Inhibin-producing ovarian granulosa cell tumor as a cause of secondary amenorrhea: case report and review of the literature

We report the case of 31-year-old patient with an inhibin B-secreting granulosa cell tumor of the left ovary who presented with secondary amenorrhea. Preoperative serum hormonal levels were as follows: follicle-stimulating hormone (FSH) 0.3 mIU/mL, luteinizing hormone (LH) 9.81 mIU/mL, estradiol 142.0 pg/mL and inhibin B 2429 pg/mL. Gonadotropin-releasing hormone (GnRH) test revealed no FSH response and a normal LH response. After removal of the tumor, the levels of FSH and inhibin B returned to within the normal range, and regular menses resumed 27 days postoperatively. In premenopausal women, secondary amenorrhea may be the initial manifestation of granulosa cell tumor. A low FSH level coupled with normal levels of E2 and LH, the inhibition of the FSH response to GnRH and an elevated inhibin level suggest the presence of an inhibin-secreting ovarian tumor and also rule out the possibility of isolated FSH deficiency.     

19例下丘脑性闭经的诊断及助孕治疗分析

目的:探讨下丘脑性闭经(hypothalamic amenorrhea,HA)的临床特征和助孕治疗方法。方法:对19例HA患者进行病例回顾分析,总结临床特征,并与19例月经规律的正常妇女进行对照,比较血FSH、LH、E2、PRL、T水平及子宫体积、卵巢体积和基础窦卵泡数。对HA患者进行人工周期和hMG促排卵治疗,总结治疗方法和效果。结果:HA患者无或部分或不全性征发育,无潮热症状,染色体核型正常;血FSH、LH和PRL水平明显低于正常妇女(P<0.01),血FSH和LH呈低～正常水平,血E2和T水平与对照组比无明显差异。HA患者子宫和平均卵巢体积明显小于对照组,基础窦卵泡数明显少于对照组(P<0.01)。HA组行人工周期治疗,其中11例行hMG促排卵治疗后有排卵,7例临床妊娠。结论:人工周期和hMG促排卵治疗是对有生育要求的HA患者的经济有效的治疗,但需从低剂量起始,按逐渐加量和减量的原则进行,预防卵巢过度刺激综合征和多胎。出现多卵泡发育时穿刺多余卵泡或中转IVF,都是较好的补救措施。     

Identification of differing etiologies of clinically diagnosed premature menopause.

Investigations were performed in eight young women to determine if the findings of secondary amenorrhea and high follicle-stimulating hormone levels were due to primary ovarian follicular atresia or to other causes. Karyotypes were determined from both peripheral leukocytes and ovarian tissue; one woman had XXX/XX/XO mosaicism. Another woman had normal ovarian histology and probably had the "gonadotropin-resistant ovary syndrome." No autoimmune antibodies were detected, but one woman with myasthenia gravis also had ovarian histology that demonstrated primary ova and a developing follicle. Only five of eight women had primary ovarian follicular atresia, and two of the other three women had conditions theoretically compatible with subsequent pregnancy.     

Women with regular menstrual cycles and a poor response to ovarian hyperstimulation for in vitro fertilization exhibit follicular phase characteristics suggestive of ovarian aging

OBJECTIVE: To investigate whether follicular phase characteristics associated with ovarian aging can be observed in women of normal reproductive age, who had previously shown a poor response to ovarian hyperstimulation for IVF. DESIGN: Observational, prospective study. SETTING: Tertiary fertility center. PATIENT(S): Eleven regularly cycling, ovulatory women, aged 29-40 years who previously presented with fewer than four dominant follicles after ovarian hyperstimulation for IVF. INTERVENTION(S): Frequent serum hormone assessments and transvaginal ultrasound during the follicular phase of a spontaneous, unstimulated cycle. MAIN OUTCOME MEASURE(S): Duration of the follicular phase; serum LH, FSH, E(2), P, inhibin A, and inhibin B levels; and number of antral follicles observed by ultrasound. Results were compared with the cycle characteristics of a reference population of 38 healthy normo-ovulatory women aged 20-36 years (as published elsewhere). RESULT(S): Poor responders had significantly fewer antral follicles than controls. Median FSH concentrations were significantly higher compared with controls, but the majority had FSH levels within the normal range. Follicular phase P levels were significantly higher in poor responders. Duration of the follicular phase, E(2), and inhibin A and inhibin B serum levels did not differ between poor responders and controls. CONCLUSION(S): Normo-ovulatory regularly cycling women with a previous poor response to ovarian hyperstimulation for IVF show follicular phase characteristics suggestive of ovarian aging.     

