Hypogonadotropic Amenorrhea Research Articles

Inhibiting Bone Loss in Anorexia Nervosa: Another Possible Benefit of Oral Contraceptives

Hypogonadotropic amenorrhea and bone demineralization are common among malnourished women, including those with anorexia nervosa (AN). To assess

Hypothalamic-Pituitary-Ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women With Chronic Amenorrhea.

Context:Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA.Objective:To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA.Patients:Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas.Interventions:Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 μg/kg/h) was infused intravenously for 12 hours.Results:Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased.Conclusions:In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.

Update in Hyper- and Hypogonadotropic Amenorrhea

Amenorrhea is a relatively common condition that is present in up to 5% of adult women at any time. The clinical significance of a lack of regular menstrual cycles extends beyond reproductive concerns. Episodes of amenorrhea as short as 90 d may have implications for bone and cardiovascular health. Prolonged amenorrhea, depending upon its underlying cause, can be a harbinger of substantial cardiovascular risk. This is an update of recent medical literature on this topic. The past few years have been marked by a greater appreciation of the early presentation of common ovulatory disorders, such as polycystic ovary syndrome, and less common disorders, such as premature ovarian insufficiency/failure. The long-term implications of functional hypothalamic amenorrhea and its genetic origins have also been further elucidated. Finally, health consequences of these and other menstrual disorders are increasingly well defined, with firmer clinical endpoints rather than merely risk factor assessments.

Pregnancy Using Gonadotropins and Performing Intrauterine Insemination in a Woman with Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism is one of the causes of infertility. In women with hypogonadotropic hypogonadism both follicle-stimulating hormone and luteinizing hormone are required to induce optimal follicular growth and steroidogenesis. We described a case of singleton pregnancy in a 38-year-old patient, presenting with primary hypogonadotropic amenorrhea and empty sella syndrome, treated with human menopausal gonadotropins and performing intrauterine insemination in first attempt. This therapy led to maturation of two follicles and one of them was fertilized. A singleton pregnancy ensued and a normal infant was delivered by cesarean section.

Daily low dose recombinant hCG and low dose recombinant FSH: a novel treatment for hypogonadotropic hypogonadism

Objective: LH in the follicular phase is known to be important to the production of C-19 steroids that serve as precursors for estrogen formation. Estrogen produced by the follicle has been speculated to have a major role in oocyte maturation. Treatment of hypogonadotropic hypogonadism with recombinantly derived FSH has previously met with poor response secondary to LH deficiency. The administration of recombinant FSH in the absence of significant endogenous LH can lead to slow follicle development associated with extremely low estradiol production. Because of this, patients with hypogonadotropic amenorrhea have classically been treated with hMG. Despite this approach, these patients may require high doses of gonadotropin and prolonged treatment. This is likely due to the short half-life of the LH component of hMG preparations. Recombinant HCG has recently become available. This drug may serve as a source of LH activity with a significantly longer half life and duration of action than the LH component of HMG. This study was undertaken to evaluate the potential benefit of using a daily low dose of recombinant hCG as an adjunct to recombinant FSH treatment for ovulation induction in a patient with severe LH deficiency.

The Cardiovascular Risk Factor Homocysteine Is Not Elevated in Young Women with Hyperandrogenism or Hypoestrogenism

The aim of the present study was to determine whether the plasma concentrations of homocysteine (Hcy) are elevated in women with hypogonadotropic hypogonadism (a condition of chronic hypoestrogenism) and in women with polycystic ovarian syndrome (PCOS, a syndrome characterized by hyperandrogenemia). A cross-sectional study was performed. The plasma concentrations of Hcy were determined in 12 normal-cycling women, in 14 women with hypogonadotropic amenorrhea (HA), and in 20 women with PCOS. The plasma LH, FSH, E₂, testosterone, free testosterone, and androstenedione levels were measured. The blood samples analyzed were taken during the early follicular phase in controls and without regard to the menstrual phase in the patients. Twelve normal-cycling women were compared with 14 women with HA and with 20 women with PCOS. Women with HA or PCOS have plasma concentrations of Hcy similar to those of healthy women with normal menstrual cycles. The results suggest that young women with chronic hypoestrogenism (HA) or hyperandrogenism (PCOS) have plasma concentrations of Hcy similar to those of healthy women with normal menstrual cycles.

