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PubMed2001

Recombinant human follicle-stimulating hormone: a scientific step to clinical improvement.

Urinary-derived follicle-stimulating hormone (FSH) preparations have been used clinically for many years. Although effective, these have a number of disadvantages, not least of which is their variable composition. The availability of recombinant human FSH (r-hFSH), produced from CHO cells, with its constant composition and exceptionally high purity, has, therefore, aroused great interest. This review focuses on the use of r-hFSH for ovarian stimulation in assisted reproduction technology protocols and the treatment of World Health Organization Group I and II anovulation. The use of r-hFSH has been shown to lead to improvements in efficacy over urinary-derived preparations, particularly in assisted reproductive treatment, and a recent meta-analysis has shown higher ongoing pregnancy rates with the recombinant product. Although the two available recombinant products from CHO cells (follitropin alpha [Gonal-F((R))] and beta [Puregon((R))]) are similar from a physicochemical perspective, some minor advantages have been reported for follitropin alpha in relation to pregnancy rates and better local tolerance to injections. The apparent higher bioactivity of r-hFSH has led to reduced total FSH consumption over shorter treatment periods compared with conventional preparations, thus reducing overall exposure for patients. This is likely to confer not only safety benefits, but also cost-effectiveness as demonstrated through pharmaco-economic modelling.

Journal Article↗
PubMedDate not supplied

Abnormal uterine bleeding in adolescents.

Menarche is an important event during adolescence. For most girls, it marks completion of puberty and the onset of reproductive capability. Menarche usually occurs when both breast and pubic hair development are at Tanner stage 4. Menstrual problems are common during adolescence due to slow maturation of the hypothalamic-pituitary-ovarian axis and can last 2 to 5 years after menarche. Although most problems are explained by anovulation, other causes must be considered and excluded in a logical and cost-effective manner. Frequently, the bleeding problems observed in adolescence require evaluation and intervention.

Adolescent↗
PubMed2002

Metformin and polycystic ovary syndrome: a literature review.

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. Anovulation, menstrual irregularities, hirsutism, and infertility are common clinical presentations. Long-term health concerns such as type II diabetes mellitus and, possibly, cardiovascular disease, have been linked to PCOS. Metformin, an oral hypoglycemic agent, has been recently advocated as treatment for some women with PCOS due to the association of PCOS with hyperinsulinemia. Metformin is utilized as sole therapy for ovulation induction as well as in combination with traditional ovulation-induction therapies. This review identified 23 prospective studies addressing the effects of metformin on PCOS. Because of the heterogeneity of the published reports, only a qualitative assessment of the data was possible. Review of this literature confirms a beneficial role of metformin in reducing insulin resistance in some women with PCOS. Other favourable biochemical effects include reduced free testosterone levels and increased sex hormone-binding globulin (SHBG). Metformin may improve menstrual regularity, leading to spontaneous ovulation, and improve ovarian response to conventional ovulation-induction therapies. There is, however, little evidence supporting the use of metformin to facilitate weight reduction, or improve serum lipids or hirsutism. Further evaluation is required to define the long-term effectiveness of metformin, who will benefit from metformin treatment, and the optimal duration of metformin therapy.

Androgens↗
PubMed2001

Clinical management of PCOS.

The polycystic ovary syndrome (PCOS) is a heterogeneous condition with genetic predisposition. It is characterized by a myriad of symptoms including oligomenorrhea or amenorrhea, anovulation or infertility, hirsutism or acne. Insulin resistance appears to be an important factor in PCOS though the lack of an etiology has led to symptom oriented therapy which includes lifestyle modification, the use of cyclical progestagens and antiandrogens. Ovulation induction by drug therapy and ovarian drilling aims to treat subfertility in women with PCOS. Therapeutic approaches to PCOS remain an ongoing source of debate. Insulin sensitizing agents may bring new hope in therapy. Future research is aimed at shedding light on the pathophysiology so as to optimize treatment of women with PCOS.

