Ovarian pathology associated with insulin resistance and acanthosis nigricans.

Insulin resistance and the skin lesions of acanthosis nigricans are not commonly seen by the gynecologist, but the ovarian pathology that can be associated with insulin resistance and acanthosis nigricans is well known. The clinical course of disease in a patient with virilization-amenorrhea associated with insulin resistance and acanthosis nigricans is presented to illustrate the association. Hyperthecosis was the ovarian pathology demonstrated; testosterone levels were in excess of 400 ng/gl. Postoperative testosterone levels were normal at 62 ng/dl. Additional ovarian pathology reported in association with insulin resistance and acanthosis nigricans includes polycystic ovary disease alone, in association with stromal luteomas, or with bilateral dermoid cysts. Furthermore, masculinizing ovarian neoplasms such as hilar cell tumors have been reported in association with ovarian hyperthecosis. When evaluating patients with androgen excess, it would be worthwhile to keep in mind the association with abnormal carbohydrate metabolism and acanthosis nigricans.

Recurrent anaphylactic reaction to intraperitoneal dextran 75 used for prevention of postsurgical adhesions.

The use of intraperitoneal dextran at the conclusion of a gynecologic surgical procedure to prevent postoperative adhesions has increased recently. Although anaphylactic reaction to dextran administered intravenously is well documented, the authors report such a reaction after intraperitoneal administration. The delayed appearance and the continuation of the undesirable reaction until the intraperitoneal reservoir of dextran was removed by means of a culdocentesis are noteworthy. Physicians should be alerted to this potential complication.

Luteal phase deficiency and infertility: difficulties encountered in diagnosis and treatment.

Uncertainty concerning the importance of luteal phase defects as a cause of female infertility is closely related to problems of diagnosis. A study was undertaken of the consistency of the parameters used in daignosing luteal phase deficiency in 14 patients; results of randomized treatment regimens were also compared. Specific diagnostic criteria utilizing the basal body temperature (BBT) chart, endometrial biopsy, and progesterone levels were used. Prolactin and luteinizing hormone levels were measured at the time of progesterone determinations. Of the 29 cycles studied, only one third showed consistent abnormalities in BBT chart, endometrial biopsy, and progesterone levels. Discrepancy between the endometrial biopsy and the progesterone level occurred in at least 50% of all cycles studied. Prolactin levels were elevated in only 1 patient, suggesting a minor role for altered prolactin metabolism in luteal phase deficiency. Randomized treatment with progesterone vaginal suppositories, clomiphene citrate, and no treatment resulted in pregnancy in 5 of 14 patients (36%).

Natural oocyte retrieval with intravaginal fertilization: a simplified approach to in vitro fertilization.

To simplify in vitro fertilization (IVF), we have combined natural-cycle oocyte retrieval with intravaginal fertilization. Our subjects ranged in age from 28-40 years and were monitored by ultrasound and steroid hormone levels. Oocyte retrieval was carried out under vaginal ultrasound-guided aspiration 32-36 hours after the onset of the LH surge. The oocyte was identified and placed in a sealed capsule containing culture media and sperm. The capsule, in a sealed cryoflex envelope, was placed in the woman's vagina and removed 42-48 hours later. The embryo was then isolated and transferred to the woman's uterus. Fifty-one retrieval cycles were attempted in 45 patients. At least one oocyte was retrieved in 88% of cycles, and fertilization was achieved in 84% of oocytes. Of the five clinical pregnancies (10%), four have delivered and one is ongoing. The cost of this procedure is approximately one-third that of standard IVF. The advantages of our method are the elimination of the use of gonadotropins, the simplicity of monitoring and oocyte retrieval, and the lack of need for expensive laboratory equipment. Natural oocyte retrieval with intravaginal fertilization may prove appropriate for those women requiring IVF who fear multiple pregnancies, have side effects from controlled ovarian hyperstimulation, or cannot afford standard IVF.

Ovulation timing by luteinizing hormone assay and follicle puncture.

Follicle puncture with oocyte harvest or ovarian inspection for an early corpus luteum was carried out in 13 patients undergoing laparoscopy during routine infertility workup. Laparoscopies were carried out 28 to 38.5 hours after the onset of the luteinizing hormone surge so that there would be a concentration of data around the expected time of ovulation. A rapid luteinizing hormone assay was used. All the corpora lutea were found 38 hours or more after the onset of the luteinizing hormone surge. Between 28 and 38 hours after the onset of the surge, intact follicles containing oocytes in various stages of maturation were found.

