oral administration of CC does not improve fertilizing capacity of sperm as measured by the zona-free hamster ova penetration test in idiopathic oligospermia.     

Anti-Mullerian hormone levels do not predict response to pulsatile GnRH in women with hypothalamic amenorrhea

Pulsatile GnRH is used to induce ovulation in women with hypothalamic amenorrhea (HA), but tools to predict response are lacking. We assessed whether baseline AMH levels are associated with response to pulsatile GnRH in 16 women with HA. AMH levels were compared between non-responders and women who achieved follicular development or pregnancy. Median AMH for the cohort was 2.2?ng/mL. AMH levels were undetectable or low in four women, normal in nine and high in three. Follicular development was observed in 13 (81%) women (82% of cycles) and pregnancy achieved in 10 (63%) women (29% of cycles). All four women with low or undetectable AMH had follicular response and three achieved pregnancy. Of the 12 women with normal or high AMH, 10 had a follicular response and seven achieved pregnancy. Median AMH levels were comparable in those who achieved follicular development and those who did not (2.2?ng/mL versus 1.3?ng/mL, p?=?0.78) and in those who became pregnant and those who did not (2.2?ng/mL versus 1.9?ng/mL, p?=?0.52). In summary, low AMH does not preclude response to ovulation induction in women with HA, suggesting that ovarian potential may not be the primary determinant of AMH concentrations in this population.     

Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study

In the present prospective study we compared, in terms of pregnancy rates, the differences between intrauterine insemination (IUI) of in vitro capacitated husband's semen and timed natural intercourse in spontaneous or clomiphene citrate (CC) stimulated cycles. A rapid urinary luteinizing hormone peak detection test was used for timing of ovulation. Forty patients suffering from longstanding infertility of male (n = 17), cervical (n = 2), and idiopathic (n = 21) origin were randomly assigned into four distinct treatment modalities during 4 consecutive cycles. A total of 132 cycles were analyzed. In 35 cycles treated with CC plus IUI, five conceptions were achieved, whereas three pregnancies occurred in 32 inseminated spontaneous cycles. Only 1 patient conceived after timed intercourse in 31 CC stimulated cycles, and no pregnancy resulted from 34 spontaneous cycles combined with timed intercourse. There was a statistically significant higher conception rate in cycles in which IUI was performed, whereas the use of CC does not seem to improve the pregnancy rate. Analysis of results for other modifying factors did not substantially affect the relative risk (odds ratio) of pregnancy.     

Combined therapy of bromocriptine, clomiphene citrate and HMG in normoprolactinemic amenorrhea patients who fail to respond to bromocriptine-clomiphene citrate therapy

The purpose of this study is to investigate the ovulatory effect of the following three methods on 40 patients with normoprolactinemic amenorrhea patients who failed to respond to clomiphene citrate (Cl) alone. Method I is the combined therapy with bromocriptine and Cl (Brc/Cl). Method II is the combined therapy with Brc/Cl and an additional small amount of HMG (less than or equal to 300 IU). Method III is the combined therapy with Brc/Cl and an increased amount of HMG (less than or equal to 1,200 IU) and HCG. The ovulation rate of method I was 57.5% (23/40) in 40 cases, and 55.6% (99/178) in 178 cycles. The pregnancy rate for this method was 23.8% (5/21). Out of the 12 nonrespondent method I cases, 5 additional cases were ovulated by method II and 3 cases were ovulated by method III. The total pregnancy rate was 42.9% (9/21) with these three methods. Seven cases were normal pregnancies, one case was a twin pregnancy and 1 case was an abortion. No other side effects were found in this study. From these results, the combined therapy with Brc/Cl or Brc/Cl + HMG had almost the same ovulatory rate as the HMG-HCG therapy, and fewer side effects.     

Effect of age on the response of the hypothalamo-pituitary-ovarian axis to a combined oral contraceptive

Objective: To examine the effect of age on the response to treatment with a combined oral contraceptive.

Design: Prospective, controlled clinical study.

Setting: Reproductive medicine unit in a tertiary care university medical center.

Patient(s): Twenty-six healthy female volunteers aged 21–45 years.

Intervention(s): After a control cycle, all the women were given a combined oral contraceptive containing 20 μg of ethinylestradiol with 75 μg of gestodene for three cycles. The women were examined through the posttreatment cycle.

Main Outcome Measure(s): Pituitary and ovarian activity was assessed with ultrasound and measurement of ovarian steroids.

Result(s): Follicular activity was observed in all treatment cycles, although ovulation was inhibited. Ovarian suppression was maximal in cycle 1. Mean endogenous E₂ levels were lower during cycles 2 and 3 in the older group. Serum FSH levels were higher in the control cycle and on day 28 of the treatment cycles in the older group. Most women ovulated during the posttreatment cycle.

Conclusion(s): Combined oral contraceptives did not inhibit all ovarian activity; maximal suppression was seen in cycle 1. Less follicular activity was observed in cycles 2 and 3 in the older group. Raised FSH levels with age reflect increasing ovarian resistance to follicular development.     

Effects of cetrorelix,a GnRH-receptor antagonist,on gonadal axis in women with functional hypothalamic amenorrhea

Background.?Gonadotropin Releasing Hormone (GnRH) antagonists (GnRHa) suppress gonadotropin and sex-steroid secretion. In normal women, acute GnRHa administration induces inhibitory effect on pituitary-gonadal axis, followed by Luteinizing Hormone (LH) rebound. Functional hypothalamic amenorrhea (HA) is characterised by impaired gonadotropin secretion and hypogonadism secondary to blunted GnRH pulsatility.