Twin pregnancy using recombinant gonadotropins in a woman with hypogonadotropic hypogonadism

In women with hypogonadotropic hypogonadism both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are required to induce optimal follicular growth and steroidogenesis. The development of molecular genetic technology has led to the availability of recombinant FSH and LH for the induction of follicular growth and ovulation. We describe a first case of a twin pregnancy in a 36-year-old patient presenting with primary hypogonadotropic amenorrhea and empty sella syndrome and treated with recombinant FSH and LH. This therapy led to the maturation of two follicles, both of which were fertilized. A twin pregnancy ensued and two normal infants were delivered.

Twin pregnancy using recombinant gonadotropins in a woman with hypogonadotropic hypogonadism

In women with hypogonadotropic hypogonadism both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are required to induce optimal follicular growth and steroidogenesis. The development ofmolecular genetic technology has led to the availability of recombinant FSH and LH for the induction of follicular growth and ovulation. We describe a first case of a twin pregnancy in a 36-year-old patientpresenting with primary hypogonadotropic amenorrhea and empty sella syndrome and treated with recombinant FSH and LH. This therapy led to the maturation of two follicles, both of which were fertilized.A twin pregnancy ensued and two normal infants were delivered.

Low-dose human chorionic gonadotropin therapy can improve sensitivity to exogenous follicle-stimulating hormone in patients with secondary amenorrhea

Objective: To assess the effect of supplementing an ovulation induction regimen of highly purified FSH with LH activity in the form of low-dose hCG therapy. Design: Case report. Setting: The Reproductive Endocrinology Center at the University of Bologna, Bologna, Italy. Patient(s): A woman with weight-related secondary hypogonadotropic amenorrhea. Intervention(s): The patient was treated first with highly purified FSH alone and then received highly purified FSH in combination with low-dose hCG therapy (50 IU/d). Main Outcome Measure(s): Pelvic ultrasound examinations, serum E 2 levels, duration of treatment, total dose of highly purified FSH, and outcome of treatment. Result(s): The concomitant administration of low-dose hCG and highly purified FSH markedly reduced the duration of treatment and the dose of highly purified FSH, and resulted in a quadruplet pregnancy in a patient in whom several previous ovulation induction procedures had been unsuccessful. Conclusion(s): Supplementation of an ovulation induction regimen with an agent that has LH activity can enhance FSH-induced folliculogenesis and markedly reduce costs in women with hypogonadotropic hypogonadism. However, this increased response can be associated with complications such as multiple gestation.

Treatment of Anovulation With Pulsatile Gonadotropin-Releasing Hormone

Filicori, M.; Flamigni, C.; Dellai, P.; Cognigni, G.; Michelacci, L.; Arnone, R.; Sambataro, M.; Falbo, A. Author Information

Changes of serum follicular stimulating hormone, luteinizing hormone and follicular sizes during electroacupuncture for induction of ovulation

Changes in follicular stimulating hormone (FSH), luteinizing hormone (LH) and follicular sizes were observed in 10 patients with chronic anovulation during electroacupuncture treatment. Seven cases were diagnosed as suffering from polycystic ovary syndrome, 2 from dysfunctional uterine bleeding, and 1 from hypogonadotropic amenorrhea. Among them 8 cases complained of infertility for an average of 2. 7years. Ovulation was confirmed by pregnancy or the combination of biphasic basal body temperature and ultrasonographic signs. During one course of 3 consecutive days of electroacupuncture treatment on acupoints Guanyuan (Ren 4), Zhongji (Ren 3), Zigong (Extra 16) and Sanyingjiao (Sp 6), ovulation resulted in 5 patients (ovulating group) and 3 of the 4 infertile women became pregnant. Five cases failed to ovulate (non-ovulating group), 3 of them reached a biphasic basal body temperature without ovulatory signs on ultrasonograph. Serum FSH, LH values and FSH pulse frequency increased significantly during-electroacupuncture treatment in the ovulating group (from 2. 10±0.42 pulses/4h to 3. 70±1.64 pulses/4 h), but not in the non-ovulating group. No apparent change was found in LH pulse frequency, or in pulse amplitudes for FSH and LH. In the ovulating group, diameters of ovarian follicules markedly increased, but their growth was limited in the non-ovulation group. The results suggest ovulation may be induced by electroacupuncture via a regulation on the hypothalamic-pituitary function, leading to normal secretion of FSH and LH.

Potential for fertility with replacement of hypothalamic gonadotropin-releasing hormone in long term female survivors of cranial tumors.