Arginine-GnRH-TRH test in patients with primary hypothalamic amenorrhea

In 8 patients with hypothalamic primary amenorrhea aged from 16 to 23 years (average age 19,4 years) a sequential stimulations test was performed with 0,5 g arginine hydrochloride per kg body weight, 25 micrograms gonadotropin-releasing hormone (GnRH) and 200 micrograms thyreotropin-releasing hormone (TRH). The response of the lactotropic, gonadotropic, thyreotropic and somatotropic cells of the pituitary was investigated. Serum levels of PRL, LH, FSH, TSH and HGH were determined by RIA. In all women hypoplastic ovaries were found by laparoscopy. In 7 patients tissue biopsies showed primordial follicles or primordial and secondary follicles, respectively. Investigations point to, that in hypothalamic primary amenorrhea at first the function of the gonadotropic and lactotropic cells of the pituitary is injured. The somatotropic cells could not be stimulated in 3 of 8 patients, the function of hypothalamo-pituitary-thyroid-axis in the stimulations test was normal in all women.     

Secondary amenorrhea and infertility caused by an inhibin-B-producing ovarian fibrothecoma

OBJECTIVE: To report a case of secondary amenorrhea and infertility caused by an inhibin-B-producing ovarian fibrothecoma. DESIGN: Case report. SETTING: Academic medical center. PATIENT: A 37-year-old woman with a 2-year history of secondary amenorrhea and infertility. INTERVENTION(S): Operative removal of a 5-cm ovarian fibrothecoma. MAIN OUTCOME MEASURE(S): Luteinizing hormone, FSH, E2, inhibin-B, TSH, and prolactin measured preoperatively and postoperatively. Immunostaining of tumor cells for inhibin and LH. RESULT(S): Preoperative hormone levels were as follows: FSH, 1.7 mIU/mL; LH, 23.4 mIU/mL; E2, 31 pg/mL; and inhibin B, 1,154 pg/mL. Three weeks postoperatively, the FSH was 1.5 mIU/mL, LH decreased to 7.1 mIU/mL, E2 increased to 276 pg/mL, and inhibin-B decreased to 17 pg/mL. The fibrothecoma did not stain for LH but was strongly positive for inhibin. Regular menstrual cycles resumed 28 days postoperatively. CONCLUSION(S): Inhibin-B produced by an ovarian tumor profoundly suppressed FSH levels and resulted in secondary amenorrhea and infertility. Use of sensitive and specific immunoassays for inhibin-A and -B may aid in the differential diagnosis of hormonally active ovarian tumors.     

Follicular fluid concentrations of vascular endothelial growth factor, inhibin A and inhibin B in IVF cycles: are they markers for ovarian response and pregnancy outcome?

OBJECTIVE(S): The aim of this study was to measure concentrations of vascular endothelial growth factor (VEGF), inhibin A and inhibin B in follicular fluid (FF) of women undergoing to in vitro fertilization (IVF) cycles and to determine their relationship with ovarian response and pregnancy. STUDY DESIGN: Follicular fluid was collected from 58 patients undergoing oocyte retrieval for IVF. Ovulation was induced with GnRH analogues and gonadotropins. Follicular fluids of mature follicles (>17 mm) were aspirated and pooled for each patient. Follicular fluid steroid hormone levels (E2, P) and VEGF, inhibin A, inhibin B concentrations were studied. The serum levels of E2, P and VEGF were also assessed on the day of the oocyte retrieval. These parameters and characteristics of the cycles were compared between the pregnant (group 1) and non pregnant (group 2) patients. RESULTS: The serum and FF VEGF levels were found to be significantly lower in the group in whom the pregnancy was achieved (P < 0.001). The FF inhibin A and FF inhibin B were found to be significantly higher in pregnant group (P < 0.001). However, age, day 3 FSH, dosage of gonadotropin administered, fertilization rate, sperm count, motile and morphologically normal sperm percentage were not significantly different in the two groups. There was an negative correlation between VEGF and number of follicles, number of oocytes, FF inhibin A, FF inhibin B. The number of oocytes retrieved, the fertilization rate were positively correlated with FF inhibin B and FF inhibin A. CONCLUSION: This study demonstrated that decreased FF VEGF, serum VEGF and elevated FF inhibin A and B are associated with better ovarian response and high pregnancy rate.     