Contraceptives, Oral↗
PubMed2026

Genomic analyses implicate hormonal and metabolic dysregulation in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) and its underlying features remain poorly understood. In this genetic study (n = 544,513), we expand the number of genetic loci from 16 to 29, and additionally identify 31 associated plasma proteins. Many risk-increasing loci were associated with later age at menopause, underscoring the reproductive longevity related to an increased oocyte number and/or availability across the lifespan. Hormonal regulation in the etiology of this condition, through metabolic and reproductive features, was emphasized. The proteomic analysis highlighted metabolic biology known to be related to PCOS. A polygenic risk score (PRS) was associated with adverse cardiometabolic outcomes, with differing relevance of testosterone and body mass index in women and men. Finally, while oligo-anovulation and anovulatory infertility are features of PCOS, we observed no impact of PCOS susceptibility on childlessness. We suggest that PCOS susceptibility confers balanced pleiotropic influences on fertility in women, and life-long adverse metabolic consequences in both sexes.

Humans↗
PubMed1998

Teenage obesity in relation to breast cancer risk.

While most studies show a higher body mass in Western women to be positively associated with an increased breast cancer risk in postmenopausal women, they show a negative association in the case of premenopausal women. A review of case-control and cohort studies suggest that such protection applies mainly to obesity in teenage girls, whereas obesity appearing after the teenage years is more likely to be associated with a higher risk of postmenopausal breast cancer. The mechanisms are uncertain. There is evidence that obesity and the components of the Western diet can independently provoke hyperinsulinaemic insulin resistance at puberty, and in adolescent girls this has been related to evidence of abnormal ovarian steroidogenesis and anovulation. This may decrease promotion of mammary carcinogenesis. If however, obesity continues after the teenage years, the higher concentration of insulin-like growth factor 1 (IGF1) associated with hyperinsulinaemia can interact with oestrogen receptors in mammary epithelium to lead to increased proliferative activity. This review postulates that the observed protective effect of early obesity against premenopausal breast cancer is likely to be replaced by an increased risk of postmenopausal breast cancer if obesity continues after the teenage years. The manifestation of breast cancer is merely postponed to an older age. Recent prospective and case-control studies suggest that increased bioavailability of IGF1 is a marker of increased breast cancer risk in premenopausal women. Nutritional intake in early life may programme later activity in the growth hormone-IGF1 axis and influence the progression of transformed cells in mammary tissue. The question remains whether deliberate weight loss can reverse the effects of weight gain.

Adolescent↗
PubMed2000

Obesity, insulin, sex steroids and ovulation.

Obesity is a major feature in women with polycystic ovary syndrome (PCOS), and evidence suggests that obesity contributes to the pathogenesis of PCOS by aggravating the intrinsic insulin resistance of these women. Hyperinsulinemia appears to increase circulating androgens in PCOS by stimulating ovarian androgen production and suppressing serum SHBG, and also appears to play a pathogenic role in the anovulation of the disorder. The use of insulin sensitizing drugs has been shown to decrease serum insulin in both obese and nonobese women with PCOS, and to simultaneously reduce circulating ovarian androgens and to improve ovulation.

Androgens↗
PubMed1996

Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycystic ovary syndrome.

