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.     

The effects of intranasal application of low dose buserelin in women with hypothalamic amenorrhea]

Low doses of the Gn-RH agonist (buserelin, 30 micrograms) were given intranasally to 14 women with clomiphene ineffective hypothalamic amenorrhea three times daily for three weeks in order to study pituitary responses and to induce follicular maturation and ovulation. Clomiphene ineffective hypothalamic amenorrhea patients were classified into two groups by LH-RH stimulation test before the treatment. Group 1 was defined as having basal serum LH and FSH levels lower than 1.5 mIU/ml, LH and FSH peaks lower than 3mIU/ml by LH-RH stimulation test. Group 2 consisted of cases other than those in Group 1. While a significant increase in basal LH and FSH (p less than 0.01, p less than 0.001) and improvement in pituitary response to LH-RH stimulation test were observed in group 1, the basal levels of LH and FSH did not increase significantly and pituitary response to a LH-RH stimulation test was decreased in group 2. It is suggested that pituitary priming occurred in group 1 and pituitary desensitization occurred in group 2. None of 14 patients showed signs of follicular maturation during or after the treatment. The results demonstrated that the biphasic pituitary response to intranasal buserelin spray and the limit of its therapeutic use for the treatment of hypothalamic amenorrhea.     

多囊卵巢综合征患者用克罗米酚促排卵结局与相关因素的探讨

目的　探讨在多囊卵巢综合征 (PCOS)患者中影响克罗米酚 (CC)促排卵因素。方法　对 94例因多囊卵巢综合征不孕患者 ,用CC促排卵治疗。采用放射免疫方法测定卵泡刺激素 (FSH)、黄体生成素 (LH)、雌二醇 (E2 )、睾酮 (T)、雄烯二酮 (A)、泌乳素 (PRL)水平及胰岛素释放反应。分析了排卵结局与年龄、基础激素水平、胰岛素抵抗 (IR)、胰岛素反应曲线下面积 (AUCI)及体重指数 (BMI)之间的关系。结果　用克罗米酚促排卵 94个周期中排卵率为 5 5 2 % (5 2 / 94) ,未排卵组的基础血雄激素、LH、AUCI 和BMI均较排卵组高。结论　PCOS患者的高雄激素、高LH血症、IR、高BMI对促排卵的结局产生负影响。     

A controlled comparison of the efficacy of clomiphene citrate in male infertility

To determine whether clomiphene citrate (CC) improves fertility in oligospermic men, 23 men with sperm concentrations between 0.5 and 20 million sperm per milliliter; normal serum gonadotropins and testosterone; and a presumptively fertile partner were enrolled in the study. After a 3-month control period, patients were randomly prescribed CC, 25 mg/day; or placebo, 1 tablet/day, for 12 months. The pregnancy rates for the CC group and the placebo group were 9.09% and 44.44%, respectively (not significant). During the treatment phase, the CC group had significantly higher levels of luteinizing hormone (LH) serum, follicle-stimulating hormone (FSH), testosterone (T), and estradiol than the placebo group. CC treatment also resulted in greater LH, FSH, and T responses to gonadotropin-releasing hormone (GnRH). There were no differences between the placebo and CC groups for the sperm penetration assay or semen parameters. The authors conclude that CC is not a useful drug in the treatment of male infertility.     

Clomiphene and dexamethasone in women unresponsive to clomiphene alone

Twelve oligomenorrhic women with polycystic ovary syndrome (PCO) in whom clomiphene (250 mg daily for 5 days) and 10,000 IU human chorionic gonadotropin had failed to induce ovulation were treated with clomiphene and dexamethasone. Eight of the 12 women underwent complete hormonal assessment during treatment. Six of the 12 ovulated and 1 conceived. Serum total and unbound estradiol and testosterone (T), serum dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding-globulin binding capacity (SHBG-BC), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were measured during clomiphene and dexamethasone therapy. SHBG-BC increased in response to clomiphene whether or not ovulation occurred. After treatment with clomiphene and dexamethasone there was a significant decrease in serum T, unbound T, and DHEA-S 2 weeks after dexamethasone administration, but there were no change in LH, FSH, or PRL. In patients who ovulated after clomiphene and dexamethasone, T and unbound T increased again after clomiphene was begun despite the continuation of dexamethasone. The women who ovulated after clomiphene and dexamethasone treatment had significantly higher pretreatment levels of DHEA-S than those who did not ovulate. Clomiphene and dexamethasone treatment may be beneficial to women who have elevated levels of DHEAS and who fail to ovulate with maximum doses of clomiphene.     

