Ovarian follicular apparatus and hormonal parameters in patients with primary and secondary amenorrhea.

Correlation between ovarian follicular apparatus and hormonal parameters such as serum gonadotropin and urinary estrogen levels was investigated in patients with primary and secondary amenorrhea. Serum gonadotropin levels were elevated in amenorrheic patients without ovarian follicles or with follicles of low developmental stage and pituitary responsiveness to LH-RH in these patients were marked compared with patients with follicles of high developmental stage or normal ovulating women in the follicular phase of the menstrual cycle. The 24-hour urinary excretion of total estrogens was low in patients without follicles or with follicles of low developmental stage and ovarian responsiveness to exogenous gonadotropins was quite low in comparison with patients with highly developed follicles or normal control subjects. Thus, serum gonadotropin and urinary estrogen measurements and LH-RH and gonadotropin loading tests are diagnostic of the presence or absence and the state of development of ovarian follicles in the diagnosis and treatment of primary and secondary amenorrhea.     

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.     

Diagnostic role of inhibin B in resistant ovary syndrome associated with secondary amenorrhea

To report two rare cases of gonadotropin-resistant ovary syndrome associated with secondary amenorrhea and normal levels of inhibin B.Case report.Two university teaching hospitals.Two women presenting with secondary amenorrhea and infertility. The control group for the inhibin B levels consisted of 30 cycling women of reproductive age.Medical history, physical examination, laboratory data, histologic findings, and IVF results.Diagnosis and treatment of resistant ovary syndrome.Case 1 was a 25-year-old woman with secondary amenorrhea and primary infertility. She had high serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (62 pg/mL). Karyotype was 46,XX, and ovarian biopsy showed primordial follicles with oocytes. Administration of GnRH analogue with hMG for 15 days did not affect E(2) levels. She had a successful pregnancy with IVF using donor oocytes. Case 2 was a 24-year-old woman with secondary amenorrhea. She had elevated serum levels of FSH and LH, low E(2) levels, and normal inhibin B levels (57 pg/mL). Karyotype was 46,XX and ovarian biopsy showed primordial follicles. Administration of GnRH analogue with hMG for 12 days did not affect E(2) levels. Both women were given estrogen-progestin replacement therapy.Inhibin B has a diagnostic role in women with gonadotropin-resistant ovary syndrome associated with secondary amenorrhea. A review of the literature confirms the uniqueness of the diagnostic role of inhibin B in these cases.     

不孕患者卵巢功能早衰病因分析

目的:探讨不孕症患者卵巢功能早衰(POF)的病因特点。方法:回顾分析符合卵巢功能早衰诊断标准的不孕症121例的病因,其中有染色体结果者45例,对其进行详细分析。结果:(1)121例不孕的卵巢功能早衰患者中,有明确发病原因者14例(11.57%),其中行卵巢手术2例,服用卵巢毒性药物或有毒物接触史3例,染色体核型异常9例;(2)原发闭经6例,继发闭经115例,原发不孕95例(78.51%),继发不孕26例(21.49%),父母系近亲结婚3例。结论:卵巢功能早衰病因中染色体异常比例较高,对卵巢功能早衰患者行染色体检查很有必要;对不孕的POF患者开展遗传学研究具有重要的意义。     

Twin gestation two years after the diagnosis of premature ovarian failure in a woman on hormone replacement therapy. A case report

BACKGROUND: Premature ovarian failure (POF) is a condition causing amenorrhea, hypoestrogenism and elevated gonadotropins before the age of 40 years and affects around 10% of patients seeking evaluation for secondary amenorrhea. Although it is a rare event, pregnancy has occurred in this group of patients. CASE: A successful twin pregnancy occurred in a 30-year-old woman two years after the diagnosis of POF. Cyclic hormone replacement therapy was initiated after the diagnosis. Twenty-one months later, ultrasound revealed an 8-week twin pregnancy. Two healthy infants, a boy and a girl, were delivered at 36 gestational weeks. CONCLUSION: There are no clinical or laboratory features that unequivocally establish the diagnosis of POF. Neither high levels of gonadotropins nor an ovarian biopsy with rare follicles excludes the possibility of pregnancy. Even though pregnancy in patients with POF is very unlikely, patients should be informed of this possibility, and a contraceptive method should be considered if pregnancy is not desired.     