OBJECTIVE: Hyperinsulinaemic women with the polycystic ovary syndrome (PCOS) may be at increased risk of vascular disease later in life, mediated by blood pressure or lipid abnormalities or by elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) activity. PAI-1 may also be involved in ovarian follicle development and ovarian connective tissue remodelling. We measured plasma PAI-1 activity and 24-hour ambulatory blood pressure records in women with and without PCOS. DESIGN: Cross-sectional study of three groups. PATIENTS: Twenty-four non-obese women with a classic ovarian ultrasound appearance of PCO and extreme menstrual disturbance (Group 1), 26 matched controls with a normal menstrual cycle and an ultrasound appearance of PCO (Group 2) and 10 matched controls with a normal menstrual cycle and normal ovarian ultrasound (Group 3). MEASUREMENTS: Twenty-four hour ambulatory blood pressure recordings (Spacelabs 90207), ovarian ultrasonography, fasting plasma insulin and glucose, plasma PAI-1 activity, HDL and total cholesterol, triglycerides, gonadotrophins and testosterone. Family history of premature vascular disease. RESULTS: Median fasting plasma insulin was significantly higher in Group 1 (45.8 pmol/l, range 12.9-161.9) than in Group 2 (28.1 pmol/l; range 13.6-91; P < 0.05) or Group 3 (26.0 pmol/l; range 13.5-63.3; P < 0.05). There were no differences between groups in 24-hour, daytime or night-time ambulatory blood pressure measurements, and no relation between plasma insulin and any blood pressure variable. Mean plasma PAI-1 activity was higher in Group 1 (10.0 +/- 7.1 AU/l) than in Group 2 (6.0 +/- 4.6 AU/l; P < 0.05) or Group 3 (5.1 +/- 3.5 AU/l; P = 0.06). There was a significant independent direct relation between fasting plasma insulin and PAI-activity (r = 0.41, R2 = 0.154; F1,59 = 11.38; P = 0.001). Groups did not differ in parental history of premature vascular disease, or in mean HDL or fasting triglyceride levels. CONCLUSIONS: The only measurable vascular risk factor associated with hyperinsulinaemia and menstrual disturbance in non-obese women with PCOS is an elevated plasma PAI-1 activity. These women did not differ from controls in ambulatory blood pressure profiles, lipid measurements or in a parental history of premature vascular disease. PAI-1 and plasminogen are involved in ovarian follicle maturation and the present finding suggests a biologically plausible link between hyperinsulinaemia, anovulation and vascular risk in PCOS.

Adult↗
PubMed1997

The counterregulatory response to hypoglycaemia in women with the polycystic ovary syndrome.

OBJECTIVE: The pathogenetic mechanisms behind insulin resistance in polycystic ovary syndrome (PCOS) are far from fully elucidated. Aberrant counterregulatory responses to hypoglycaemia have been reported in patients with insulin resistance, and recent reports suggest that plasma glucose may be regulated at lower levels in women with PCOS. In this study we investigated the complete hormonal counterregulatory response to hypoglycaemia in women with PCOS. DESIGN: Prospective cross-sectional study. PATIENTS: Eight obese (BMI > or = 25) and 10 non-obese (BMI < 25) women with PCOS, diagnosed by means of ultrasonography and clinical signs of chronic anovulation. Eight obese and 9 non-obese controls. MEASUREMENTS: Hypoglycaemia was induced by an intravenous bolus of soluble insulin (0.15 IU/kg body weight). The counterregulatory responses of cortisol, GH, catecholamines, glucagon, chromogranin A (CGA), and neuropeptide Y (NPY) were studied together with symptoms of hypoglycaemia. RESULTS: The obese women with PCOS had a more pronounced truncal-abdominal body fat distribution (waist hip ratio, WHR) and were hyperinsulinaemic, compared with the obese controls. All the women exhibited blood glucose levels (< 2 mmol/l) well below the threshold for the hormonal counterregulatory response and for the appearance of clinical symptoms. The non-obese women with PCOS showed a greater increase in serum concentrations of GH than the lean controls. The obese women with PCOS exhibited blunted responses of noradrenaline and NPY, but similar increases of adrenaline and CGA, compared with the obese controls. They also showed a lower symptom score during hypoglycaemia. The response of noradrenaline to hypoglycaemia correlated inversely with fasting insulin levels in the women with PCOS. Among all the obese women (PCOS and controls pooled) basal levels of noradrenaline correlated inversely with the WHR. CONCLUSIONS: All the women with PCOS, independent of BMI, body fat distribution and insulin levels, showed preserved counterregulatory responses to hypoglycaemia. The reduced plasma levels of noradrenaline and the lower perception of hypoglycaemic symptoms in the obese women with PCOS could both reflect a lower activation of the sympathetic nervous system. This aberration seems related to truncal-abdominal obesity and hyperinsulinaemia. The finding of an increased response of GH in the lean women with PCOS could support previous suggestions of an altered activity of the GH/IGF-I system in these women.