Clinical evaluation of patients with weight loss-related amenorrhea: neuropeptide Y and luteinizing hormone pulsatility.

AIM: To characterize patients with weight loss-related amenorrhea and controls with respect to the pulsatility of neuropeptide Y (NPY) and luteinizing hormone (LH). SUBJECTS: Nine young women (aged 20.23+/-2.11 years) diagnosed with weight loss-related amenorrhea (body mass index (BMI) 17.52+/-2.43 kg/m2) and five age-matched (age 21.88+/-3.12 years) normally menstruating (every 28-33 days) controls with normal BMI (23.62+/-3.11 kg/m2) (mean value+/-standard deviation). METHODS: Basal hormonal evaluation included serum follicle-stimulating hormone (FSH), LH, estradiol (E2) and NPY. A pulsatility study investigated NPY and LH episodic release. Patients from control the group were studied during the mid-follicular phase (days 6-8) of the menstrual cycle. RESULTS: Patients with weight loss-related amenorrhea had lower FSH, LH and E2 levels than controls (p < 0.01). Basal serum NPY levels were lower in amenorrheic patients than in menstruating women (p < 0.01). The numbers of NPY and LH peaks were higher in patients with weigh loss-related amenorrhea than in controls (p < 0.01 and p < 0.05, respectively). CONCLUSION: Increased NPY pulsatility may have pathophysiological significance in weight loss-related hypothalamic amenorrhea.     

Possibility of ovulation induction using naloxone in women with hypothalamic amenorrhea]

Within the study we treated 6 women suffering from hypothalamic amenorrhea with 4 mg naloxone intravenous daily. The duration of the study was at most 30 days. The estimation of hormonal baseline and changes occurs daily, furthermore everyday sonographic folliculometry. In 2 patients the chronic opiate receptor blockade leads to a drastic stimulation of gonadotropin secretion. One of these women (responder in Naloxone-Test) has a long standing elevation of LH and FSH resulting in an ovulation 2 days past end of the therapy. The other women (non-responder in Naloxone-Test) reaches a follicular growth till 17 mm follicle diameter following in preterm atresia during therapy. In another woman (minimal-responder in Naloxone-Test) occurs a short and weak elevation of gonadotropins without any basic stimulation of the hypothalamic-pituitary-ovary axis. The results of this study show that: 1. it's possible to discern an opioid mediated hypothalamic amenorrhea and 2. a Naloxone-Test or Naloxone-Stimulation-Test should be put before starting a therapy with opiate antagonists in hypothalamic amenorrhea.     

The influence of endogenous opioids in hypothalamic amenorrhea. Diagnostic and therapeutic aspects

We investigated the possibility of induction of ovulation by means of chronic opioid receptor blockade with naloxone. Daily 4 mg were given as an intravenous bolus injection in 4 women suffering from hypothalamic amenorrhea till the 30th day of therapy. A possible maturation of ovarian follicles and a subsequent ovulation should be proved by means of daily determination of LH, FSH, estradiol and progesterone as well as of a sonographic folliculometry. The day prior to and the first day of naloxone treatment we took blood samples every 10 minutes during 4 hours for determination of LH pulse frequency and amplitude. Neither we found any alteration of the basal values of LH, FSH and estradiol, nor we observed a follicular growth. These results lead us to the conclusion to introduce a naloxone stimulation test as a further diagnostic step. In this way opioid mediated hypothalamic ovarian insufficiencies could be registered and a sufficient therapy could be reached.     

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.     