Converting an IVF cycle to IUI in low responders with at least 2 follicles

OBJECTIVE: To assess the utility of transforming an in vitro fertilization (IVF) cycle with low ovarian response to an intrauterine insemination (IUI) cycle. STUDY DESIGN: The inclusion criteria were women undergoing IVF because of idiopathic infertility, a mild to moderate male factor or IUI failure, with at least 1 normal, patent tube. When ovarian stimulation produced 2-4 follicles > or = 18 mm, the IVF cycle was converted to an IUI cycle. In cases with 4 follicles, estradiol had to be < 800 pg/mL. A total of 57 cycles were analyzed. RESULTS: The clinical pregnancy rate (PR) was 14.0% (8/57) in IVF cycles converted to IUI vs. 17.3% in our general IUI population (240/1,389). Converted cycles were associated with longer ovarian stimulation and with lower estradiol levels and less mature follicles than was IUI in the general population. There was a trend toward higher PR in women starting ovarian stimulation with 225 IU of gonadotropins (18.2%) than in those starting with higher doses (8.6%) (P > .05). CONCLUSION: In IVF low responders with at least 1 normal, patent tube when 2-4 follicles are observed, converting the IVF cycle to an IUI cycle yields a PR of 14.0%. This option should be considered in the management of low responders, especially those not stimulated with high doses of gonadotropins.     

Binovular follicles in the adult human ovary

The human ovary may contain binovular or polyovular follicles at birth, but they are unusual later in life. Binbovular follicles were found in bilateral ovarian biopsies from a patient with primary amenorrhea who had been treated with exogenous gonadotropins. The fine structural morphology of these follicles has shown that both oocytes were in the resting meiotic prophase, that their respective vitelline bodies faced each other across the intervening plasma membranes, and that the adjacent oocytes made mutual contacts similar to those found between granulosa cells and oocytes. From the appearance of the multivesicular bodies in nearby stromal fibroblasts it is suggested that these follicles had formed by fusion of two adjacent primordial follicles by a mechanism similar to the depolymerization of the ground substance in the apex of the Graafian follicle that leads to ovulation.     

月经紊乱患者的细胞遗传学分析

目的 分析原发闭经、继发闭经及月经稀发患者的染色体核型,探讨性染色体异常对性腺发育的影响。方法 将176例患者分为两组,其中82例原发闭经组,94例继发闭经及月经稀发组。每例行外周血培养,制片及G显带,并行染色体核型分析。结果 176例患者发现性染色体异常38例,异常检出率为29.6％(38/176),其中原发闭经组33例,异常检出率为40.2％(33/82);继发闭经及月经稀发组检出性染色体异常5例,异常检出率为5.3％(5/94);两组异常检出率差异有显著性(P<0.05)。性染色体异常大体上分为三大类:含Y染色体(15例),X染色体数目异常(18例),X染色体结构异常(5例),嵌合体均以45,X系为主,共10例。结论 两条完整的染色体是女性性腺发育及正常卵巢功能所必须,性染色体异常是原发闭经的主要原因之一,常规细胞遗传学检查是必要的;继发闭经及月经稀发也不应忽视此项检查。     

Etiology, clinical features and prognosis in secondary amenorrhea.

A clinical investigation of 356 patients with secondary amenorrhea revealed that 95% of patients with postpill amenorrhea and 56% of patients with anorexia nervosa recovered in 6 years. The corresponding recovery rates for patients with psychogenic amenorrhea and amenorrhea following self-induced weight loss were 72% for both groups, and in patients with the amenorrhea-galactorrhea syndrome and idiophatic functional amenorrhea the recovery rates at 6 years were 64 and 61% respectively. Unlike the other groups with functional amenorrhea, patients with the amenorrhea-galactorrhea syndrome had impaired ovarian responsiveness to exogenous gonadotropins. Bromocriptine treatment resulted in disappearance of the galactorrhea and restoration of the menses and/or ovulation in nine of 18 patients; of these three became pregnant. The effect of bromocriptine did not persist for long after treatment ceased, and permanent recovery was recorded only in four patients. The group with functional amenorrhea included 34 patients who wished to become pregnant. Gonadotropin treatment was successful in 20 patients, clomiphene-hCG in two, tamoxifen in two, bromocriptine in two, and combined bromocriptine and clomiphene in one. Thus, the overall pregnancy rate in patients with functional amenorrhea was 79%. The groups with ovarian amenorrhea inclutients with assumed ovarian failure responded to large doses of exogenous gonadotropins by ovulation and three became pregnant. Ovarian wedge resection was ineffective in all five cases with polycystic ovaries, but two patients became pregnant after treatment with clomiphene and chorionic gonadotropin, and one with exogenous gonadotropins.     

