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PubMed1987

Evidence that estrogen may be a key factor in hyperprolactinemic anovulation: a case report.

Although anovulation associated with hyperprolactinemia is not an uncommon cause of infertility, the precise mechanism of the pathogenic process that induces hyperactivity (hypertrophy with hyperplasia) of pituitary lactotropes is unknown. We have recently experienced a case of anovulation and hyperprolactinemia in a woman with ergot alkaloid intolerance in whom ovulation was restored by tamoxifen citrate administration. Since tamoxifen citrate administration also suppressed prolactin levels, it was suggested that a low but sustained serum level of estradiol and consequently continuous estrogenic stimulation may be an important causative factor in the development of hyperprolactinemic anovulation.

Adult↗
PubMed1995

A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics.

OBJECTIVE: To determine if dopamine (D3) receptor genotypes are associated with anovulation and response to ovulation induction with clomiphene citrate. DESIGN: Clinical and laboratory characteristics of anovulatory patients and ovulatory controls were compared with findings at the DNA level. SETTING: An outpatient clinic at an university medical center. PATIENTS: One hundred eighty human Hispanic female volunteers (130 of these with documented ovulatory status) were studied. INTERVENTIONS: Genomic DNAs were extracted from each patient. Polymerase chain reaction with subsequent restriction digest was performed to analyze the D3 receptor allele status (two possible alleles). MAIN OUTCOME MEASURES: Menstrual history, serum T, and midluteal serum Ps from spontaneous and clomiphene cycles were correlated with D3 receptor genotype. RESULTS: Hispanic females with the 22 genotype compared with the other genotypes (11 and 12) were more likely to have irregular menses, an elevated serum T (> or = 70 ng/dL [conversion factor to SI unit, 3.467]), and hyperandrogenic chronic anovulation. These patients tended to be resistant to ovulation induction requiring a significantly higher dose of clomiphene to achieve an ovulatory response (22 genotype [mean +/- SEM] [140.0 +/- 19.0 mg] versus 11 [77.1 +/- 17.5 mg] or 12 [69.2 +/- 13.1 mg]). This effect was independent of patient age, weight, or serum T level. CONCLUSIONS: Hyperandrogenic chronic anovulation may have a genetic component. Genetic analysis may be useful in predicting resistance to ovulation induction with clomiphene.

Alleles↗
PubMed2005

Effect of anovulation factors on pre- and postmenopausal ovarian cancer risk: revisiting the incessant ovulation hypothesis.

Risk factors for ovarian cancer may differ between pre- and postmenopausal women. The authors used data from a multiethnic, population-based, case-control study, conducted between 1993 and 1999 in Hawaii and Los Angeles, California, to examine whether menopause modified the effect of ovulation on ovarian cancer risk. A structured questionnaire was administered to 558 histologically confirmed epithelial ovarian cancer cases and 607 population controls. Lifetime ovulatory (log)years were significantly associated with an increased risk of ovarian cancer (odds ratio = 1.78, 95% confidence interval: 1.24, 2.57), particularly among premenopausal women (odds ratio = 2.49) but not among postmenopausal women (odds ratio = 0.88) (p(interaction) = 0.006). Factors that induced anovulation, including oral contraceptives, pregnancy, and breastfeeding, were associated with a reduced risk of ovarian cancer. Among anovulation factors, prolonged oral contraceptive pill use provided a greater protective effect against premenopausal ovarian cancer than against postmenopausal ovarian cancer (for > or =5.4 years of use vs. never use: odds ratio = 0.28, 95% confidence interval: 0.15, 0.52 vs. odds ratio = 0.58, 95% confidence interval: 0.31, 1.08, respectively), but the difference was not significant (p(interaction) = 0.20). Association of breastfeeding and pregnancy with ovarian cancer risk was also similar between pre- and postmenopausal women (respective p(interaction) = 0.72 and 0.43). The authors' data support the hypothesis that lifetime ovulation is involved in the pathogenesis of pre- but not postmenopausal ovarian cancer, while the protective effects of anovulation factors persist from pre- to postmenopausal women.