Bromocriptine response in normoprolactinemic patients with polycystic ovary disease: a preliminary report.

Recent work has suggested that a central deficiency or defect of dopamine may contribute significantly to the inappropriate gonadotropin secretion commonly associated with polycystic ovary disease. To evaluate this hypothesis, 2.5 to 5 mg of the dopamine agonist bromocriptine was administered daily to patients with polycystic ovary disease. Prolactin (PRL) levels were normal in all cases and there was no evidence of galactorrhea. All patients had failed to conceive while on clomiphene citrate. Seven patients were treated for a total of nine cycles. Ovulation occurred in four cycles, and two of these patients conceived. In five cycles, no ovulation occurred. Among ovulatory cycles, PRL levels declined, but not to undetectable levels. There was also a periovulatory drop in dehydroepiandrosterone sulfate. Levels of luteinizing hormones rose initially and then dropped to below baseline postovulation. Among anovulatory cycles, PRL fell to undetectable levels and dehydroepiandrosterone sulfate was unaffected. Luteinizing hormone levels rose initially and then dropped slightly. In both ovulatory and anovulatory cycles, follicle-stimulating hormone (FSH) levels remained low. These preliminary data suggest: 1) bromocriptine appears capable of altering gonadotropin secretion in polycystic ovary disease, and 2) variable results on ovulation in polycystic ovary disease may reflect the diverse etiology of the pathophysiology of polycystic ovary disease and/or choosing inappropriate dosages of bromocriptine.

Clinical aspects of the polycystic ovary syndrome.

One hundred and one patients with polycystic ovary syndrome (PCO) were treated during an 11-year interval. Sixty-seven cases were classified as typical PCO with enlarged ovaries of probable ovarian origin (Type I) and 34 as atypical PCO of probable adrenal origin (Type II). Fifty-five patients were treated for anovulatory infertility with clomiphene citrate or other endocrine therapy as indicated. There was a 91% ovulatory response and 51% conception rate from therapy in cases of Type I PCO. In Type II PCO, adrenal suppressive therapy resulted in a 55% ovulatory response. Our data support the concept that anovulation of ovarian origin as seen in PCO Type I responds to clomiphene therapy, while anovulation secondary to adrenal hyperandrogenization should be treated by adrenal suppressive therapy.

Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy.

A study was undertaken to determine the length of time serum beta-subunit of human chorionic gonadotropin (beta-hCG) could be detected following removal of ectopic pregnancy. Seven patients underwent complete removal of trophoblastic tissue by either salpingectomy or partial resection of the involved fallopian tube. Nine other patients had conservative surgical treatment by either linear salpingostomy or fimbrial expression of the fallopian tube. Serum beta-hCG levels were determined serially in all these patients. The results demonstrate that the initial titer of hCG is a significant factor in determining the length of time that it can be detected in the serum postoperatively. In addition, decreasing titers, conforming to the disappearance curve of hCG, as constructed in this study, are a helpful aid in avoiding further surgery in the group of patients who had a conservative removal of the trophoblastic tissue. Finally, the serum clearance of hCG by radioimmunoassay may take at least up to 24 days after surgery.

Diagnostic value of androgen measurements in polycystic ovary syndrome.

A group of 51 women with a diagnosis of polycystic ovary syndrome (PCO) were investigated. They were further classified into PCO Type I and PCO Type II based on clinical and laboratory investigations. Serum levels of unbound (free) and total testosterone, testosterone binding globulin (TBG), and androstenedione were measured in these women and compared with values in normal women. Mean levels of all these steroids were elevated in women with PCO. No difference in adrogen levels was found between women with PCO Type I and PCO Type II. Serum unbound testosterone concentrations correlated better with the presence and severity of hirsutism than did the total testosterone.

Rapid hCG-specific radioimmunoassay for menstrual aspiration.

Fifty-one women with missed periods ranging from 5 to 14 days who suspected a pregnancy underwent an aspiration curettage with a flexible soft-tipped cannula attached to a Karman-type syringe. Sera from these women were measured for human chorionic gonadotropin (hCG) by a rapid 2-hour solid phase radioimmunoassay using an antibody with a specificity for the beta subunit of hCG. The sensitivity and specificity of this assay insured detection of bCG with 100% accuracy at the time of the missed period. Of the 51 women, 33 (64.7%) were found to have hCG in their serum, and 29 (56.8%) had histologic evidence diagnostic of pregnancy.