Growth hormone deficiency as the only identifiable cause for primary amenorrhea

Background: There is much evidence that growth hormone plays an important role in the development and function of the reproductive system of both males and females. Growth hormone exerts its effects on the ovarian follicular cycle directly or by local production of insulin-like growth factor 1 (IGF-1). It is known that growth hormone deficiency during childhood may delay pubertal development, but there is limited data about primary amenorrhea in GH-deficient girls with sufficient stimulated gonadotropin levels.Methods: Case series.Results: In the evaluation of primary amenorrhea and delayed puberty, 3 cases of adolescent females aged 17-19 years were identified as isolated GH-deficiency. Among the 3 patients, 2 had history of intracranial surgery due to hydrocephalus (shunt operation) or prolactin-secreting pituitary macro-adenoma (transphenoidal surgery, one year before). 17-year-old patient with shunted hydrocephalus and 19-year-old patient with primary amenorrhea showed short statue (< 5%) and delayed bone maturation. The patient undertaken transphenoidal surgery for prolactinoma showed normal height and bone maturation. There was no familial history of delayed puberty. On physical examination, 3 patients showed variable degree of breast development from Tanner stage II to IV without sex-steroid replacement. In sella MRI, small pituitary gland were identified in 2 patients with short statue and delayed bone maturation. All of the 3 patients underwent combined pituitary function test. After insulin-induced hypoglycemia, peak growth hormone levels of the 3 patients were 0.08, 1.4 and 1.4 ng/ml and were compatible with growth hormone deficiency. Peak LH after intravenous gonadrelin (FACTREL) were 19.0 to 56.1 mIU/ml and LH % responses were 217 to 1100% and were hence defined as not being gonadotropin deficiency. Other anterior pituitary functions were normal in all of the 3 patients.Conclusions: We found isolated growth hormone deficiency as the only identifiable cause for primary amenorrhea in three patients with sufficient gonadotropins secretion. These findings suggest a complementary role of GH to gonadotropins in the occurrence of menarche.     

The hormonal micromilieu and oocyte status in the stimulated in vitro fertilization cycle

FSH, LH, PRL, estradiol-17 beta and progesterone were determined in 651 follicular fluids of 173 patients treated by ovarian stimulation for IVF. The stimulation was performed according to 5 different schemes: clomiphene/HCG, HMG (Pergonal)/HCG, HPG (Anthrogon)/HCG, clomiphene/HPG/HCG, Folistiman (heterologeous pituitary gonadotropin)/HCG. The mean levels of hormones of all follicles of each stimulation scheme were determined and differences between the groups were estimated by Student's t-test and the x-square-test. Additionally, in a hierarchy of follicles made depending on the follicular fluid volume the hormonal levels were compared between different rank numbers of one stimulation group and between different groups of stimulation. The maturation of oocytes judged by a maturation index and their ability for cleavage in culture after insemination was investigated in relation to the hormonal content of the follicular fluid. Stimulation by gonadotropins (Pergonal, Anthrogon, Folistiman) led to an decreased mean level of follicular steroids. This was related to an increased part of follicles poor in steroids after stimulation by gonadotropins. Within the follicular population follicles stimulated by clomiphene/HCG had a reduction of the levels of estradiol in higher rank numbers, but there were no clear evidences for such a reduction in the other stimulated groups. In all stimulation groups a significant reduction of progesterone levels was observed in higher rank numbers of follicles. Oocytes with a high maturation index mainly derived from follicles rich in progesterone. After insemination, development of oocytes in culture was compatible even with very high or low levels of hormones. There was no relation of the levels in FSH and LH to cumulus expansion and levels of estradiol of the follicular fluid. There was also no clear correlation between the levels of prolactin in follicular fluid and the cleavage rate.     