Resistant ovary syndrome. Case report

Patients with primary amenorrhea, sexual infantilism and elevated pituitary gonadotropins are frequently diagnosed with hypogonadism hypergonadotropic and suspected ovarian failure, secondary to a chromosomal abnormality, intrinsic ovarian failure or altered receptors for gonadotropins, mainly FSH (ovarian resistance). We report the case of a 16-year-old, admitted to the endocrinology clinic for primary amenorrhea and lack of development of secondary sexual characteristics. A complete physical examination revealed: height of 1.58 m and 57 kg weight, with incipient breasts (Tanner I), sparse pubic and axillary hair (Tanner I). The ultrasound reported small uterus and ovaries. Laboratory studies reported high levels of FSH and LH, estradiol and testosterone levels before puberty, prolactin, TSH, T3 and T4 normal. Normal female karyotype. Diagnostic laparoscopy was performed which showed two ovarian slips; biopsy was taken and reported both abundant primordial follicles and spindle cell stroma without evidence of primary and antral follicles, which integrates the diagnosis of resistant ovary syndrome.     

Do basal inhibin A and inhibin B levels have value in the diagnosis of polycystic ovary syndrome?

In the present study we aimed to investigate whether basal inhibin A and B levels in women with polycystic ovary syndrome (PCOS) would be used in diagnosis of the condition. Forty women with PCOS and 40 women with normal cycles (control group) were evaluated. There was no statistically significant difference in mean age and mean body mass index between the two groups (p?>?0.05). Serum levels of inhibin A and B, follicle-stimulating hormone (FSH), luteinizing hormone and total testosterone, and total ovarian volume, were determined in the PCOS group and the control group on day 3. In the PCOS group, total follicle number was obtained by counting follicles of diameter ??2?mm in both ovaries. Results were evaluated using Student's t test, Pearson correlation and regression tests. There was no significant difference in mean basal inhibin A or inhibin B levels between the two groups. Basal inhibin B levels showed a statistically significant negative correlation with basal FSH levels and a positive correlation with total follicle number in the PCOS group (p?<?0.05 and p?<?0.01, respectively). We conclude that basal inhibin A or B levels cannot be used in the diagnosis of PCOS.     

Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles

OBJECTIVE: To examine whether follicle loss due to ovarian aging is responsible for the occurrence of regular menstrual cycles in aging women with polycystic ovary syndrome (PCOS), the size of the FSH-sensitive follicle cohort was estimated by the exogenous follicle-stimulating hormone ovarian reserve test (EFORT) and related to the follicle count as measured by ultrasound. DESIGN: Prospective study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): Twenty-seven aging women with PCOS (35.8-49.4 years): 20 with regular menstrual cycles and 7 with oligomenorrhea or amenorrhea. INTERVENTION(S): EFORT and transvaginal ultrasound. MAIN OUTCOME MEASURE(S): Baseline (cycle day 2, 3, or 4) FSH, androstenedione (A), T, E(2), and inhibin B levels, the E(2) and inhibin B increment after the EFORT, and the follicle count. RESULT(S): After correction for the body mass index (BMI), the inhibin B increment was higher in the irregular menstrual group, but the E(2) increment did not differ significantly between the two groups. Ultrasound showed a median follicle count of 8.5 (4.0-18.0) in women with regular menstrual cycles (n = 16), compared with 18.0 (8.0-35.0) in irregularly menstruating women (n = 7). The follicle count was significantly correlated to the FSH-induced E(2) increment (r = 0.656) as well as to the inhibin B increment (r = 0.654). The regularly menstruating group was significantly older, had a higher basal FSH concentration, and had lower androgens than the irregularly menstruating group. CONCLUSION(S): The smaller follicle count, the older age, the higher FSH concentration, and the lower FSH-induced inhibin B increment found in women with PCOS and a regular menstrual cycle confirm that a decrease in the size of the follicle cohort due to ovarian aging is largely responsible for the regular menstrual cycles in aging PCOS women.     

Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin

OBJECTIVE: To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-alphaC. DESIGN: Prospective randomized trial. SETTING: In vitro fertilization (IVF) program at a university hospital. PATIENT(S): Infertile women undergoing IVF-ET treatment. INTERVENTION(S): Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2-3 days during the luteal phase. MEASUREMENTS AND MAIN RESULTS: Luteal phase serum levels of inhibin A and pro-alphaC, P, and E(2). RESULT(S): Levels of inhibin A, pro-alphaC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-alphaC levels were 91.5 +/- 23.6 and 184.1 +/- 23.5 pg/mL in the GnRH agonist-treated women compared with 464.7 +/- 209.1 and 7,351.6 +/- 934.3 pg/mL in women treated with hCG. CONCLUSION(S): Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.     