Methods.?We studied the effects of a GnRHa, cetrorelix (CTX 3.0?mg), in six women with HA (age 30.7?±?3.2 years; BMI 21.5?±?1.7 kg/m²) and six control subjects (CS, 28.2?±?0.6 years; 22.6?±?0.9 kg/m²) on LH, Follicle-Stimulating Hormone (FSH) and oestradiol levels over 4?h (08.00–12.00 am) before, +24?h and +96?h after CTX; LH, FSH, and oestradiol were also evaluated at +6, +8, +12, +48, +72?h after CTX.

Results.?CS: CTX reduced (p?<?0.05) LH, FSH, and oestradiol (nadir at +12?h, +24?h, and +24?h); LH rebounded at +96?h, FSH and oestradiol recovered at +48?h and +72?h. The 4-h evaluation showed LH and FSH reduction (p?<?0.05) at +24?h, with LH rebound at +96?h. HA: CTX reduced (p?<?0.05) LH, FSH, and oestradiol, (nadir at +24?h, +48?h, and +48?h, recovery at +48?h, +72?h, and +96?h). The 4-h evaluation showed gonadotropin reduction (p?<?0.05) 24?h after CTX, without any rebound effect.

Conclusions.?One single CTX dose still modulates gonadotropin secretion in HA. Its ‘paradoxical’ stimulatory effect on gonadotropins needs to be verified after prolonged administration.     

Body composition variables and leptin levels in functional hypothalamic amenorrhea and amenorrhea related to eating disorders

The purpose of the study was to identify diagnostic criteria that can distinguish between subjects with functional hypothalamic amenorrhea largely related to minimal energy deficiency and those in whom failure of adaptive response to stress prevails. We studied 59 young women with secondary amenorrhea related to modest eating disorders and 58 who complained of stressful events in their history. We assessed anthropometric measurements, body composition using dual energy X-ray absorptiometry (DEXA) and bioelectrical impedance analysis (BIA), and basal endocrine profile. Subjects with disordered eating had lower body mass index (BMI), fat mass (FM) measured with both techniques, lumbar mineral density and direct and indirect measures of lean mass. Leptin and free tri-iodothyronine(FT₃) concentrations also proved lower in the group of subjects with eating disorders, although there was no significant difference in cortisol between the two groups. Leptin levels were positively associated not only with fat mass, but also with body cell mass indexed to height and phase angle, parameters studied with BIA as expression of active lean compartment. A multivariate model confirmed the utility of integrating endocrine data with the study of body composition. The use of bioelectrical impedance analysis proved to be, in clinical use, a valid diagnostic alternative to DEXA, especially considering body cell mass and phase angle.     

Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase

Fifteen young women with a diagnosis of secondary hypothalamic amenorrhea of at least 2 years' duration were given either 50 mg naltrexone daily or placebo, following a randomized double-blind crossover scheme. Seven patients did not menstruate with either therapy. In the other eight, the following results were recorded (mean +/- SD and range): a cycle length of 28.7 +/- 7.6 (12-45) days for naltrexone compared with 30.8 +/- 5.9 (16-43) days for placebo, a follicular phase length of 20.8 +/- 5.4 (14-34) days for naltrexone and 23.2 +/- 4.3 (19-32) days for naltrexone and 8.3 +/- 1.6 (5-10) days for placebo. The number of ovulatory cycles was 18 of 24 (75%) with naltrexone and eight of 24 (33%) with placebo (P less than .05). Most luteal phases were short. In five normally menstruating women, we gave either naltrexone or placebo in the luteal phase using a crossover blinded scheme. Steroidogenesis in the normal luteal phase was not impaired by naltrexone therapy. In functional hypothalamic amenorrheic patients with normal weight, menstruation might be restored by either placebo or naltrexone, but naltrexone provides a clinical and therapeutic advantage by increasing the ovulation rate.     

Women with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrations

Objective: To test the hypothesis that increased cortisol secretion is specific to women with decreased GnRH drive and not found in eumenorrheic women or those with other causes of anovulation.

Design: Cortisol concentrations in blood were determined at 30-minute intervals for 24 hours in three well-characterized groups: women with functional hypothalamic amenorrhea, those with other causes of anovulation, and eumenorrheic women.

Setting: Academic medical center.

Patient(s): Women aged 20 through 35 years, with well-defined reproductive states.

Intervention(s): Venous blood samples were obtained from, and psychometric inventories were completed by, the participants.

Main Outcome Measure(s): Twenty-four-hour cortisol levels, 24-hour LH pulse patterns, and serial P levels were measured in women with functional hypothalamic amenorrhea, eumenorrheic women, and those with other causes of anovulation.

Result(s): Cortisol secretion was higher in women with functional hypothalamic amenorrhea (n = 19) than in those with other causes of anovulation (n = 19) or eumenorrheic women (n = 19). Six women who recovered from functional hypothalamic amenorrhea had cortisol levels comparable to those of eumenorrheic women and those with other causes of anovulation.

Conclusion(s): These data underscore the association between increased hypothalamic-pituitary-adrenal activity and reduced GnRH drive and support the concept that functional hypothalamic amenorrhea develops in response to stress-induced alterations in central neural function that modify hypothalamic function.     

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.     

The role of anti-Mullerian hormone in predicting the response to clomiphene citrate in unexplained infertility

Objective

To determine the role of anti-Mullerian hormone (AMH) levels in predicting the response to clomiphene citrate (CC) therapy for ovulation induction in women with unexplained infertility.