Assessment of the role of laparoscopic ovarian biopsy.

Seventy-four patients with either endocrine and/or infertility problems were subjected to laparoscopic ovarian biopsy. The patients were divided into 4 categories: those with primary amenorrhea, secondary amenorrhea, ovarian androgenic hyperfunction, and infertility. The results were critically examined to evaluate the procedure in the investigation and treatment of each of these disorders. It was concluded that laparoscopic ovarian biopsy is most helpful in primary amenorrhea but justified in secondary amenorrhea only if a histologic diagnosis of premature ovarian failure is though to be essential. Patients with ovarian androgenic hyperplasia should not be candidates for the procedure as the laparoscopic appearance of the ovaries offered equally valuable information and the hazards of biopsy in this particular group of patients outweighed its diagnostic and therapeutic usefulness. The ovarian biopsy offered very little benefit for the infertility patients.     

Ovarian sex cord stromal tumors with annular tubules: a report of 6 cases

Six patients with ovarian sex cord stromal tumor with annular tubules (SCTAT) were diagnosed and treated from 1968 through 1988, accounting for 6% of a total of 99 cases of ovarian sex cord stromal tumors admitted during the same period. Of these, 3 were operated on for the first time and 3 were recurrent cases referred from other hospitals. The menstrual disturbance was characterized by menometrorrhagia followed by sustained amenorrhea. Glandular atrophy and decidual change of stromal were observed in 3 of the 4 endometrial samples available for histologic examination. Serum hormone assays carried out in 2 cases revealed elevated levels of both estradiol and progesterone. The primary tumor was unilateral in 5 cases and bilateral in one the recurrent tumors were exclusively retroperitoneal and ipsilateral to the primary ovarian tumors. In these cases, lymphatic metastasis was also observed in the ipsilateral pelvic lymph nodes. Complete and sustained remission has been achieved in all 3 patients receiving primary surgery by unilateral salpingo-oophorectomy. After removal of the metastatic tumors in 3 recurrent cases, 2 have survived with residual diseases for 2 and 9 years respectively and one died 4 years after the secondary surgery.     

Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: a European series and a proposal for prevention

Severe ovarian hyperstimulation syndrome (OHSS) was recorded in 8 of 413 patients after the use of gonadotropin-releasing hormone agonists (GnRH-a) associated with gonadotropins for in vitro fertilization. Seven of the 8 patients were pregnant. Common factors associated with the development of OHSS were high serum estradiol values on the day of ovulation induction and many follicles greater than or equal to 12 mm. Based on this experience, a new therapeutic schedule was used in a group of 10 patients who, after GnRH-a and gonadotropin stimulation, were judged to be at high risk of OHSS on the day of human chorionic gonadotropin (hCG). No hCG was administered and gonadotropins were stopped. The administration of GnRH-a was continued and, after a further period of pituitary desensitization, follicular stimulation was recommended with a lower dose of gonadotropins. No cases of OHSS occurred and 3 patients became pregnant.     

The scope and limitations of laparoscopic ovarian biopsy in the diagnosis of secondary amenorrhea.

Laparoscopically directed ovarian biopsy has been evaluated in 39 cases of secondary amenorrhea. The definite diagnosis was achieved in 29 cases. In 10 cases, ovarian histopathology alone was insufficient, and the estimations of gonadotropins were essential for the final diagnosis. The scope and limitations of this procedure for the differential diagnosis of premature ovarian failure and hypothalamic-pituitary lesions are discussed.     