Role of dehydroepiandrosterone sulfate as a prehormone for ovarian steroidogenesis

The endocrine effects of induction of ovulation with menotropins were studied in 43 patients: 11 with hypothalamic amenorrhea and 32 with the polycystic ovary syndrome. Patients with polycystic ovary syndrome had higher base-line values of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17 beta-estradiol, dehydroepiandrosterone sulfate, testosterone, and a higher testosterone-free index than those with hypothalamic amenorrhea. During treatment with menotropins, patients with polycystic ovary syndrome had higher values of serum LH, prolactin, dehydroepiandrosterone sulfate, testosterone, percent free testosterone, testosterone-free index, and body weight than those with hypothalamic amenorrhea; serum FSH, dose of menotropins per kilogram body weight, and total follicular volume were higher in patients with hypothalamic amenorrhea than in those with polycystic ovary syndrome. Multiple linear regression after log transformation demonstrated that the testosterone-free index was predicted statistically by total ovarian volume and dehydroepiandrosterone sulfate and that serum 17 beta-estradiol was predicted statistically by total ovarian volume and testosterone-free index. Adding dexamethasone to menotropins in six patients with polycystic ovary syndrome produced significant decreases in 17 beta-estradiol, dehydroepiandrosterone sulfate, testosterone, and testosterone-free index. Higher concentrations of endogenous serum LH and dehydroepiandrosterone sulfate in patients with polycystic ovary syndrome in comparison with those with hypothalamic amenorrhea were associated with higher concentrations of serum testosterone, a lower total follicular volume, and an effective response to menotropins at a lower serum FSH and a lower dose of menotropins per kilogram body weight. These data suggest that serum dehydroepiandrosterone sulfate may be a precursor for ovarian steroidogenesis.     

Ovulation induction with luteinizing hormone--releasing hormone in amenorrheic, infertile women.

Thirteen women with infertility thought due to anovulation were treated with LRH. Etiologic diagnoses of amenorrhea included hypothalamic or "idiopathic" and PCOD. All patients had normal gonadotropins and otherwise normal endocrinologic and infertility evaluations; none had ovulated with clomiphene. Patients were studied for six 35 day cycles, single blind, and received LRH or placebo by subcutaneous injections for 28 days/cycle (LRH dosage 1.0 mg 2 or 3 times each day). Frequent assessments of physical status, cervical mucus, vaginal cytology, and serum LH, FSH, estrogen, and progesterone were performed. Ovulation was documented by basal temperature, serum progesterone and, on occasion, endometrial biopsy. Follow-up was continued for 6 months after therapy. Of the 13 patients treated, eight have ovulated and five have conceived. There were no complications of therapy.     

Steroid profiles in patients with amenorrhea during induction of ovulation with HMG

Serum concentrations of various hormones in seven normal women were measured daily for 5 days before and after ovulation. Steroid levels were also measured in severe amenorrheic patients during the induction of ovulation with HMG-HCG. Blood samples from the patients of II grade amenorrhea were collected on the day when the cervical mucus increased more than 200 mm3 in HMG therapy. HCG was given after the blood samples were obtained. Ovulation was successfully induced in six patients and they were classified as group I. In 8 patients induction of ovulation did not succeed and these patients were classified as group II. Hormone levels including LH, FSH, estradiol (E2), progesterone (P4), 17 alpha OH-P4 (17P4), delta 4 androstenedione (delta 4 A), testosterone (Tes.), pregnenolone (P5), 17 alpha OH-P5 (17P5), DHA, delta 5 androstenediol (delta 5 AD), and 20 alpha OH-P4 (20P4) were measured by specific RIA. The following results were obtained. Steroid levels during normal ovulatory cycle: Levels of E2 (380 +/- 16 pg/ml), P5 (6.9 +/- 4.1 ng/ml), and Tes. (3.3 +/- 1.2 ng/ml) showed a peak on the day before LH surge. A significant increase in P4, 17P5 and 20P4 levels was observed after ovulation. Hormone levels in group I: FSH in group I was significantly higher while LH was lower than that in normal women measured during -1 to -3 days from LH surge. On the other hand, among the steroids measured, significantly low Tes. and high 17P5, and E2 levels were noticed in group I. Comparison of hormone levels between group I and II: FSH and LH levels showed no significant difference between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrinological background of pituitary desensitization during pulsatile LH-RH therapy for ovulation induction in amenorrheic women