Adult↗
PubMed1997

Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology. The aims of this study were to identify whether ovarian thecal cell steroidogenesis is abnormally regulated in PCOS by measuring steroid responses to a single dose of hCG before, and during, suppression of endogenous LH levels by GnRH analogue (GnRHa). DESIGN: Serum levels of LH, FSH, 17 alpha hydroxyprogesterone (17OHP), androstenedione, testosterone and dehydroepiandrosterone sulphate were measured before, and 48 hours after, a single intramuscular injection of 10,000 IU hCG. The test was repeated 4 weeks after suppression of endogenous LH levels by GnRHa. PATIENTS: The ovarian responses to hCG were compared in three groups of women. Eleven women had normal ovaries and regular cycles, eight had polycystic ovaries but not clinical features of the syndrome (PCO group) and eight had polycystic ovaries, anovulation and either severe hirsutism or alopecia (PCOS group). RESULTS: Before GnRHa treatment, LH levels were significantly higher in the PCOS group but hCG stimulated a similar rise in 17OHP in all three groups. Following analogue, LH levels were suppressed in all three groups but the 17OHP responses to hCG were significantly higher in both the PCO and PCOS groups compared with normal controls. CONCLUSIONS: These findings provide further evidence in favour of an intrinsic abnormality of thecal cell steroidogenesis in the polycystic ovary.

17-alpha-Hydroxyprogesterone↗
PubMed1995

Endocrine bases of lactational anoestrus in the sow.

Parturition in the sow is followed by a period of anovulation which is prolonged by lactation. Follicular development and luteinizing hormone (LH) secretion are depressed during the last month of pregnancy. After parturition, LH secretion increases but is again inhibited by the establishment of lactation. Lactating sows are submitted to stimuli originating from the young, whose intensity culminates 3-14 d post-partum (pp), and to high nutrient requirements for milk production. The inhibitory effects of sucklings are imposed during the first 3 d pp and seem to be mediated by the action of opioids at the hypothalamic level. The nutritional deficit constitutes an additional inhibitory factor. As lactation continues, LH secretion progressively increases. A further rise in LH occurs at weaning. Variations in follicle-stimulating hormone (FSH) profiles are less marked. The divergence observed between LH and FSH might be explained by different mechanisms of control; FSH secretion depends mainly on ovarian inhibition whereas LH secretion depends mainly on factors related to lactation. Folliculogenesis progressively resumes during lactation and follicles acquire the ability to respond to the weaning-associated stimuli and begin preovulatory growth. Hormones modified by lactation, such as prolactin, insulin, growth hormone and insulin-like growth factor I, may influence folliculogenesis directly at the ovarian level or via modifications of gonadotrophin secretions. In conclusion, the inhibition of the hypothalamo-pituitary-ovarian axis during lactation is mainly due to suckling-induced neuroendocrine reflexes. We hypothesize that the nutritional deficit becomes relatively more important during the third and fourth weeks pp.

Anestrus↗
PubMed2006

Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle: a review.

Cystic ovarian follicles (COF) are an important ovarian dysfunction and a major cause of reproductive failure in dairy cattle. Due to the complexity of the disorder and the heterogeneity of the clinical signs, a clear definition is lacking. A follicle becomes cystic when it fails to ovulate and persists on the ovary. Despite an abundance of literature on the subject, the exact pathogenesis of COF is unclear. It is generally accepted that disruption of the hypothalamo-pituitary-gonadal axis, by endogenous and/or exogenous factors, causes cyst formation. Secretion of GnRH/LH from the hypothalamus-pituitary is aberrant, which is attributed to insensitivity of the hypothalamus-pituitary to the positive feedback effect of oestrogens. In addition, several factors can influence GnRH/LH release at the hypothalamo-pituitary level. At the ovarian level, cellular and molecular changes in the growing follicle may contribute to anovulation and cyst formation, but studying follicular changes prior to cyst formation remains extremely difficult. Differences in receptor expression between COF and dominant follicles may be an indication of the pathways involved in cyst formation. The genotypic and phenotypic link of COF with milk yield may be attributed to negative energy balance and the associated metabolic and hormonal adaptations. Altered metabolite and hormone concentrations may influence follicle growth and cyst development, both at the level of the hypothalamus-pituitary and the ovarian level.

Animals↗
PubMed2000

The female athlete.

