Bromocriptine induced pregnancy in two cases of euprolactinemic hypothalamic amenorrhea.

Two euprolactinemic women with hypothalamic amenorrhea, previously unsuccessfully submitted to clomiphene citrate therapy, were treated with bromocriptine. PRL secretion was studied in basal conditions and under dynamic tests: TRH and chlorpromazine. Serum FSH, LH and 17-beta-estradiol were determined before and during the treatment. Both patients conceived, and one delivered a healthy baby at term. Bromocriptine appears to be an effective drug for treating women with hypothalamic amenorrhea, particularly those unresponsive to clomiphene.     

Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea

Ovulatory menstrual cycles were induced by the administration of the specific opiate antagonist naltrexone at a dose of 50 mg/day for 28 days in 3 women suffering from secondary hypothalamic amenorrhea. The occurrence of ovulation was based on demonstration of follicular growth and corpus luteum formation by ultrasonography and a LH midcycle surge and rise of progesterone. After discontinuation of treatment, the women became amenorrheic again and serum gonadotropins as well as estradiol declined to the low levels found before naltrexone administration. Naltrexone or other specific opiate antagonists may be useful agents for the induction of ovulation in patients with hypothalamic amenorrhea.     

A case of type 1 diabetes mellitus with hypothalamic amenorrhea: successful pregnancy following subcutaneous pulsatile administration of LHRH]

A 27-year-old woman with type 1 diabetes mellitus was admitted to the Shimane Medical University Hospital because of secondary amenorrhea. She had been treated with insulin since July, 1986. Fasting plasma glucose and HbA1c levels were controlled within normal limits. However, body weight gradually decreased and amenorrhea started in 1988. Physical examination revealed emaciation with BMI of 17.3. Basal levels of plasma T3, somatomedin C, LH, FSH and estradiol levels were low, whereas HGH levels were slightly elevated. Plasma LH markedly increased in response to LHRH administration. She was diagnosed as having weight loss-related hypothalamic amenorrhea. Induction of ovulation was not obtained with clomiphene citrate. Treatment with subcutaneous pulsatile administration of LHRH (20 micrograms every 120 min) resulted in an increase in plasma levels of LH, FSH and estradiol, which was accompanied by ovulation and corpus luteum formation. Further treatment with pulsatile LHRH administration was followed by conception. Two gestational sacs were detected by ultrasonography. One of them was absorbed at the early stage of pregnancy. She was delivered of one healthy female infant without complications. These findings suggest that it is important not only to control plasma glucose levels but to keep the appropriate weight and support the psychological aspects of the subject in the treatment of diabetes mellitus. Subcutaneous pulsatile LHRH therapy may be effective for the induction of ovulation in clomiphene-resistant hypothalamic amenorrhea; however, it will be necessary to solve the problem of dosage and the interval of LHRH administration in the future.     

GONADOTROPHIN RELEASE IN OVARIECTOMIZED PATIENTS

Administration of clomiphene citrate (150 mg/day) for 5 days to twenty-four ovariectomized patients and seven normal female patients evoked a significant release of FSH and LH in the normal control group and suppressed the gonadotrophin secretion in the castrated patients. A similar suppressive effect on gonadotrophin secretion was noted in eight ovariectomized patients treated for 10 days with low doses (50 μg/day) of ethinyl oestradiol. It is suggested that in the ovariectomized hypoestrogenic patients, clomiphene acted as an oestrogen, suppressing by a negative feedback action gonadotrophin release in a way similar to ethinyl oestradiol. In the normal control group with an adequate steroid environment, clomiphene acted (probably at the hypothalamic level) as an oestrogen antagonist and stimulated gonadotrophin secretion. In view of our findings, it seems as if the ability of anovulatory patients to respond to clomiphene treatment by increased gonadotrophin secretion depends upon the absolute concentration of the compound in the different organs and by the quantitative relation of clomiphene to the endogenous oestrogens. There is still a considerable degree of uncertainty about the exact mode of action of clomiphene (1-[p-β-diethyl-aminoethoxyphenyl]-1,2, dipheny1-2 chloroethylene citrate) a non-steroidal oestrogen antagonist. However, it appears increasingly evident that this compound which possesses antioestrogenic properties acts probably in an indirect manner, by competing with oestradiol for the receptor sites at the hypothalamic centres regulating gonadotrophin secretion, thus stimulating gonadotrophin releasing hormone (LHRH) secretion, with a subsequent release of FSH and LH (Igarashi et al., 1967; Seki et al., 1970). By contrast, in prepubertal children, a paradoxical suppression of both LH and FSH release was demonstrated following administration of clomiphene (Kelch et al., 1971). The explanation offered for this phenomenon was that the immature hypothalamic gonadostat is hypersensitive to sex steroids, and as clomiphene has intrinsic oestrogenic properties, it could account for the unexpected gonadotrophin suppression rather than stimulation in the prepubertal child. A similar effect could be obtained in prepubertal children by administration of low doses of oestrogens (Kelch et al., 1971). In order to gain additional information on the mode of action of clomiphene at the hypothalamic and pituitary levels, we studied the effect of clomiphene and of low doses of oestrogens on LH and FSH release in ovariectomized patients. These patients provide a suitable model for the investigation of the mode of action of clomiphene on a normal hypothalamic-pituitary system in an environment free of gonadal steroid (Tepperman, 1973).     