Adult↗
PubMed2000

Nutritionally induced anovulation in beef Heifers: ovarian and endocrine function during realimentation and resumption of ovulation.

Nutritionally induced anovulatory and cyclic Angus x Hereford heifers were used to evaluate follicular growth and concentrations of hormones and metabolites during anovulation and resumption of ovulation. Anovulatory heifers were fed to gain 0.6 (LGAIN) or 1.5 (HGAIN) kg/day until resumption of ovulation, and heifers with normal estrous cycles were fed a maintenance diet (M). Follicles >/= 4 mm in diameter were measured by daily ultrasonography in HGAIN and LGAIN heifers during one follicular wave before realimentation (Wan) and in two waves (W-2, W-1) immediately before the wave resulting in first ovulation or luteinization (W0). Ovaries of M heifers were evaluated to determine the day of ovulation of the second-wave dominant follicle (DF). Resumption of ovulation after realimentation occurred 23 days earlier in HGAIN than in LGAIN. Maximum diameter, growth rate, and persistence of dominant follicles increased, while persistence of first subordinate follicles decreased between anovulation and resumption of ovulation in anovulatory heifers. Concentrations of LH in serum were similar for HGAIN and LGAIN and gradually increased during realimentation. The increase in estradiol before the first ovulation was less in realimented heifers compared with cyclic heifers. Concentrations of insulin-like growth factor-I (IGF-I) in HGAIN and LGAIN gradually increased during realimentation but were lower than concentrations of IGF-I in cyclic heifers at ovulation. Increased diameter, growth rate, and persistence of the DF were associated with increased concentrations of LH, estradiol, and IGF-I during the transition from nutritionally induced anovulation to resumption of ovulatory cycles.

Animal Nutritional Physiological Phenomena↗
PubMed2006

PCOS according to the Rotterdam consensus criteria: Change in prevalence among WHO-II anovulation and association with metabolic factors.

OBJECTIVE: The current report aims to compare the prevalence of polycystic ovary syndrome (PCOS) diagnosed according to the new Rotterdam criteria (Rott-PCOS) versus the previous criteria as formulated by the National Institutes of Health (NIH) (NIH-PCOS) in women with normogonadotropic (WHO-II) anovulation and assess the frequency of obesity and related factors determined in these women. DESIGN: Cohort study based on large anovulation screening database. SETTING: Two large tertiary referral centres for reproductive medicine. POPULATION: WHO-II normogonadotropic, anovulatory, infertility cases. METHODS: WHO-II cases were extracted from the screening database and classified according to both the Rotterdam and NIH criteria for PCOS. Within these two classes, the prevalence of obesity, hyperglycaemia and insulin resistance was assessed and compared and their relation to the difference in diagnostic criteria applied was analysed. MAIN OUTCOME MEASURES: Prevalence of diagnosis PCOS in the WHO-II anovulation group. Prevalence of obesity, hyperglycaemia and insulin resistance in the two diagnostic classes. RESULTS: The Rott-PCOS group appeared to be more than 1.5 times larger than the group classified as NIH-PCOS (91 versus 55% of the WHO-II cohort). Especially, women with ovarian dysfunction and polycystic ovaries at ultrasound scan, but without hyperandrogenism, were added to the PCOS diagnostic group. The Rott-PCOS exhibited a lower frequency of obesity, hyperglycaemia and insulin resistance compared with the NIH-PCOS group. Obese women in the Rott-PCOS group without androgen excess had a different metabolic profile compared with obese women in the NIH-PCOS group, with lower rates of hyperglycaemia and hyperinsulinism, despite comparable distributions of body weight. CONCLUSION: The present findings indicate that with the new Rotterdam consensus criteria, oligo/anovulatory women with less severe metabolic derangement will be added to the heterogeneous group of women with PCOS.

Anovulation↗
PubMed1982

Metergoline in the management of hyperprolactinemic amenorrhea and anovulation.