Dysfunction of the hypothalamic-pituitary axis presenting as hypogonadotropic amenorrhea is a common sequelae of treatment for cranial tumors with surgery and/or radiation. We hypothesized that the site of the defect in this condition is hypothalamic, rather than pituitary, in the majority of patients. Nine women with acquired hypogonadotropic hypogonadism after treatment with transphenoidal pituitary surgery (n = 3), transphenoidal surgery plus conventional radiotherapy (XRT; n = 1), hypothalamic surgery plus XRT (n = 2), or XRT with or without noncentral nervous system surgery (n = 3) underwent assessment of endogenous pulsatile LH secretion and a standard GnRH test followed by iv administration of a physiological replacement regimen of exogenous GnRH. A total of 25 cycles were completed at doses of 75 or 100 ng/kg.bolus. Ovulation occurred in 78% of patients, with all ovulatory patients who desired fertility becoming pregnant. The hormonal responses in these cycles did not differ from the patterns of sex steroids and gonadotropins in normal women. The response to pulsatile GnRH was not influenced by GH deficiency or PRL abnormalities. Of the two patients who failed to ovulate, there was no evidence of folliculogenesis in one, whereas the second consistently developed follicles, but proved incapable of mounting a LH surge despite adequate preovulatory estradiol levels. Both patients had a history of pituitary radiation and surgery. There was no consistent relationship between the results of GnRH testing and the pattern of pulsatile LH secretion. However, the only patient who failed to achieve folliculogenesis was the only patient without a FSH response to GnRH testing and an apulsatile baseline study. Hypothalamic GnRH deficiency is the etiology of hypogonadism in the majority of patients after treatment with hypothalamic or pituitary surgery or cranial irradiation. Therefore, exogenous pulsatile GnRH represents a physiological replacement therapy that completely restores normal gonadotropin dynamics, resulting in ovulation and fertility.

Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles.

Pulsatile GnRH (pGnRH) was administered to 292 anovulatory patients in 600 consecutive cycles between February 1984 and February 1993. This represents the largest single pGnRH series ever reported. Patients were divided into the following groups: primary hypogonadotropic amenorrhea (PHA), 73 patients, 161 cycles; other hypogonadotropic hypogonadisms (OHH), 57 patients 107 cycles; multifollicular ovary (MFO), 39 patients 75 cycles; polycystic ovary (PCO), 85 patients 172 cycles; and other hyperandrogenic anovulations (OHA), 38 patients 85 cycles. GnRH was administered iv at a dose of 1.25-20.0 micrograms every 30-120 min; most cycles (505) were performed with a regimen of 2.5-5.0 micrograms GnRH every 60-90 min. In 228 cycles of MFO, PCO, and OHA patients, pGnRH was preceded by GnRH agonist (GnRH-A) suppression. Ovulatory rates were 75%, and pregnancy occurred in 105 cycles (pregnancy rate of 18%/treatment cycle and 23%/ovulatory cycle). Ovulatory and pregnancy rates were higher in PHA, OHH, and MFO and lower in PCO and OHA. Only 4 multiple pregnancies occurred (3.8%), none after GnRH-A suppression. The abortion rate was 30% and was highest in PCO (45%). GnRH-A pretreatment improved ovulatory rates only in PCO (from 49% to 71%; P < 0.001), whereas it had no significant effect on pregnancy and abortion rates in any group. Higher weight and insulin were associated with lower ovulatory and pregnancy rates; higher LH and testosterone were associated with lower ovulatory rates only. We conclude that 1) pGnRH is a highly effective ovulation induction method; 2) pGnRH does not cause ovarian hyperstimulation; 3) low dose pGnRH is associated with a remarkably low incidence of multiple pregnancy; 4) GnRH-A pretreatment improves pGnRH outcome in PCO and further lowers the incidence of multiple pregnancy; 5) pGnRH is associated with relatively elevated abortion rates, particularly in PCO; and 6) pGnRH is less successful in overweight patients and when high baseline LH, testosterone, and insulin levels are present.

Changes in serum immunoreactive inhibin during ovulation induction in women with amenorrhea.