Patient-tailored conventional ovulation induction algorithms in anovulatory infertility.

Conventional treatment of normogonadotropic anovulatory infertility is ovulation induction using the antiestrogen clomiphene citrate, followed by follicle-stimulating hormone. Multiple follicle development, associated with ovarian hyperstimulation, and multiple pregnancy remain the major complications. Cumulative singleton and multiple pregnancy rate data after different induction treatments are needed. Newer ovulation induction interventions, such as insulin-sensitizing drugs, aromatase inhibitors and laparoscopic ovarian electrocoagulation, should be compared with conventional strategies. Ovulation induction efficiency might improve if patient subgroups with altered chances for success or complications with new or conventional techniques could be identified, using multivariate prediction models based on initial screening characteristics. This would make ovulation induction more cost-effective, safe and convenient, enabling doctors to advise patients on the most effective and patient-tailored treatment strategy.     

Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

The present prospective follow-up study was designed to identify whether clinical, endocrine, or ultrasound characteristics assessed by standardized initial screening of normogonadotropic oligo/amenorrheic infertile patients could predict conception in 160 women who reached ovulation after clomiphene citrate (CC) medication. Additional inclusion criteria were total motile sperm count of the partner above 1 million and a negative history for any tubal disease. Daily CC doses of 50 mg (increasing up to 150 mg in case of absent ovarian response) from cycle days 3-7 were used. First conception (defined as a positive urinary pregnancy test) was the end point for this study. A cumulative conception rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who did conceive presented more frequently with lower age (P < 0.0001) and amenorrhea (P < 0.05) upon initial screening. In a univariate analysis, patients with elevated initial serum LH concentrations (>7.0 IU/L) had a higher probability of conceiving (P < 0.01). In a multivariate analysis, age and cycle history (oligomenorrhea vs. amenorrhea) were identified as the only significant parameters for prediction of conception. These observations suggest that there is more to be gained from CC ovulation induction in younger women presenting with profound oligomenorrhea or amenorrhea. Screening characteristics involved in the prediction of ovulation after CC medication in normogonadotropic oligo/amenorrheic patients (body weight and hyperandrogenemia, as shown previously) are distinctly different from predictors of conception in ovulatory CC patients (age and the severity of cycle abnormality). This disparity suggests that the FSH threshold (magnitude of FSH required for stimulation of ongoing follicle growth and ovulation) and oocyte quality (chances for conception in ovulatory cycles) may be differentially regulated.     

BLOCKAGE OF THE POSITIVE FEEDBACK EFFECT OF OESTRADIOL DURING PROLONGED ADMINISTRATION OF CLOMIPHENE CITRATE TO NORMAL WOMEN

The effect of clomiphene citrate on the occurrence and timing of the endogenous LH surge in superovulated cycles is unclear. To study further this event, five normally ovulating women were treated with clomiphene citrate 100 mg per day in two different cycles, that is, for 5 days in one cycle (days 2 to 6, CC-5) and for 15 days in another cycle (days 2 to 16, CC-15). During the CC-5 cycle, the normal pattern of LH levels seen in spontaneous cycles was observed with an endogenous LH surge in all women followed by ovulation and normal luteal function. In contrast, during the CC-15 cycle, a continuous and progressive increase of basal LH levels was seen with no surge, resulting in follicular luteinization but no ovulation. The results suggest that in normal women treated with clomiphene the occurrence of an endogenous LH surge is dependent on a significant decrease in the circulatory concentration of clomiphene at mid-cycle.     

Ovarian refractoriness to gonadotropins in cases of inappropriate lactation: restoration of ovarian function with bromocryptine.

In ten patients with amenorrhea-galactorrhea who had hyperprolactinemia, ovulation could not be induced clomiphene citrate or exogenous gonadotropins. Treatment with bromocryptine in eight of these patients resulted in suppression of PRL in all, cessation of galactorrhea and ovulation in seven and conception in five.     