A novel mutation in exon8 of the follicle-stimulating hormone receptor in a woman with primary amenorrhea

The FSH receptor (FSHR) gene mutation are rare, but recently have been detected in several cases with primary amenorrhea. We report a 25-year-old female who had primary amenorrhea, moderately developed secondary sex characteristics and normal sized ovaries with small antral follicles. Her ovaries reacted slightly to clomiphene citrate therapy; they did not react to the ordinary dose of human menopausal gonadotropin (hMG) (150 IU/day × 9 days), but did react to high-dose hMG (300 IU/day × 6 days) treatment. These ovarian responses to hMG stimulation suggested an FSHR dysfunction of her ovaries. We extracted genomic DNA and analysed FSHR gene sequence after we obtained the written informed consent from the patient under the approval by the Ethics Committee of Yamaguchi Grand Medical Centre and the Yamaguchi University School of Medicine. Direct sequencing revealed a heterozygous mutation 662T?>G resulting in the substitution of valine for glycine at position 221 in exon8 of the FSHR extracellular domain, which was also confirmed by the PCR-RFLP method. The sequencing results also showed two SNPs, 919G?>A (Ala307Thr) and 2039G?>A (Ser680Asn), in exon10. A novel mutation in exon8 of FSHR was identified in a woman with primary amenorrhea whose ovaries reacted to high-dose hMG treatment.     

Premature ovarian failure

The diagnosis of premature ovarian failure was made in 35 women (ages 17 to 40) with increased concentrations of follicle-stimulating hormone and luteinizing hormone. Three had primary amenorrhea, 29 had secondary amenorrhea (less than one to 15 years), and three had irregular menstrual intervals of less than six months. Symptoms and signs of estrogen deficiency were present in fewer than 50% of these women and were not helpful in distinguishing the different causes of ovarian failure. Six of these women had an autoimmune disorder associated with ovarian failure. Thirteen of 16 women had a normal 46,XX karyotype, and five of 14 women who had an ovarian biopsy had a specimen that contained follicles with oocytes. Two women conceived after they developed ovarian failure and while taking cyclic estrogen and progestin.     

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。     

Results of human menopausal gonadotropin therapy at the Boston Hospital for Women (1979-1981)

To evaluate our results with induction of ovulation with human menopausal gonadotropins, we reviewed our experience from 1979 to 1981. Twenty-two women and 89 treatment cycles were evaluated. The patients were assigned to group 1 (amenorrhea, low FSH and LH, and no evidence of endogenous estrogens, as indicated by lack of withdrawal bleeding after medroxyprogesterone acetate) or group 2 (amenorrhea, with normal gonadotropins and evidence of endogenous estrogens by progestin withdrawal bleeding). Three patients underwent HMG therapy for inadequate luteal phase; none of them became pregnant. All patients from group 1 became pregnant (8/8), and 45% (5/11) of patients from group 2 became pregnant. The difference in pregnancy rates is significant (P less than .05). The cumulative pregnancy rate for each group was calculated by the life table method. All the cases of multiple gestation (three) came from group 1, and all the cases of ovarian hyperstimulation (five) came from group 2. In summary, in our experience patients from group 1 had a higher pregnancy rate and a greater incidence of multiple gestation than patients in group 2, who had a greater chance of developing ovarian hyperstimulation.     

"Lowresponder" in der In-vitro-Fertilisation

Premature ovarian failure is defined as loss of ovarian function before the age of 40. The etiology is usually heterogenous. The prevalence of premature menopause is 1% in women before the age of 40 and 0.3% before the age of 35. Several laboratory and stimulation tests are able to quantify the ovarian reserve of follicles, such as day 3 serum FSH, inhibin B, clomiphene challenge test and GnRH stimulation tests. Diminished ovarian reserve is usually associated with a low ovarian response to exogenous administration of gonadotropins. Low responders in in-vitro fertilization, intracytoplasmatic sperm injection and related procedures are defined as cycles and patients where less than 4 preovulatory oocytes can be retrieved on oocyte pick-up. There are several studies looking at the time of onset of natural menopause after ovarian hyperstimulation with low or no response. In summary, it has been shown that in the majority of women with low ovarian response, there will be progressive loss of ovarian function within a short period of time and onset of menopause at an earlier age than in a control group of women with normal ovarian response to exogenous gonadotropins. Therefore, a cycle of ovarian hyperstimulation with low response despite increased dose of exogenous FSH and prolonged duration of administration should be interpreted as an early and first indicationof impending ovarian failure.