In order to elucidate the endocrinological background of patients in whom ovulation induction by pulsatile LH-RH administration resulted in failure, 16 women with hypothalamic amenorrhea were treated with 10 to 20 micrograms of LH-RH injected subcutaneously every 2 hrs. Six women did not ovulate, and 5 of them showed pituitary desensitization since the basal gonadotropin concentration gradually decreased and the response to LH-RH test (100 micrograms i.v.) became blunted by the treatment. No significant differences between the ovulated and desensitized groups were seen in basal LH, FSH, E2, PRL levels, LH/FSH ratio and response to LH-RH test performed prior to the treatment. In addition, the plasma LH-RH profile after subcutaneous injection of 10 micrograms of LH-RH was highly pulsatile in both groups. However, in the desensitized group, all were obese, showed impaired GH response to both insulin tolerance and GH-RH tests, and had episodic LH secretion with higher frequency compared to the ovulated group. These results suggest that the desensitized women had occult pituitary dysfunction and hypersecretion of endogenous LH-RH which stimulated the pituitary close to the level of desensitization. The mechanism of hypersecretion of endogenous LH-RH is discussed.     

Comparison between tamoxifen and clomiphene therapy in women with anovulation

Forty-eight women with various types of menstrual disorder were treated with tamoxifen: 30 of them ovulated as judged by serum progesterone concentrations and the basal body temperature (BBT) record. Serial determinations of serum FSH, LH, prolactin, and estradiol-17 beta showed that tamoxifen acts primarily on the hypothalamic-pituitary axis. Before or after the tamoxifen treatment cycles, 30 women received clomiphene. The ovulation rate in women with primary and secondary amenorrhea was similar, while women with oligomenorrhea tended to be more responsive to tamoxifen than to clomiphene. There was no difference between the drugs in the duration of the luteal phases nor in the pregnancy rate. The side effects during treatment with clomiphene were pronounced than during tamoxifen therapy.     

Pituitary responses to synthetic luteinizing hormone-releasing hormone in thirty-four cases of amenorrhea or oligomenorrhea associated with galactorrhea.

Pituitary responses to 100 mcg. of luteinizing hormone-releasing hormone (LH-RH) administered subcutaneously were studied in 34 cases of amenorrhea or anovulatory oligomenorrhea associated with galactorrhea. Twenty-six patients had pituitary prolactin-secreting tumors (group I); eight patients had a normal sella turcica and remission of the syndrome either spontaneously or after thyroid replacement therapy (group 2). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to LH-RH were variable in each group of patients, ranging from poor to exaggerated, and no statistically significant difference could be observed between the groups. A positive correlation was found between FSH pituitary responses and basal FSH levels (r=0.50; P less than 0.01). No positive correlation was observed between either LH responses and basal LH levels or the gonadotropin responses and plasma estradiol levels, serum prolactin concentrations, duration of amenorrhea, or size of the tumor.     

Serum prolactin, gonadotropins, and estradiol in menstruating and amenorrheic mothers during two years' lactation

Serum prolactin, LH, FSH, and estradiol were measured in single blood samples collected from 465 nursing mothers in Central Africa (Kivu, Za?re) during the first 2 postpartum years. Lactating mothers were hyperprolactinemic during 15 to 18 postpartum months. Both serum prolactin and FSH were higher in amenorrheic than in menstruating nursing mothers; the difference was more apparent during the first than during the second year. Mean serum LH and estradiol were significantly higher in menstruating then in amenorrheic nursing mothers during the second postpartum year but not during the first. There was a significant association of hyperprolactinemia with amenorrhea. Furthermore, postpartum, the incidence of amenorrhea declined parallel to that of hyperprolactinemia.     

The "treatment" of unexplained infertility with danazol.

In order to investigate the possible stimulating effect of danazol on fertility, a randomized clinical trial was performed on 40 women with unexplained infertility. Of these 40 women, 21 received 200 mg of danazol daily for 100 days and 19 received a placebo treatment during the same period. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, estrone, estradiol, progesterone, and testosterone were followed before, during, and after treatment. Danazol administration induced anovulation in all women, with prompt resumption of normal ovulatory function after discontinuation of the drug. No influence was seen on serum LH, FSH, and testosterone levels, but serum estrone, estradiol, and progesterone levels decreased significantly during treatment. Serum prolactin levels also decreased, but not significantly. No pregnancies occurred in the placebo group during a 6-month follow-up period. In the danazol group, five pregnancies occurred, of which two were ectopic and three went to term. The difference in pregnancy rate between both groups was statistically significant (P less than 0.05).     