Changes in serum immunoreactive (IR)-inhibin were measured by RIA in two studies, in order to elucidate, firstly whether the pattern of IR-inhibin secretion is similar to that of estradiol (E2), and secondly, whether inhibin suppresses endogenous FSH release. Study 1: Purified urinary FSH (pFSH) or human menopausal gonadotropin (hMG) were daily injected intramuscularly into women with hypogonadotropic amenorrhea at 12 to 14 week intervals. PFSH and hMG stimulated IR-inhibin release in a similar fashion in the ovulatory cycles, but the increase in estradiol (E2) during pFSH administration was delayed and lower than that during the hMG cycles. This suggests that E2 and IR-inhibin are secreted independently from the granulosa cells. Study 2: Ovulation induction was performed in 18 cycles of 9 women with polycystic ovarian disease (PCOD) by the step-down administration of pFSH. The serum FSH concentration in cycles with premature LH release increased even after the dose of pFSH was reduced, and were significantly higher than those of cycles without premature LH release. It was also found that the serum IR-inhibin concentration in cycles with the premature LH release was 2 to 4 times as high as in cycles without premature LH release. This suggests that IR-inhibin does not suppress endogenous FSH release associated with premature LH release.

The value of luteal support with progesterone in gonadotropin-induced cycles

To evaluate the effect of luteal support with vaginal P suppositories in hMG- and hCG-induced cycles. Between March 1988 and February 1989 patients did not receive luteal support, while between March 1989 and January 1990 P was given routinely in the luteal phase. Induction protocol and patient selection remained otherwise unchanged. Infertility clinic of a tertiary care hospital. Twenty-seven patients with hypogonadotropic amenorrhea (World Health Organization [WHO] group I) (11 women with luteal support, 16 women without) and 102 patients with euprolactinemic clomiphene citrate (CC)-resistant anovulation (WHO group II) (52 women with luteal support, 50 women without). Vaginal P suppositories 200 mg/d in the luteal support group. Pregnancy rate (PR), pregnancy outcome. The overall PR in 118 cycles with luteal support was 26.3% whereas 10.4% pregnancies were achieved in 115 cycles of the control group. The influence of luteal support was more pronounced in patients with CC-resistant anovulation (25.2% versus 6.9%) than in patients with hypogonadotropic amenorrhea (33.3% versus 21.4%, not significant). The abortion rate was not significantly changed. Luteal support with P increases the PR after hMG and hCG induction. The need for supplementary P seems to be related to the underlying cause of ovarian disturbance.

Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea.

To compare the efficacy and safety of ovulation induction with exogenous gonadotropins vs. pulsatile GnRH in patients with hypogonadotropic amenorrhea, results from 30 patients in 111 cycles of gonadotropins and 41 patients in 118 cycles of pulsatile GnRH were analyzed retrospectively. Exogenous gonadotropins were administered using an individually adjusted protocol, using a starting dose of 150 IU. Pulsatile GnRH was delivered iv at a physiological frequency based upon our normative data. The doses administered ranged from 75-250 ng/kg. Preovulatory serum estradiol (E2) and luteal phase progesterone (P) levels were compared to those in normal cycling women (n = 87). The mean body mass index, age, and baseline gonadotropin levels were similar in the two groups. Overall ovulatory rates and conception rates per cycle and per patient were not significantly different between the two groups. However, the cumulative chance of conception after six cycles of treatment by life table analysis appeared to be higher with pulsatile GnRH treatment (96%) than with exogenous gonadotropins (72%). The risk of multiple gestation was also higher with exogenous gonadotropins (14.8% vs. 8.3%), although this was not statistically significant. All higher order multiple gestations (triplets or more) occurred in the gonadotropin-treated group. More than two dominant follicles were seen on ultrasound in 47.6% of gonadotropin-treated cycles compared to 18.9% of cycles with pulsatile GnRH treatment (P < 0.01). Three or more follicles were seen in 16.6% of the gonadotropin cycles compared to 5.4% with pulsatile GnRH (P < 0.05). No case of severe ovarian hyperstimulation was observed in either group, although the mean luteal phase ovarian size was significantly higher in the gonadotropin group (P < 0.05). Mean peak preovulatory E2 levels were significantly higher in the gonadotropin group (1684.5 +/- 124.4 vs. 1315.3 +/- 74.9 pmol/L; P < 0.05). The mean luteal phase P level 1 week after ovulation was significantly higher than normal in the gonadotropin group (84.9 +/- 10.8 vs. 61.1 +/- 3.2 nmol/L; P < 0.05), but was not significantly different from that in the pulsatile GnRH group (70.3 +/- 6.0 nmol/L). We conclude that pulsatile GnRH, when compared to exogenous gonadotropins, results in high rates of ovulation and conception, but a decreased risk of multiple folliculogenesis, higher order multiple gestations, and ovarian enlargement.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of exogenous gonadotropins and pulsatile gonadotropin- releasing hormone for induction of ovulation in hypogonadotropic amenorrhea