PIP: Aspiration curettage was performed on 51 women who suspected pregnancy and had missed periods from 5 to 14 days. Sera obtained from the patients were analyzed for human chorionic gonadotropin (HCG) by a rapid, 2-hour solid-phase radioimmunoassay using an antibody with a specificity for the beta subunit of HCG. 33 of the women (64.7%) were found to have serum values ranging from 8 mIU/m1 to 3997 mIU/m1. 29 of the women (56.8%) showed histologic evidence of pregnancy. Generally, more women had HCG in their serum as the number of days following the missed period increased. The test can detect HCG with 100% accuracy at the time of the missed period.

The regulation of follicle growth: some clinical implications in reproductive endocrinology.

OBJECTIVE: To review the literature concerning the regulation of follicle growth, to describe a model for unifollicular ovulation based upon the information gleaned, and to discuss some clinical implications in reproductive endocrinology underscored by this expanding knowledge. DESIGN: Studies relating to follicular growth in lower animals and primates were reviewed. From the most pertinent articles the individual agents playing a significant role in the regulation of follicle growth were identified along with their mechanisms of action. A model for unifollicular development was proposed based upon the results of the review of these studies. Refinements in the management of some clinical problems in reproductive endocrinology were discussed based upon this model. RESULTS: From a review of these studies it appears that in the human and primate menstrual cycle one follicle is selected because it has adequate FSH receptors when plasma FSH levels are high. This follicle becomes dominant despite falling FSH levels because of increased sensitivity of the follicle to FSH brought about by intraovarian growth regulators. CONCLUSIONS: Improved care of patients requiring ovulation induction for differing indications should be possible with this more comprehensive knowledge of natural follicle growth.

The relationship between the pituitary response to luteinizing hormone-releasing hormone and the ovulatory response to clomiphene citrate.

Luteinizing hormone-releasing hormone (LH-RH), at a dose level of 10 mug, was administered intravenously to 31 patients, 9 with oligomenorrhea and 22 with secondary amenorrhea. A serum luteinizing hormone level higher than 45 mIU/ml at 30 or 45 minutes after injection was considered to be a "positive response" to LH-RH. All 9 patients in the oligomenorrheic group and 11 of the 22 patients with secondary amenorrhea had a "positive" response. The patients were then treated with increasing doses of clomiphene citrate until an ovulatory dose was reached. Eight of the nine patients with oligomenorrhea ovulated with doses of up to 150 mg of clomiphene daily for 5 days. Of the 11 patients in the group with secondary amenorrhea who had a "positive" response to LH-RH, 7 ovulated at a dose of 150 mg (or less) of clomiphene citrate, while only 1 of the 11 patients with a "negative" response ovulated while receiving a similar dosage of clomiphene. These results suggest that a simplified LH-RH test might be of value in selecting the level of therapy for ovulation induction.

Artificial insemination homologous and its role in the management of infertility.

Fifty-seven cases of homologous artificial insemination (AIH) were reviewed as well as the reason for performing the insemination. Three patients had AIH because of impotence, and two conceived. Twenty-nine patients whose husbands had sperm counts of less than 40 million/ml had AIH combined with split ejaculates, and seven (24.1%) became pregnant. Twenty-five patients had AIH because of persistent, unexplained, poor postcoital tests despite a normal semen picture, and eight (32%) became pregnant.