Endocrine evaluation of induction of ovulation with pulsatile and continuous administration of human menopausal gonadotropin (hMG) in anovulatory women

To evaluate the endocrine profiles during induction of ovulation with pulsatile and continuous administration of hMG (Pergonal), 3 patients with polycystic ovarian disease (PCO) and 4 patients with hypothalamic amenorrhea were selected as the subjects. The total dose of hMG per day was 150 IU in each patient. hMG pulse was administered intravenously via a portable infusion pump every 90 min in 4 patients including 3 PCO cases (9.375 IU/pulse) and every 18 min in one patient (1.875 IU/pulse). The remaining 2 patients received continuous subcutaneous infusion of hMG (150 IU/day). Following hMG treatment, 8,000 to 10,000 IU of hCG was used to induce ovulation. All 7 patients ovulated and 4 of them conceived. Pregnancy resulted in 2 patients following pulsatile (every 90 min) administration and in 2 patients after continuous infusion. The duration of hMG treatment needed to induce ovulation was similar among the three modes of administration and within the range of 7 to 10 days. A sustained elevation of circulating FSH levels was observed in all patients and serum estradiol increased more than 3,000 pg/ml in 6 of 7 patients during the course of treatment. Mean (+/- SE) midluteal progesterone level was 107.1 +/- 20.9 ng/ml. Moderate to severe ovarian hyperstimulation occurred in all patients. These results indicate that both pulsatile and continuous administration of hMG are similarly effective in inducing ovulation. They also appear to indicate that the hMG-induced follicular development is profoundly affected by the maintenance of high levels of FSH in the circulation rather than by the mode of administering hMG, whether pulsatile or continuous.     

Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment.

OBJECTIVE: To determine if chronic treatment with the long-acting oral opioid antagonist naltrexone can increase luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in women with secondary amenorrhea. DESIGN: Prospective. SETTING: Large reproductive endocrinology unit of an academic hospital. PATIENTS: Three groups of women with oligomenorrhea or amenorrhea: (1) hypothalamic amenorrhea; (2) anorexia nervosa; and (3) polycystic ovarian disease (PCOD). INTERVENTION: Naltrexone 50 mg every day for 4 days. MAIN OUTCOME MEASURES: Luteinizing hormone pulse pattern, frequency and amplitude, mean LH and FSH levels, measured by serial blood sampling over a 6-hour period before and after naltrexone. RESULTS: Naltrexone caused a significant increase (P less than 0.05) of the LH pulse frequency in patients with hypothalamic amenorrhea and in PCOD but not in anorexia nervosa. The mean levels of LH and FSH and LH pulse amplitudes were not significantly changed by naltrexone. The naltrexone nonresponders were underweight either because of simple weight loss or anorexia nervosa and had low levels of estradiol and an LH pulse pattern similar to the luteal one. CONCLUSION: The luteal LH pulse pattern in weight loss-related amenorrhea is caused by a nonopioid, undernutrition-linked factor.     

Normoprolactinemic anovulation nonresponsive to clomiphene citrate: ovulation induction with bromocriptine

Ovulation under bromocriptine was studied in 14 women with normoprolactinemic amenorrhea (5 primary, 9 secondary), unresponsive to clomiphene citrate (CC). On bromocriptine alone, ovulation occurred in 4 (28.6%). In the same subjects, bromocriptine was subsequently associated with CC. Seven patients ovulated (50.0%), including 3 that had responded to bromocriptine alone. Ovulation occurred once or twice in 6 of the 9 cases of secondary amenorrhea (66.6%). In several occasions, when ovulation induction failed, luteinized unruptured follicles were found under ultrasonographic monitoring. Four patients who had a negative response to progestin challenge did not ovulate with the treatment. Women with plasma prolactin in the upper normal range had a greater probability of achieving ovulation induction.