Mast cell distribution and density in the normal uterus--metachromatic staining using lectins

OBJECTIVE: To investigate the correlation between the early follicular phase serum inhibin B levels and other indicators of ovarian reserve. STUDY DESIGN: Seventy-four women aged 24-40 years (mean 32) with different infertility etiologies were investigated in the early follicular phase of a spontaneous mentrual cycle. The volume of the ovaries was measured and the total number of follicles <5 mm in size counted by ultrasound. Serum levels of FSH, estradiol (E2) and inhibin B were measured on the same day. In stepwise regression analysis inhibin B levels were correlated with age, body-mass-index, the ultrasound measurements, cause of infertility, parity, FSH and E2. RESULTS: FSH, BMI and the number of follicles proved to be statistically significant independent predictive factors for the inhibin B levels, FSH and BMI correlating negatively and the number of follicles positively with inhibin B serum concentrations. CONCLUSION: The number of small follicles reflect the inhibin B production of the ovaries. BMI being as strong predictive factor of inhibin B levels as FSH could in part explain the impaired likelihood of conceiving in obese patients.     

The role of inhibin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder which, in its severest manifestations, is associated with anovulation, hyperandrogenism and metabolic imbalance. The biochemical markers for the condition can include a significantly raised LH:FSH ratio and a raised testosterone concentration, indicating a derangement of the hypothalamo--pituitary--ovarian axis which may be primary or secondary to a primary ovarian pathology. The bioactive inhibins are heterodimeric glycoproteins consisting of alpha-betaA (inhibin A) and alpha-betaB (inhibin B) subunits. They play an endocrine role in co-regulating (with oestradiol) the suppression of FSH during the late follicular and luteal phases of the ovarian cycle and they are implicated in intraovarian paracrine signalling. Inhibin B, which is the predominant form in small pre-ovulatory follicles, increases in concentration from early in the follicular phase to reach a peak coincident with the onset of the decrease in FSH which forms the basis of the pattern of mono-ovulation seen in normo-ovulatory women. Several unique features of the dysovulation of women with PCOS, namely their failure to recruit and develop a dominant follicle despite having 'normal' concentrations of endogenous FHS, the raised LH:FSH ratio and their exquisite sensitivity to exogenous FSH injections, may be explained by their significantly higher inhibin B concentrations. Studies into inhibin B parameters in women with PCOS demonstrate that women with anovular PCOS have significantly higher concentrations of circulating inhibin B and that they lack the pulsatile pattern of secretion that can be detected in normo-ovulatory women during the mid-follicular phase. The inhibin B response to ovulation induction with clomiphene citrate in women with PCOS differs from that in normo-ovulatory women taking the antioestrogen. Women with PCOS who over-respond to ovulation induction with injected FSH in a 'low-dose' step-up protocol' and recruit multiple follicles have significantly higher concentrations of pre-treatment inhibin B than PCOS subjects who do not.     

The role of inhibin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder which, in its severest manifestations, is associated with anovulation, hyperandrogenism and metabolic imbalance. The biochemical markers for the condition can include a significantly raised LH:FSH ratio and a raised testosterone concentration, indicating a derangement of the hypothalamo-pituitary-ovarian axis which may be primary or secondary to a primary ovarian pathology. The bioactive inhibins are heterodimeric glycoproteins consisting of α-βA (inhibin A) and α-βB (inhibin B) subunits. They play an endocrine role in co-regulating (with oestradiol) the suppression of FSH during the late follicular and luteal phases of the ovarian cycle and they are implicated in intraovarian paracrine signalling. Inhibin B, which is the predominant form in small pre-ovulatory follicles, increases in concentration from early in the follicular phase to reach a peak coincident with the onset of the decrease in FSH which forms the basis of the pattern of mono-ovulation seen in normoovulatory women. Several unique features of the dysovulation of women with PCOS, namely their failure to recruit and develop a dominant follicle despite having ‘normal’ concentrations of endogenous FHS, the raised LH:FSH ratio and their exquisite sensitivity to exogenous FSH injections, may be explained by their significantly higher inhibin B concentrations. Studies into inhibin B parameters in women with PCOS demonstrate that women with anovular PCOS have significantly higher concentrations of circulating inhibin B and that they lack the pulsatile pattern of secretion that can be detected in normo-ovulatory women during the mid-follicular phase. The inhibin B response to ovulation induction with clomiphene citrate in women with PCOS differs from that in normo-ovulatory women taking the anti-oestrogen. Women with PCOS who over-respond to ovulation induction with injected FSH in a ‘low-dose’ step-up protocol’ and recruit multiple follicles have significantly higher concentrations of pre-treatment inhibin B than PCOS subjects who do not.     

Do basal inhibin A and inhibin B levels have value in the diagnosis of polycystic ovary syndrome?