PIP: 57 cases of homologous artificial insemination (AIH) among patients with at least 2 years of involuntary infertility and a minimum of 4 treatment cycles were reviewed. Patients were classified into 4 groups by indication for AIH: 1) faulty delivery with a fertile semen specimen; 2) oligospermia (sperm count 20 million/ml); 3) subfertile semen (sperm count 20-40 million/ml with at least 35% motility after 6 hours); and 4) persistent, unexplained, poor postcoital tests with a negative spermagglutination test and husbands with a fertile semen specimen. Female partners were further classified according to whether another infertility related factor was (group B) or was not (group A) present. 17 patients (29.8%) conceived, for a total of 18 pregnancies. There were 15 term deliveries and 3 spontaneous abortions. An average of 3.8 treatments was required to achieve pregnancy. Overall, 52.9% of the pregnancies were achieved by the 4th treatment cycle and 76.4% by the 5th. 8 (27.5%) of the 29 women in group A and 9 (32.1%) of the 28 women in group B became pregnant. 2 of the 3 cases receiving AIH because of faulty delivery of semen conceived. In cases in which there was oligospermia and no female factor, 4 of 12 women (33.3%) became pregnant when split ejaculate was used. 3 of the remaining 8 patients had artificial insemination with donor semen and all conceived. No pregnancies occurred among 5 group A women in whom AIH split ejaculate was performed due to subfertile semen; however, 2 of 2 group B patients in this category conceived. If all patients with sperm counts 40 million/ml are combined, 4 of 17 patients (23.5%) in group A and 3 of 12 patients (25%) in group B became pregnant. 3 of 10 (30%) group A women and 5 of 15 (33.3%) group B women became pregnant where there were unexplainedly poor postcoital tests. Overall, 5 of 22 (22.7%) normal and abnormal women whose partners had oligospermia and 2 of 7 (28.5%) whose husbands had sperm counts between 20-40 million/ml conceived, for a total rate of 24.1%. On the basis of these pregnancy rates, AIH with split ejaculates appears to be a worthwhile procedure in oligospermia and subfertility. The overall 32% pregnancy rate in patients with poor postcoital tests but normal sperm counts suggests that AIH is a useful mode of treatment in these cases as well.

Sixteen years' experience with therapeutic donor insemination.

Therapeutic donor insemination was performed in 107 "normal" patients, using an intracervical technique and two inseminations per cycle on alternate days. Seventy-seven patients became pregnant (71.9%), and 103 conceptions occurred. Of these pregnancies, 72.8% occurred in the first 3 months of treatment and 95.2% occurred within 6 months. The spontaneous abortion rate was 18.4% The number of females born was slightly higher (54%) than the number of males (46%). There was one complication in this series (acute pelvic inflammatory disease), most probably due to inadvertent intrauterine (endometrial) insemination.

Emotional aspects of infertility.

PIP: The psychologic aspects of infertility in men and women are reviewed, neuroendocrinologic factors thought to affect reproduction physiologically are described, and awareness of the stresses that infertility places on a couple's relationship is encouraged. Studies have found infertile women to be more neurotic, dependent, and anxious than fertile women, experiencing conflict over their femininity and fear associated with reproduction. In contrast to these reports, a double blind study could not determine the difference in the psychologic makeup of women who were infertile because of demonstrated somatic causes and those women in whom no somatic cause could be found and who were considered infertile on an emotional etiologic basis. Other studies have similarly come to negative conclusions regarding the relationship between psychologic factors and infertility. The 1st set of studies failed to consider the stress that infertility itself places on the couple. Emotional factors may negatively affect fertility in the male. Up to 10% of infertile males have had improvement in their semen analysis after cessation of all treatment for a prolonged period of time. The concept that emotional stress might lead to oligospermia was further supported in a report describing testicular biopsies obtained from men awaiting sentencing after raping and impregnating women. A more obvious effect of the emotional stress infertility places on the male is the occurrence of impotence. It has been estimated that up to 10% of infertilty may be partially or completely explained on the basis of male sexual dysfunction. The gradual unraveling of the complexities of neuroendocrinology have permitted increased understanding of the role that stress might play in infertility. Catecholamines, prolactin, adrenal steroids, endorphins, and serotonin all affect ovulation and in turn are all affected by stress. Such stress might result from infertility or habitual abortion. Infertility is frequently perceived by the couple as an enormous emotional strain, and counseling may prove helpful as a part of the initial infertility evaluation, an adjunctive measure during treatment, or a final measure to help patients cope with acceptance of their infertility problem. Although statistical evidence is overwhelmingly against the relationship of adoption and subsequent conception, it does appear that a small percentage of patients do achieve pregnancy following adoption. Possibly this can be explained by a reduction in stress, and subsequently, alterations in the neuroendocrinologic characteristics of the infertile couple.^ieng

The role of counseling in infertility.

Sixty-two couples with infertility received infertility counseling along with the infertility investigation and treatment. At the end of the study a questionnaire was sent to all patients in order to evaluate the incidence of psychologic symptoms associated with their infertility and their response to counseling. The study confirmed the presence of a high incidence of emotional symptomatology in the self-selected patients. It showed that male partners are also affected, but less so. Finally, it has demonstrated that infertility counseling serves to enhance the quality of life in many patients who have become the victims of their "infertility crises."