Ovulation induction in normogonadotropic anovulation (PCOS)

Treatment of normogonadotropic anovulatory infertility (World Health Organization class 2, or WHO2) is by induction of ovulation using clomiphene citrate (CC), followed by follicle-stimulating hormone (FSH) in cases of treatment failure. Not all patients will become ovulatory or will conceive with this treatment. Others, exhibiting multifollicular instead of monofollicular development, may encounter complications such as ovarian hyperstimulation and multiple pregnancy. Recently introduced alternative treatment interventions-such as insulin-sensitizing drugs, aromatase inhibitors, or laparoscopic electrocautery of the ovaries-may offer the possibility of improving the efficacy of the classical ovulation induction algorithm. Based on initial patient characteristics, it may be possible to identify specific patient subgroups with altered chances of success or complications while using one of these interventions. Regarding CC and FSH ovulation induction, this has been performed using multivariate prediction models. This approach may enable us to improve safety, cost-effectiveness, and patient convenience in future ovulation induction.     

Naltrexone does not reverse the inhibitory effect of chronic restraint on gonadotropin secretion in the intact male rat.

There is considerable evidence suggesting that endogenous opioids may play an important role in acute stress-induced decreases in luteinizing hormone (LH) release. Studies were undertaken to analyze the role of endogenous opioids in chronic stress-induced decrease in circulating LH and follicle-stimulating hormone (FSH). Chronic restraint (6 h daily over 4 days) evoked a decrease in circulating LH and FSH. Naltrexone treatment, (2 mg/kg three times daily) during the 4 days of restraint, caused an increase in plasma concentrations of LH and FSH, and antagonized the LH suppressory effect of morphine (10 mg/kg) administration. Despite this, naltrexone treatment was ineffective in preventing the inhibitory effect of chronic restraint stress on circulating LH and FSH. Chronic restraint also induced a decrease in hypothalamic LH-releasing hormone (LHRH) content in saline-treated rats. On the contrary, in naltrexone-treated rats, chronic restraint evoked an increase in hypothalamic LHRH content. Thus endogenous opioids and chronic stress seem to act by different mechanisms on the hypothalamic LHRH neuron. In unstressed orchidectomized rats, naltrexone administration did not modify circulating LH, but increased plasma concentrations of LH in acutely restrained rats. These data suggest that endogenous opioids may mediate gonadotropin secretion during acute stress, but not during chronic stress.     

Induction of ovulation in the patient with polycystic ovarian disease

Induction of ovulation is difficult to achieve in patients with PCOD when they are resistant to therapy with clomiphene citrate; moreover, treatment with human menopausal gonadotropins subjects the PCOD patient to the risk of multifollicular ovulation and hyperstimulation. This article summarizes the hormonal picture and the initial therapeutic approach to the patient with PCOD. The proper administration, usage, and monitoring of conventional ovulation-inducing agents for these patients are discussed. Some of the newer approved agents that can be used in special patients who have not responded to conventional ovulation induction are also described.     

Clinical review 15: Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone

Pulsatile GnRH therapy has yet to achieve widespread acceptance as an alternative to exogenous gonadotropin therapy in women with hypothalamic amenorrhea and complete GnRH deficiency. However, when a physiologically based replacement regimen of pulsatile GnRH is used, a high rate of ovulation and conception can be anticipated in patients with complete GnRH deficiency and hypothalamic amenorrhea. Women with polycystic ovarian syndrome may also benefit from pulsatile GnRH, although rates of ovulation are lower. Pretreatment with a GnRH agonist may improve these rates considerably, but experience is limited. Whether an iv or sc route of administration is chosen, a simplified clinical monitoring protocol can be created which requires a minimum of patient monitoring while assuring maximum safety. Seventy five nanograms per kg appears to be a reasonable initiating dose, with subsequent increases in those who do not respond. The frequency of GnRH administration is best based on the GnRH pulse frequency in normal women. However, further information is needed to determine whether such a variable frequency is clearly superior to a fixed frequency regimen. When used appropriately, pulsatile GnRH is safe, effective, and offers an excellent alternative to conventional gonadotropin therapy for women with disordered endogenous GnRH secretion. Most importantly, and as opposed to exogenous gonadotropin therapy, pulsatile GnRH can be administered by most physicians in the office setting without the necessity of on-line E2 monitoring. This feature will enable more patients to receive treatment by their local physicians, whereas exogenous gonadotropin therapy should be administered by appropriately equipped referral centers. In the future, further studies will be required to determine which other categories of patients might benefit from pulsatile GnRH.     