Over the past 30 years, the number of women participating in organized sports has grown dramatically. Several forms of menstrual irregularities have been described in the female athlete: primary and secondary amenorrhoea, oligomenorrhoea, short luteal phases and anovulation. The incidence of menstrual irregularities is much higher in activities where a thin body is required for better performance. The hormonal pattern seen in these athletes is a hypothalamic amenorrhoea profile. There appears to be a decrease in gonadotrophin-releasing hormone (GnRH) pulses from the hypothalamus, which in turn decreases the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and shuts down stimulation of ovary. Recently, another type of amenorrhoea has been described in swimmers which is characterized by mild hyperandrogenism. Athletes with low weight are at risk of developing the female athletic triad, which includes amenorrhoea, osteoporosis and disordered eating. Athletes with this triad are susceptible to stress fractures. Other issues include the pregnant athlete. Intensive exercise during pregnancy can cause bradycardia. Safe limits of aerobic exercise in pregnancy depend on previous exercise habits. Infertility, which may develop with exercise, is probably reversible with reduction of exercise or weight gain. High impact sports activities may produce urinary incontinence. Oestrogen replacement therapy is often prescribed in amenorrhoeic athletes, but bone loss may not be completely reversible.

Body Constitution↗
PubMed2002

Hyperandrogenism in girls with juvenile neuronal ceroid lipofuscinosis.

Acne and hirsutism are common findings in girls with juvenile neuronal ceroid lipofuscinosis (JNCL). A study on their hormonal status was conducted to investigate the mechanisms underlying these symptoms. Sixteen girls with JNCL entered the study. Ten of the girls had periodic menstruation, while three were given medroxyprogesterone acetate therapy to prevent menstrual bleeding, and three had earlier undergone an ovariectomy. Ten age- and weight-matched healthy girls served as controls. Age at menarche, menstrual cycle length, acne, and hirsutism were assessed. Extensive hormonal laboratory tests were made in the early follicular phase. In addition, 1.5 Tesla magnetic resonance imaging of the lower abdomen was performed to search for structural abnormalities of the ovaries. The mean age at menarche in these JNCL patients was 11.6 years. Of the patients with periodic menstruation, four of ten had irregular (prolonged) cycles, but, in patients with regular cycles, the mean ovarian cycle was short (26 days). Hyperandrogenism, characterized by acne, hirsutism and/or hyperandrogenaemia, was found significantly more often in the patients than in the controls (p<0.01). No significant differences were found in the laboratory parameters. Polycystic ovaries were found in two of seven of the patients who menstruated, but in none of the healthy controls. Hyperandrogenism is common in patients with JNCL. In addition, there is an early menarche and signs of anovulation. The factors underlying these hormonal changes seem complex, possibly including a neurodegenerative process, the obesity associated with JNCL, and the drugs used for symptomatic treatment of the patients.

Acne Vulgaris↗
PubMed2005

Polycystic ovary syndrome in adolescent girls.

Polycystic ovary syndrome (PCOS) has traditionally been thought of as a triad of oligomenorrhea, hirsutism, and obesity. PCOS is now recognized as a heterogeneous disorder that results in overproduction of androgens primarily from the ovary leading to anovulation and hirsutism and is associated with insulin resistance. Symptoms in the adolescent include oligomenorrhea, hirsutism, acne, and weight gain. These symptoms are often attributed to normal pubertal events, which can lead to a delay in diagnosis. Insulin resistance, impaired glucose tolerance and diabetes have been shown to occur in adolescents with PCOS. Treatment should be instituted early to decrease symptoms and long-term sequellae of PCOS. Weight loss, oral contraceptives and antiandrogens are very effective in treating the symptoms of this disorder. Insulin-sensitizing medications show promise, but should be used with caution until larger randomized trials have shown short- and long-term benefit and efficacy over traditional therapies in the adolescent population.

Adolescent↗
PubMed2001

[Treatment of high risk pregnancy with gravibinon].