84 patients with elevated serum PRL levels, ranging from 25 to 253 ng/ml, were treated with an antiserotonin agent, metergoline, at the dose of 12 mg/day for 90 days. The clinical complaint was of amenorrhea in 70 cases (plus galactorrhea in 44 cases) and of anovulation in 14 cases (plus galactorrhea in 6 cases). Hyperprolactinemia was due to a pituitary adenoma in 18 cases; in 53 cases it was of unknown origin, while in 7 cases it followed treatment with neuroleptics or with oral contraceptives and in 6 cases it followed a puerperium. In patients with amenorrhea, metergoline induced the appearance of menses in 61 cases (94%), and of ovulation in 46 cases (82%). In 13 of the 14 patients with anovulation, ovulation was restored. Galactorrhea disappeared in 40 out of 50 patients. Metergoline normalized serum PRL levels (less than 20 ng/ml) in 46 cases and significantly reduced serum PRL levels in all but 3 of the remaining patients. In spite of suggested nonhormonal contraceptive measures, 14 patients became pregnant; 2 had abortions and the remaining 12 patients completed by vaginal delivery, uneventful pregnancies. These results indicate metergoline as a safe and effective drug in the management of hyperprolactinemic amenorrhea and anovulation. 49 patients were followed for 2 additional months, receiving no treatment (24 cases) or metergoline at a reduced daily dosage (8 mg/day, 25 cases). Within 60 days, 60% of the first group had relapse of the clinical condition and a rebound elevation of serum PRL levels while only 20% of the second group experienced relapse of amenorrhea and rebound elevation of serum PRL levels (p less than 0.01).

Amenorrhea↗
PubMed1987

Changing pituitary reactivity to follicle-stimulating hormone and luteinizing hormone-releasing hormone after induced ovulatory cycles and after anovulation in patients with polycystic ovarian disease.

Pituitary reactivity to GnRH, characteristic of polycystic ovarian disease (PCOD), has been attributed both to a primary ovarian cause and to hypothalamic-pituitary dysfunction. If the heightened pituitary reactivity characteristic of PCOD patients is secondary to chronic anovulation, ovulatory cycles should produce changes in the LH to FSH ratio and reduce the augmented response to GnRH. In a randomized cross-over study of 10 women with PCOD, GnRH (100 micrograms) was injected iv on the fifth day of 2 consecutive cycles, 1 of them following anovulation and progesterone withdrawal bleeding and the other following an induced ovulatory cycle. Mean basal plasma 17 beta-estradiol, progesterone, and FSH levels were similar after ovulatory and anovulatory cycles. However, mean basal serum testosterone (P less than 0.05) and LH (P less than 0.01) levels were significantly lower, as were LH levels 30, 60, and 90 min (P less than 0.01) and FSH levels 60 and 90 min (P less than 0.05) after GnRH injection, after an ovulatory cycle than after an anovulatory cycle. The pituitary response to GnRH in those PCOD patients, therefore, was more normal after an ovulatory cycle than after an anovulatory cycle. We conclude that the heightened pituitary reactivity characteristic of PCOD patients is associated with chronic anovulation.

Adult↗
PubMed1998

Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation.

Polycystic ovary syndrome is the most common cause of anovulatory infertility. Anovulation in polycystic ovary syndrome is characterized by the failure of selection of a dominant follicle with arrest of follicle development at the 5-10 mm stage. In an attempt to elucidate the mechanism of anovulation associated with this disorder we have investigated at what follicle size human granulosa cells from normal and polycystic ovaries respond to LH. Granulosa cells were isolated from individual follicles from unstimulated human ovaries and cultured in vitro in serum-free medium 199 in the presence of LH or FSH. At the end of a 48-h incubation period, estradiol (E2) and progesterone (P) were determined in the granulosa cell-conditioned medium by RIA. In ovulatory subjects (with either normal ovaries or polycystic ovaries), granulosa cells responded to LH once follicles reached 9.5/10 mm. In contrast, granulosa cells from anovulatory women with polycystic ovaries responded to LH in smaller follicles of 4 mm. Granulosa cells from anovulatory women with polycystic ovaries were significantly more responsive to LH than granulosa cells from ovulatory women with normal ovaries or polycystic ovaries (E2, P < 0.0003; P, P < 0.03). The median (and range) fold increase in estradiol and progesterone production in response to LH in granulosa cell cultures from size-matched follicles 8 mm or smaller were E2, 1.0 (0.5-3.9) and P, 1.0 (0.3-2.5) in ovulatory women and E2, 1.4 (0.7-25.4) and P, 1.3 (0.3-7.0) in anovulatory women. Granulosa cells from anovulatory (but not ovulatory) women with polycystic ovaries prematurely respond to LH; this may be important in the mechanism of anovulation in this common endocrinopathy.