Hypothyroidism and amenorrhea due to hypothalamic insufficiency. A study in four young women.

Four women, aged 17 to 23, were evaluated for secondary amenorrhea of 12 to 36 months' duration. All were considered to have hypothalamic hypothyroidism on the basis of low thyroxine (T4) concentrations, inappropriately low thyrotropin (TSH) levels, with a normal TSH response to thyrotropin-releasing hormone (TRH, 500 microgram intravenously) in three, and absence of a pituitary lesion. Nevertheless, menses did not resume after adequate replacement with thyroid hormone. Investigation of the pituitary-gonadal axis revealed a normal increase in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) following the intravenous administration of gonadotropin-releasing hormone (GnRH). Three subjects received clomiphene citrate, 100 mg/day for five days, but a normal menstrual cycle was not induced. It is concluded that the amenorrhea was not due to thyroid hormone deficiency but, like the hypothyroidism, to a hypothalamic abnormality involving secretion of the appropriate releasing hormone.     

Hypothalamic dysfunction

A pulsatile GnRH stimulus is required to maintain gonadotropin synthesis and secretion. The frequency and amplitude of GnRH pulses determine gonadotropin subunit gene expression and secretion of pituitary LH and FSH. Rapid frequency (more than 1 pulse per h) GnRH pulses favor LH while slower frequencies favor FSH secretion. During ovulatory cycles, an increase in GnRH frequency during the follicular phase favors LH synthesis prior to the LH surge, while following ovulation, luteal steroids slow GnRH pulses to favor FSH synthesis. Thus, a changing frequency of GnRH stimulation of the gonadotrope is one of the mechanisms involved in differential gonadotropin secretion during ovulatory cycles. In hypothalamic amenorrhea a majority of women exhibit a persistent slow frequency of LH (GnRH) pulses, which reflects excess hypothalamic opioid tone and can be temporarily reversed by opioid antagonists. At the other end of the spectrum, in polycystic ovarian syndrome, LH (GnRH) pulses are persistently rapid and favor LH synthesis, hyperandrogenism and impaired follicular maturation. Administration of progesterone can slow GnRH pulse secretion, favor FSH secretion and induce follicular maturation. Thus, the ability to change the pattern of GnRH secretion is an important factor in the maintenance of cyclic ovulation, and loss of this function leads to anovulation and amenorrhea.     

Twenty-four-hour secretory patterns of gonadotropins and prolactin in a case of Chiari-Frommel syndrome.

Plasma LH, FSH and prolactin secretory patterns were derived from the measurement of 20-min interval plasma samples obtained during a complete 24-h period in a patient with persistent postpartum amenorrhea and galactorrhea (Chiari-Frommel syndrome), before and after clomiphene citrate therapy. During nocturnal sleep, polygraphic monitoring was carried out to precisely identify sleep onset, specific sleep stages and waking periods. During the evening and nighttime hours, LH and FSH concentrations were markedly reduced, compared to the daytime patterns both before and after clomiphene therapy. A sleep associated rise of prolactin concentration was present, similar to the pattern found in normal subjects but at higher concentrations. The reciprocal nature of the nocturnal secretory patterns for LH and FSH and prolactin in this patient suggests an alteration in hypothalamic dopaminergic mechanisms which are thougt to control the secretion of these hormones.     

HYPOTHALAMIC FUNCTION IN WOMEN WITH SECONDARY HYPOGONADISM AND UNRESPONSIVE TO CLOMIPHENE THERAPY

Seven women with secondary hypogonadism who had been previously unresponsive to two 5-d courses of clomiphene citrate, were treated with clomiphene citrate 100 mg daily for 10 d. LH and FSH concentrations were measured in serum collected at 15-min intervals for 5 h before and on the 10th day of treatment and oestradiol was measured in the first two samples on each day. Four women responded with an increase in the amplitude of LH pulses and in mean LH values and in three there was a marked increase in serum oestradiol concentrations. Three women who showed no gonadotrophin response were subsequently unresponsive to pulsatile LHRH therapy. These preliminary data are consistent with the hypothesis that hypothalamic hypogonadotrophism may result from hypersensitivity of the hypothalamus to oestrogen negative feedback and that the hypothalamic potential for secretion of LHRH is unimpaired. Prolonged treatment with clomiphene may provide a simple test of hypothalamic function in women with normal pituitary function.     

Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa

Anorexia nervosa (AN) is a state of leptin and gonadotropin deficiency. Leptin levels are decreased in normal weight women with hypothalamic amenorrhea and leptin may be a sensitive marker of overall nutritional status. The aim of the study is to provide additional information on plasma leptin levels and on gonadotropin responses after clomiphene testing in patients with AN who recovered weight but were still amenorrheic. We evaluated 17 patients with AN, female age 20+/-1.2 yr who reached goal weight [body mass index (BMI) 14.9+/-0.5 to 19.3+/-0.4 kg/m2]. At diagnosis serum leptin levels were 2.2+/-0.1 microg/l while after behavioural therapy and hypercaloric diet for 6-12 months serum leptin levels rose to 6.4+/-1.4 microg/l significantly lower compared with those in the control (no.=10, age 28+/-6.2 yr, BMI 21.1+/-0.3 kg/m2, leptin 9.3+/-0.7 pg/l; p<0.05). None of the patients resumed spontaneous menstrual cycles after weight gain. They were tested with a 10-day administration of clomiphene citrate. All had a significant rise in LH secretion (from 1.7+/-0.3 IU/l to 8.3+/-0.9 IU/l, p<0.01) and serum estradiol levels (from 19.0+/-5.4 to 937.7+/-241.2 pg/ml, p<0.03). Nine out of 17 patients menstruated after clomiphene. Serum leptin levels were not different in those who menstruated from those who did not (6.4+/-1.4 to 6.8+/-1.4 microg/l, p>0.05). Body compositon was studied in 12 additional carefully matched patients with AN who recovered weight. Six of them resumed spontaneous menstrual cycles. Neither BMI, body fat, nor leptin appeared as significant determinants of menstrual status. In conclusion, relative hypoleptinemia persists, independent of fat mass, in weight recovered patients with AN. A normal response to clomiphene in weight-recovered yet still amenorrhoeic patients with AN, offers reassurance that the axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, fat intake and persisting psychological factors still affect plasma leptin levels and reproductive functions in weight-recovered patients with amenorrhea.     

Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome

CONTEXT: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). OBJECTIVE: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. DESIGN: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. SETTING: Study volunteers at multiple academic medical centers were included. PARTICIPANTS: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. INTERVENTIONS: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. MAIN OUTCOME MEASURES: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk. RESULTS: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. CONCLUSION: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.     

Hypothalamic-pituitary-gonadal function in patients with myotonic dystrophy.

Gonadal function was studied in three post-pubertal siblings (two male and one female) and one unrelated male patient with myotonic dystrophy. The diagnosis was confirmed in all cases by electromyography and muscle biopsy. Basal levels of plasma immunoreactive LH, FSH, testosterone, and estradiol were measured. Hypothalamic, pituitary, and gonadal reserve and responsiveness were evaluated by clomiphene, LHRH, and HCG tests. Histologic examination of gonadal biopsies was also performed. The results showed that gonadal failure present in the four patients had different characteristics. In the same family, hypothalamic amenorrhea was observed in the female patient, and hypothalamic eunuchoidism and hypergonadotropic hypogonadism with marked tubular and leydig cells failure in the male patients. The non-related male patient had hypergonadotropic hypogonadism with tubular failure but with a compensatory leydig-cell hyperplasia. These data are interpreted as demonstrating different expressivity of the hypogonadism associated with the same inherited muscle disease.     

Normal pregnancies after treatment of hyperprolactinemia with bromoergocryptine, despite suspected pituitary tumors.

Bromocryptine treatment was administered to 15 patients with amenorrhea and galactorrhea (AG) and to 1 patient with amenorrhea. All of them had increased plasma PRL levels. Of these 16 patients, 4 had a normal sella turcica (ST; group STO), 4 had a slight enlargement (group ST+), and 7 had a clear enlargement of ST (ST++) but no evidence of suprasellar extension. Ovulation was restored in 15 patients by bromocryptine treatment only. In one patient, ovulation resumed only after human pituitary gonadotropin treatment in combination with bromocryptine. There was no correlation between basal prolactinemia, PRL stimulability or suppressibility, the size of ST, or the efficiency of bromocryptine treatment. Every patient with normal LH response to either LRH or clomiphene or both resumed ovulation. Ovulation resumed in 3 patients among the 4 with abnormal LH response to either LRH or clomiphene or both. Among the 14 who desired pregnancy, 13 became pregnant. To date, 12 patients (ST++, 5; ST+, 3; STO, 4) have delivered normal babies. The courses of pregnancy were normal. During pregnancy, no change of ST was noted on lateral and frontal skull x-ray performed in every patient at trimonthly intervals. There was no change in the sellar index in 10 patients after pregnancy, as compared to the pretreatment status. In the presence of a pituitary adenoma or in patients with hyperprolactinemia and amenorrhea and galactorrhea, bromocryptine treatment may cure sterility without pituitary complication during pregnancy.