Comparison of exogenous gonadotropins and pulsatile gonadotropin- releasing hormone for induction of ovulation in hypogonadotropic amenorrhea

Endovaginal doppler flow measurements of the ovarian artery in patients with a normal menstrual cycle and with polycystic ovary syndrome during in vitro fertilization

Women with a normal menstrual cycle (n = 21, controls), polycystic ovary syndrome (n = 10) and hypogonadotropic amenorrhea (n = 3) were stimulated with clomiphen-citrate (4th day to 8th day of the cycle) and with human menopausal gonadotropin (8th day to 11th day). The vascular impedance of the ovary carrying the dominant follicles was monitored by endovaginal pulsed Doppler flow measurement. Simultaneously, serum levels of LH, E2 and 17-OHP were assayed. Contrary to controls, women with polycystic ovary syndrome or hypogonadotropic amenorrhea showed decreased hormone levels and no lowering of the vascular impedance. In controls, the lower pulsatility index is caused by neovascularization around the dominant follicle and by E2-induced vasodilatation in the ovarian artery.

Endocrine Response Determines the Clinical Outcome of Pulsatile Gonadotropin-Releasing Hormone Ovulation Induction in Different Ovulatory Disorders*

To accrue systematic information in different ovulatory disorders on the precise relationship among endocrine response, clinical outcome, and the occurrence of complications, we treated 114 patients with pulsatile GnRH (2.5-5.0 micrograms, iv, every 60 min) for 187 cycles and compared them to 20 normal menstrual cycles. Thirty of these patients had primary hypogonadotropic amenorrhea (PHA; 40 cycles), 33 had other forms of hypogonadotropic hypogonadism (HH; 55 cycles), and 51 had polycystic ovary syndrome (PCOS; 92 cycles). Daily blood samples were drawn for hormone determinations. In PCOS, 50 cycles were preceded by GnRH analog suppression. PHA treatment cycles were characterized by the reestablishment of a normal endocrine pattern, almost no dose-related endocrine differences, elevated ovulatory (93%) and conception rates (23%), and no multiple pregnancies. In the HH subjects the ovulatory (91%) and pregnancy rates (31%) were high; however, while the lower GnRH dose elicited a normal endocrine pattern, the 5-micrograms dose induced excessive folliculogenesis and high estradiol levels and was associated with most of the multiple pregnancies of this study (three of four). GnRH analog suppression was successfully used to avoid recurrence of ovarian over-stimulation in two HH subjects. Finally, GnRH analog suppression in PCOS permitted normalization of the follicular phase endocrine pattern, achievement of good ovulatory (76%) and pregnancy (28%) rates, and avoidance of multiple pregnancies; however, luteal phase steroid secretion was abnormal, and the abortion rate remained elevated (43%). Obesity was associated with a reduced ovulatory rate in PCOS, but not in hypogonadotropic, subjects. Thus, we can conclude that in pulsatile GnRH ovulation induction: 1) a profound hypogonadotropic condition, whether spontaneous as in PHA or induced with GnRH analogs as in other ovulatory disorders, is associated with optimal menstrual cycle restoration, high ovulatory and conception rates, and virtually absent risks of multiple pregnancy; 2) residual hypothalamic activity in HH may be responsible for supraphysiological pituitary-ovarian stimulation and result in multiple pregnancy unless a low GnRH dose (2.5 micrograms/bolus) or GnRH analog pretreatment is employed; 3) obesity does not affect treatment outcome in hypogonadotropic patients; and 4) the high spontaneous abortion rate in PCOS may be related to corpus luteum dysfunction.

Improvement of spontaneous pregnancy rate after stopping gonadotropin therapy for anovulatory infertility

In a prospective study, 140 patients with infertility because of ovulatory factors (group A) were followed up for 6 months after failure to achieve pregnancy using human menopausal gonadotropin (hMG) therapy. They included cases of oligomenorrhea, polycystic ovarian disease (PCOD), and hypogonadotropic amenorrhea. They were treated with hMG alone or in combination with clomiphene citrate or gonadotropin-releasing hormone agonist analog. The control group (B) included 83 infertile patients because of similar ovulatory factors. They were followed up for 6 months not preceded by ovulation induction. The overall pregnancy rate (PR) in group A (20.7%) was significantly higher than group B (7.2%). The PR was significantly higher in oligomenorrhea and PCOD patients when compared with the control group. There was no significant difference in the hypogonadotropic group.