Adult↗
PubMed2002

Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation.

The endocrine-metabolic hallmarks of polycystic ovary syndrome are hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation. We hypothesized that dyslipidemia and anovulation in nonobese women with polycystic ovary syndrome are essentially secondary to the concerted effects of hyperandrogenism and insulin resistance. We tested this hypothesis by comparing the efficacy of anti-androgen (flutamide) or insulin-sensitizing (metformin) monotherapy to that of combined therapy in normalizing the endocrine-metabolic and anovulatory status of nonobese, young women with hyperinsulinemic hyperandrogenism. Thirty-one young women (mean age, 18.7 yr; body mass index, 21.9 kg/m(2); hirsutism score, 16; monthly ovulation rate monitored by weekly serum progesterone, 10%) were randomly assigned to receive once daily flutamide (250 mg; n = 10), metformin (1275 mg; n = 8), or combined flutamide- metformin therapy (n = 13) for 9 months. At baseline, there were no endocrine-metabolic differences among treatment groups. Compared with monotherapy, combined flutamide-metformin therapy resulted in greater improvements in insulin sensitivity, in testosterone, androstenedione, dehydroepiandrosterone sulfate, and triglyceride levels, and in low-density lipoprotein/high-density lipoprotein-cholesterol ratio (all P < 0.005). Monthly ovulation rates increased after 9 months to 75 and 92%, respectively, with metformin alone or with combined therapy, but were unimproved with flutamide alone. All treatments were well tolerated. In conclusion, combined anti-androgen and insulin-sensitizing treatment in young, nonobese women with hyperinsulinemic hyperandrogenism had additive benefits on insulin sensitivity, hyperandrogenemia, and dyslipidemia. The data from this small study suggest that dyslipidemia is secondary to excess androgen action in concert with the hyperinsulinemia associated with insulin resistance. In contrast, anovulation seems to be mainly attributable to insulin resistance and hyperinsulinemia.

Adult↗
PubMed2000

Anovulation in non-reproductive female Damaraland mole-rats (Cryptomys damarensis).

Within colonies of Damaraland mole-rats (Cryptomys damarensis), anovulation in non-reproductive females is thought to play an important role in maintaining reproductive skew. Pituitary sensitivity and ovarian structure were examined in three groups of females that differed with respect to their social environment and breeding status to determine whether anovulation is due to inhibitory social cues or is merely the result of a lack of copulatory stimulation. The contribution of gonadal steroid negative feedback to neuroendocrine differences in the reproductive systems of the respective groups was also investigated. LH secretion after a 0.5 micrograms GnRH challenge in females that had been removed from the presence of the breeding individuals for at least 6 months (removed non-reproductive females) was significantly higher than in non-reproductive females in the colony, but significantly lower than in reproductive females. In both removed non-reproductive females and reproductive females, corpora lutea were observed in ovaries of seven of eight females, indicating that ovulation occurs spontaneously in subordinate females on removal from the breeding pair. Circulating progesterone concentrations in removed non-reproductive females were significantly higher than in non-reproductive females, indicating that circulating progesterone is not responsible for infertility in non-reproductive females. Indeed, after hystero-ovariectomy, reproductive females continued to show significantly greater GnRH-stimulated LH secretion than non-reproductive females. Thus, differential inhibition of gonadotrophin secretion in breeding and non-breeding females occurs independently of gonadal steroids. It is concluded that female Damaraland mole-rats are spontaneous ovulators and that anovulation results from inhibitory social cues within the colony, not a lack of copulatory stimulation. Since non-reproductive females are infertile, inhibition of the hypothalamo-pituitary-gonadal axis has the potential to play a causal role in maintaining reproductive skew in colonies of C. damarensis.