A retrospective study was carried out in 47 patients 22 to 43 years of age, with a mean of 32.3 years, with a total of 51 high-risk pregnancies. The patients were treated with Gravibinon starting at the 5th week of pregnancy, and continuing up to the 20th. Indications for treatment were low progesterone or low estradiol levels, or both; these patients made up Group I. Group II patients showed a rapid drop in the progesterone and estradiol values after stimulation therapy despite ongoing pregnancy. The third group comprised women with PCO syndrome, who had previously anovulation or corpus luteum insufficiency. The pregnancy rate was 66.7%. In 9.8% a biochemical pregnancy was diagnosed through the hormone measurements. These biochemical pregnancies were not influenced by Gravibinon treatment. In 3.9% an empty cavity was found. In 11.8% abortion occurred prior to the 16th week of gestations despite Gravibinon treatment. In 7.8% late abortions occurred. In one case pregnancy was terminated owing to chromosomal anomalies. The pregnancy rate in all three groups was nearly equal, with group I at 20%, group II at 21.4%, and group III at 20%. In these high-risk groups it was found that treatment with an estrogen/progestin combination such as Gravibinon appears to be an effective treatment of an endangered pregnancy. An increased risk of specific anomalies was not observed.

Abortion, Habitual↗
PubMed2002

Homocysteine and steroids levels in metformin treated women with polycystic ovary syndrome.

UNLABELLED: Risk for atherosclerosis is increased in women with polycystic ovary syndrome (PCOS). Homocysteine (Hcy) is one of the independent risk factors for ischemic heart disease. We examined the effect of metformin (M) treatment on Hcy levels, steroids and glycide tolerance in PCOS. MATERIAL AND METHODS: 9 women with PCOS (defined as hyperandrogenemia and chronic anovulation); age 20 +/- 3.8 yrs, BMI 28.1 +/- 6.5 kg/m(2); examined in the follicular phase of spontaneous menstrual cycle before and after 27 +/- 4 weeks of treatment with M 1000 mg/day. The plasma concentrations of Hcy, DHEA, DHEA-S, cortisol (F), allopregnanolone (HPO), 17OHpregnenolone (17OHPl), insulin (I) and blood glucose (G) before and after the course of M were measured. RESULTS: After the course of M, Hcy significantly increased (10.1 +/- 2.6 to 13.4 +/- 5.1 micromol/l, p < 0.05.). There was no significant change in levels of I, HPO, F, DHEA-S and 17OHPl. DHEA levels increased significantly (from 26.9 +/- 15.7 to 44.4 +/- 24.6 nmol/l, p < 0.05). A borderline significant trend towards reduction in waist-hip ratio was seen (from 0.986 +/- 0.042 to 0.951 +/- 0.085; p < 0.06). CONCLUSIONS: Treatment with metformin in women with PCOS can lead to the increase in homocysteine levels--a risk factor for atherosclerosis.

17-alpha-Hydroxypregnenolone↗
PubMed2002

Regulation of gonadotropin secretion: implications for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism and chronic anovulation. Although the etiology of PCOS is unknown, perturbations of gonadotropin secretion are one of the hallmarks of this disorder. In normal menstrual physiology, the monotropic rise of plasma follicle-stimulating hormone (FSH) during the luteal-follicular transition is critical for follicular development and subsequent ovulation. One of the mechanisms by which FSH is differentially synthesized involves the luteal slowing of gonadotropin-releasing hormone (GnRH) pulse frequency by ovarian steroids. In PCOS, plasma leutinizing hormone (LH) is commonly increased, FSH is typically in the lower follicular range, and LH (and by inference GnRH) pulse frequency is persistently rapid at approximately one LH pulse per hour. The etiology of the neuroendocrine abnormalities in PCOS remain unclear; however, recent studies have revealed decreased sensitivity of the GnRH pulse generator to inhibition by ovarian steroids, particularly progesterone. This abnormality is reversed by the androgen receptor antagonist flutamide, suggesting that elevated androgen levels may alter the sensitivity of the hypothalamic GnRH pulse generator to steroid inhibition and lead to enhanced LH secretion. As such, women with PCOS require higher levels of progesterone to slow the frequency of GnRH pulse secretion, resulting in inadequate FSH synthesis and persistent LH stimulation of ovarian androgens. The decreased sensitivity of the GnRH pulse generator may help to explain the genesis of PCOS during puberty. In normal early puberty, sleep-entrained increases in LH stimulate ovarian steroids, which subsequently suppress LH frequency and amplitude during the subsequent day. In hyperandrogenemic girls destined to develop PCOS, this nocturnal increase in ovarian steroids may not be adequate to suppress the GnRH pulse generator, leading to a persistently rapid LH pulse frequency, impaired FSH production, and inadequate follicular development.

Drug Resistance↗