In the present study we aimed to investigate whether basal inhibin A and B levels in women with polycystic ovary syndrome (PCOS) would be used in diagnosis of the condition. Forty women with PCOS and 40 women with normal cycles (control group) were evaluated. There was no statistically significant difference in mean age and mean body mass index between the two groups (p > 0.05). Serum levels of inhibin A and B, follicle-stimulating hormone (FSH), luteinizing hormone and total testosterone, and total ovarian volume, were determined in the PCOS group and the control group on day 3. In the PCOS group, total follicle number was obtained by counting follicles of diameter > or =2 mm in both ovaries. Results were evaluated using Student's t test, Pearson correlation and regression tests. There was no significant difference in mean basal inhibin A or inhibin B levels between the two groups. Basal inhibin B levels showed a statistically significant negative correlation with basal FSH levels and a positive correlation with total follicle number in the PCOS group (p < 0.05 and p < 0.01, respectively). We conclude that basal inhibin A or B levels cannot be used in the diagnosis of PCOS.     

Revelation of a polymicrocystic ovary syndrome after one month's treatment by pulsatile GnRH in a patient presenting with functional hypothalamic amenorrhea

Polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea (HA) are the most frequent causes of endocrine infertility, but their association is an uncommon occurrence. We report the case of a 28-year old woman suffering from infertility and amenorrhea. Her weight was normal (BMI = 19) and she had no hirsutism. She self-reported food restriction and a 10 kg weight loss 5 years ago, concomitant with the onset of amenorrhea. At the initial evaluation, the patient was considered as having HA due to food restriction. At ultrasonography, ovaries were small and multifollicular (right and left area: 2.2 and 2.5 cm(2), respectively; number of cysts 2-9 mm in diameter: 15 and 12, respectively), and no stromal hypertrophy was noted. She has been treated for 1 month by intravenous pulsatile GnRH administration. Although the doses were increased from 5 to 15 microg/pulse every 90 min, no E2 response and no follicular development were observed. Hormonal re-evaluation revealed normal levels of serum LH, FSH and androgens, and a normal LH/FSH ratio. However, a typical aspect of PCO was found at ultrasound (right and left area: 6.5 and 5.5 cm(2), respectively, and more than 15 small cysts arranged peripherally around an increased central stroma in each ovary). The treatment has been then switched to hMG, using the low dose step-up regimen and starting with 75 U/day. In the absence of response after 2 weeks, the dose was increased to 112.5 U/day and a multifollicular reaction occurred, leading to cancellation. In conclusion, we hypothesize that this patient had a "hidden" PCOS when she was hypogonadotrophic and that it developed very rapidly after restitution of a normal gonadotropin level under exogenous GnRH. This occurred despite a low insulin level, showing that hyperinsulinism is not a prerequisite for the development of PCOS in every case.     

Ovarian hyperstimulation in polycystic ovary syndrome during therapy with leuprolide acetate

Continuous exposure to GnRH eliminates the pituitary as a source of gonadotropins and may have direct suppressive effects on the ovary. A woman with PCO syndrome received leuprolide acetate (1 mg/d SC) for 4 weeks before and simultaneously with hMG stimulation. Human chorionic gonadotropin (5,000 IU) was administered IM on the 8th day of hMG therapy. There were 10 follicles greater than 15 mm and a polycystic appearance to the ovaries with 25 follicles measuring less than 10 mm. The serum E2 concentration was 2,280 pg/mL. She developed severe ovarian hyperstimulation and required hospitalization for 12 days for fluid management. A viable intrauterine pregnancy was present. Four weeks of pretreatment with leuprolide did not prevent hyperstimulation in the presence of an intrauterine pregnancy.     

Ovarian failure without gonadotropin elevation in a patient with post-traumatic isolated hypogonadotropic hypogonadism

A woman with secondary amenorrhea following head trauma showing isolated gonadotropin deficiency of hypothalamic origin did not respond to massive doses of hMG therapy (11 250 IU daily dose). Ovarian biopsy showed the absence of follicles, despite persistently low FSH levels. In this case the occurrence of premature ovarian failure was only suspected from the lack of response to hMG and diagnosed by ovarian histology.     

Familial 46,XX gonadal dysgenesis

Two sisters, ages 18 and 25, presented with primary amenorrhea and underwent clinical, hormonal, cytogenetic, and pathologic evaluation. Both were of normal stature and lacking of somatic stigmata. Both patients had normal 46,XX karyotype on peripheral blood. Streak gonads were seen in both patients and a rather scanty number of primordial follicles was found in one patient. FSH, LH, and urinary estrogens were consistent with streak gonad syndrome. Autosomal recessive inheritance has been suggested in familial aggregates with XX gonadal dysgenesis.