Animals↗
PubMed1997

Ad libitum suckling by an unrelated calf in the presence or absence of a cow's own calf prolongs postpartum anovulation.

Our objective was to determine whether onset of first postpartum ovulation would be altered in suckled cows nursing an unrelated calf in the presence or absence of their own nonsuckling calf. In a 2-yr study, Angus x Hereford cows were assigned randomly to five treatments between d 13 and 18 postpartum for 4 wk: 1) own calf was weaned (OCW, n = 9); 2) own calf was present continuously (OCP, n = 12); 3) own calf was present continuously but restricted from udder contact (OCR, n = 9); 4) unrelated calf was present continuously after own calf was removed (UCP, n = 10); and 5) unrelated calf was present continuously and own calf was present but restricted as in the OCR treatment (OCR + UCP, n = 10). Interval to the first increase in progesterone (ovulation) was less (P < .05) in OCW (14.7 +/- 3.4 d) and OCR (19.9 +/- 3.4 d) than in the OCP (35.0 +/- 2.9 d), UCP (38.0 +/- 3.4 d), and OCR + UCP (37.6 +/- 3.4 d) treatments. The OCW cows showed no maternal bond with their own calves after 4 wk of treatment, whereas OCR, OCP, and OCR + UCP cows were bonded to their own natural calves. Cows in the UCP treatment, suckled by unrelated calves, formed new maternal bonds with those calves, resulting in prolonged anovulation. Further, OCR + UCP cows had prolonged anovulation because maternal bonds were maintained with their own restricted calves while milk was removed by unrelated calves. We conclude that milk removal preceded by a continuously reinforced cow-calf bond (original or reestablished) is essential to prolong anovulation in beef cows.

Analysis of Variance↗
PubMed1999

Nutritionally induced anovulation in beef heifers: ovarian and endocrine function preceding cessation of ovulation.

Angus x Hereford heifers were used to determine endocrine and ovarian function preceding nutritionally induced anovulation. Six heifers were fed to maintain body condition score (M), and 12 heifers were fed a restricted diet (R) until they became anovulatory. Starting on d 13 of an estrous cycle, heifers were given PGF2alpha every 16 d thereafter to synchronize and maintain 16 d estrous cycles. Ovarian structures of M and R heifers were monitored by ultrasonography daily from d 8 to ovulation (d 1 of the subsequent cycle) until R heifers became anovulatory. Concentrations of LH and FSH were quantified in serum samples collected every 10 min for 8 h on d 2 and 15 (48 h after PGF2alpha), and estradiol and IGF-I were quantified in daily plasma samples from d 8 to 16 during the last ovulatory cycle (Cycle -2) and the subsequent anovulatory cycle (Cycle -1). During the last two cycles before anovulation, M heifers had 50% larger (P < .0001) ovulatory follicles than R heifers and 61% greater (P < .0001) growth rate of the ovulatory follicles. There was a treatment x cycle x day effect (P < .001) for concentrations of estradiol. The preovulatory increase in estradiol occurred in the R and M heifers during Cycle -2 but only in M heifers during Cycle -1. A treatment x cycle x day effect (P < .05) influenced LH concentrations. During Cycle -2, LH concentrations were similar for M and R heifers, but during Cycle -1, M heifers had greater LH concentrations than did R heifers. Concentrations of FSH were greater (P < .05) in R than M heifers after induced luteolysis when R heifers failed to ovulate. There was a treatment x cycle interaction (P < .05) for IGF-I concentrations, and M heifers had 4.7- and 8.6-fold greater IGF-I concentrations than did R heifers during Cycle -2 and -1, respectively. We conclude that growth rate and diameter of the ovulatory follicle, and concentrations of LH, estradiol, and IGF-I are reduced before the onset of nutritionally induced anovulation in beef heifers.

Animal Nutritional Physiological Phenomena↗
PubMed1982

Depressed prolactin levels in diabetic women with anovulation.