Ovulation induction in polycystic ovary syndrome with urinary follicle-stimulating hormone or human menopausal gonadotropin.

In patients with polycystic ovarian disease (PCOD) ovulation was induced with a combination of human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) or with urinary follicle-stimulating hormone (uFSH; Metrodin, Serono Laboratories, Inc., Randolph, MA) alone. hMG/hCG and uFSH resulted in comparable rates of ovulation and conception in patients with PCOD. The incidence of hyperstimulation and the potential for multiple births appeared lower with uFSH. The fact that endogenous ovulation did not occur in hMG patients who had hCG withheld or in 3 of the 11 uFSH patients who had preovulatory levels of estradiol and follicles greater than 15 mm may imply that these similarly derived gonadotropins in some instances block endogenous ovulation.

Luteal phase serum progesterone levels after follicle aspiration with and without clomiphene citrate treatment.

Peripheral serum progesterone (P) levels were studied on random days after the spontaneous luteinizing hormone (LH) surge in women who underwent follicle aspiration. Comparisons were made with ovulatory women treated with clomiphene citrate (CC) undergoing follicle aspiration and women undergoing midcycle general anesthesia and laparoscopy without follicle aspiration. There were no differences in mean P levels in the group of women who underwent follicle aspiration, compared with the group who did not. Women treated with CC showed higher P levels during the first week of the luteal phase. During the second week of the luteal phase P levels were similar, regardless of follicle aspiration alone or in combination with CC use. In the groups not using CC, more individual women had P levels less than 10 ng/ml. Follicle aspiration does not appear to reduce luteal phase P levels in groups of patients in the natural menstrual cycle or receiving CC. Some individual patients, however, appear to be at risk for lower P levels, particularly after follicle aspiration or general anesthesia, in the natural cycle.

Induction of timed ovulation with synthetic luteinizing hormone-releasing hormone in women undergoing insemination therapy. I. Effect of a single parenteral administration at midcycle.

Synthetic LH-RH was administered by various routes to 19 patients during 37 treatment cycles in an attempt to trigger ovulation in association with insemination therapy. Thirty-five cycles were ovulatory; four pregnancies occurred, but two of them ended in spontaneous abortion. In 20 cycles, the hyperthermia response occurred one to three days after LH-RH administration, suggesting that ovulation occurred as a direct consequence of administered LH-RH. Low levels and delayed peak secretion of progesterone were found in two patients who had serial progesterone determinations during the luteal phase after LH-RH administration. Ovulation timing with LH-RH appears feasible, but efforts to ensure the availability of a mature follicle are required.

PIP: The efficacy of synthetic luteinizing hormone-releasing hormone (LH-RH) in the induction of ovulation was evaluated during 37 treatment cycles in 19 women receiving artificial insemination therapy. 100-150 mcg of LH-RH was singly injected during the immediate preovulatory period, and insemination was performed on the same day. There were 35 presumed ovulations and 4 pregnancies, 2 of which ended in spontaneous abortion. The hyperthermia response occurred 1 to 3 days after LH-RH administration in 20 cycles. It is suggested that the LH-RH directly induced ovulation. 2 patients who had serial serum progesterone tests prior to treatment showed lowered and delayed peak progesterone secretions during the luteal phase. In the absence of reliable evidence of a mature follicle, multiple LH-RH injections may be required to improve the pregnancy rate for artificial insemination.

Gonadotropin levels and secretory patterns in patients with typical and atypical polycystic ovarian disease.

Gonadotropin levels and secretory patterns were studied in 28 oligomenorrheic patients with various types of polycystic ovary disease (PCO). On the basis of ovarian morphology and histology, the patients PCOuld be separated into two distinct categories arbitarily designated "typical" (type I) and "atypical" (type II) PCO. Although no differences were noted in symptomatology or 17-ketosteroid, testosterone, or follicle-stimulating hormone levels, the 12 type I patients demonstrated widely fluctuating, but markedly elevated, luteinizing hormone (LH) levels, while the 16 type II patients demonstrated lower and less fluctuating LH levels which were comparable to those found during the normal follicular phase. It is likely that type I PCO is a distinct entity similar to that described by Stein and Leventhal, while type II co represents a heterogenous spectrum of disorders, many of which remain obscure.