The circulating levels of prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol-17 beta were determined by radioimmunoassay in 76 normal healthy women in the follicular phase of the menstrual cycle, 54 consecutive anovulatory non-diabetic women and 20 consecutive diabetic women with anovulation. An elevated plasma PRL concentration was found in 1/20 (5%) of the diabetic women and in 17/54 (32%) of the non-diabetic anovulatory women (p less than 0.05). Plasma concentrations of estradiol-17 beta and gonadotropins in diabetics did not differ (p greater than 0.05) from those found in non-diabetic women with anovulation. Diabetic women with secondary amenorrhea had significantly (p less than 0.05) lower plasma concentrations of PRL and estradiol-17 beta than non-diabetic women with amenorrhea and normal controls. Furthermore, this group of diabetic women had lower median plasma LH concentrations than the non-diabetics with secondary amenorrhea and normal controls, but this difference was not significant (p greater than 0.05). These data indicate that diabetic patients with anovulation have hypothalamic and/or pituitary defects. Furthermore, the low prolactin and LH levels despite a low estradiol-17 beta concentration may suggest an increased hypothalamic dopamine activity in patients with diabetes mellitus and secondary amenorrhea.

Adolescent↗
PubMed1985

Anovulation: etiology, evaluation and management.

Every woman begins and ends her years of cyclic menstrual function with periods of anovulation, with or without vaginal bleeding. Many women, however, experience anovulation during their reproductive years. It may be an occasional problem or a chronic condition. In some cases, the anovulatory state requires only a little time or minimal pharmacological intervention to correct. Once homeostatis is achieved, the system returns to its cyclic function. Other cases of anovulation result from serious pathology or congenital anomalies which may be difficult to diagnose and even more difficult to correct. The right medical intervention can usually return the woman to a state of good overall health, but pregnancy may not always be achievable. This article reviews the physiology of ovulation, the reasons for its failure, the diagnostic process and the latest in therapeutic management.

Anovulation↗
PubMedDate not supplied

Estimated prevalence of undiagnosed glucose intolerance from hyperandrogenic anovulation among women requesting electrolysis.

OBJECTIVE: Hyperandrogenic anovulation is the principal risk factor for non-insulin-dependent diabetes mellitus (NIDDM) in young women. Since many of these women undergo depilatory therapy, the purpose of this study was to estimate the probability of undiagnosed glucose intolerance associated with hyperandrogenic anovulation among premenopausal women requesting electrolysis. DESIGN: Case-series study. INTERVENTIONS: Women (N = 791) attending one of 27 electrology clinics in the United States, Canada and Germany received questionnaires requesting anthropometric data; personal information regarding age, surgery and medication use, and family histories of excess hair growth in female relatives and diabetes in parents or siblings. RESULTS: Of 652 respondents less than age 50 years, 643 (98.6%) women had hirsutism, of whom 465 had regular menstrual cycles. One hundred seventy-eight (27.3%) women less than 50 years of age had hirsutism with irregular menses, and one-half of these women also were obese. Regardless of adiposity, one-third of hirsute women with menstrual irregularity knew the cause of their androgen excess, while the remaining two-thirds were unaware of the reason for their excess hair growth. CONCLUSIONS: Assuming a 20% risk of glucose intolerance in obese hyperandrogenic anovulatory women by the fourth decade of life, the estimated prevalence of undiagnosed glucose intolerance from hyperandrogenic anovulation is 1.7% among women requesting electrolysis before age 50 years.

Adolescent↗
PubMed2005

Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation.

BACKGROUND: Infertility due to anovulation is a common problem in women. The first line oral treatment is with anti-oestrogens, such as clomiphene citrate. Unfortunately there may be resistance and alternative and adjunctive treatments have been developed. These include tamoxifen, dexamethasone, bromocriptine and aromatase inhibitors (AIs). OBJECTIVES: To determine the relative effectiveness of anti-oestrogen agents, with or without medical adjuncts, in women with WHO group 2 anovulation. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group trial register (searched 5th July 2004), CENTRAL (The Cochrane Library Issue 2 2004), MEDLINE (1966 to June 2004) and EMBASE (1980 to June 2004) for identification of relevant randomised controlled trials (RCTs). Additionally the United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs were searched. SELECTION CRITERIA: RCTs that compare oral anti-oestrogen agents for ovulation induction (alone or in conjunction with medical adjuncts) in anovulatory subfertility, were considered for inclusion in the review. Metformin and other insulin sensitizing agents were not included. Hyperprolactinaemic infertility was not included. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment was done independently by two reviewers. The primary outcome was live birth, secondary outcomes were: pregnancy, ovulation, miscarriage, multiple pregnancy, overstimulation, ovarian hyperstimulation syndrome and patient reported adverse effects. MAIN RESULTS: Twelve RCTs were found and included in this review. No trials reported live birth as an outcome. Miscarriage and multiple pregnancy rates were poorly reported. Clomiphene was shown to be effective in increasing pregnancy rate when compared to placebo (fixed OR 5.8, 95% CI 1.6 to 21.5; NNT 5.9, 95% CI 3.6 to 16.7). No evidence of a difference in effect was found between clomiphene and tamoxifen (fixed OR 1.0, 95% CI 0.5 to 2.1). The use of clomiphene in combination with tamoxifen did not find any evidence of effect on pregnancy rate when compared to clomiphene alone (fixed OR 3.3, 95% CI 0.1 to 91.6). The comparison between two AIs (letrozole and anastrozole) did not find any evidence of a difference in effect on pregnancy rate (fixed OR 1.9, 95% CI 0.4 to 8.9). For the intervention of clomiphene plus ketoconazole vs clomiphene no evidence of a difference in effect for pregnancy rate was found (fixed OR 2.4, 95% CI 0.9 to 6.4). For clomiphene plus bromocriptine vs clomiphene no evidence of a difference in effect on pregnancy rate was found (fixed OR 1.0, 95% CI 0.3 to 3.0) rates. However, clomiphene plus dexamethasone treatment resulted in a significant improvement in the pregnancy rate (fixed OR 11.3, 95% CI 5.3 to 24.0; NNT 2.7, 95% CI 2.1 to 3.6) when compared to clomiphene alone as did clomiphene plus pretreatment with combined oral contraceptives (fixed OR 27.2, 95% CI 3.1 to 235.0; NNT 2.0, 95% CI 1.4 to 3.4). AUTHORS' CONCLUSIONS: This review shows evidence supporting the effectiveness of the current first line treatment, clomiphene citrate. No evidence of a difference in effect was found between clomiphene and tamoxifen. The use of dexamethasone as an adjunct to clomiphene therapy appears promising as do combined oral contraceptives. This review has highlighted a gap in the literature on effects of these drugs on outcomes such as miscarriage rate. Evidence in favour of these interventions is flawed. RCTs of adequate power and of high methodological quality are required for the older treatments such as clomiphene, alone and with medical adjuncts, and also for the newer drugs such as the AIs.

Anovulation↗
PubMed2000

Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation.

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.

Animals↗
PubMedDate not supplied

The mechanism of the effect of combination treatment with clomiphene and bromocriptine in patients with normoprolactinemic anovulation.

The combination treatment with bromocriptine and clomiphene citrate was applied to 11 normoprolactinemic anovulatory patients who did not respond to clomiphene citrate alone. This combination treatment restored ovulation in 8 of these patients (72.7%). Conception was observed in 2 patients (18.1%) out of 11. The patients who responded to combination treatment showed a significant increase in the serum level of estradiol in the preovulatory phase, of progesterone in the mid-luteal phase, and a significant decrease of serum prolactin. They also showed significant increase in the frequency of luteinizing hormone (LH) pulsatility on day 12 of the cycle from 1.38 +/- 0.86 to 3.75 +/- 0.83 pulses/4h. The 3 patients who did not respond to combination treatment showed no increase in the serum level of estradiol or progesterone, but showed increase in the frequency of LH pulsatility in spite of continuous anovulation. These results indicate that the combination treatment with bromocriptine and clomiphene citrate is effective for treatment of patients with normoprolactinemic anovulation who do not respond to clomiphene alone, and suggest that the mechanism of the effect of combination treatment is related to an increase in the frequency of LH pulsatility caused by bromocriptine, which in turn stimulates follicular maturation.

Adolescent↗