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Objective: To develop and validate an enzyme-linked immunosorbent assay (ELISA) for total urinary follicle-stimulating hormone (FSH) that can be used to evaluate frozen-thawed urine samples., Design: A method was developed for dissociating urinary FSH into subunits by boiling. An ELISA for the free beta subunit of FSH was used to measure total FSH in urine samples collected from male and female volunteers. The urinary FSH values were compared with serum FSH concentrations in paired samples., Setting: A clinical research laboratory., Patient(s): Serum and urine samples from normal male and female volunteers and from men with infertility were used to develop and validate an assay for total urinary FSH., Intervention(s): None., Result(s): Urinary FSH concentrations in frozen-thawed urine were highly correlated to matched serum FSH concentrations., Conclusion(s): A microtiter plate ELISA for FSH beta subunit provides an economical method for evaluating FSH secretion in men and women. This method has practical applications for population-based epidemiologic studies in which urine samples are collected in the field and stored frozen before analysis.

Objective: To report the successful use of recombinant human FSH in a patient with a history of a severe systemic immunoglobulin E (IgE)-mediated reaction to urofollitropin., Setting: University hospital., Patient: A 38-year-old infertility patient who had experienced a whole-body rash with hives, tachycardia, fever, and other symptoms after urofollitropin administration, with confirmation of IgE-mediated sensitivity to urofollitropin by intradermal skin testing., Intervention: In vitro fertilization-ET after the use of recombinant human FSH to stimulate ovarian follicular development., Results: Establishment of a clinical pregnancy., Conclusions: Our case provides evidence for the involvement of nongonadotropin proteins as the direct cause of some adverse reactions from conventional urine-derived human FSH preparations.

Objective: To investigate adverse reactions to hMG preparations in two women in IVF programs., Design: Two case reports with skin tests for delayed hypersensitivity (DH) to hMG and a biopsy of one delayed reaction., Setting: Allergy and infertility clinics in university medical center., Patients: Two affected patents with a history of local reactions to the injected hMG, one of whom also had fever, and nine control subjects., Interventions: Skin tests and biopsy., Main Outcome Measures: Delayed hypersensitivity skin response to hMG in affected patients indicated by timing and biopsy results. Negative skin test with the purified hFSH, which was also used in treatment with no adverse effects., Conclusion: Use of the purified preparation avoids DH reaction.

Active immunization of four adult rhesus monkeys with highly purified ovine follicle-stimulating hormone (FSH) resulted in the production of specific FSH antibodies and a suppression of spermatogenesis for the observation period of 2 years. Although testicular volume was markedly reduced, endocrine function did not appear to be affected. Serum testosterone and bioassayable LH levels as well as the frequency of spontaneous ejaculations were the same as in control animals. No adverse side effects were noted over the 2-year period. These results may encourage investigations on active immunization with FSH as a possible approach to male fertility control.

A male patient presented with polyostotic fibrous dysplasia, elevated serum gonadotropin levels, primary gonadal failure, and an immunoglobulin M (IgM) monoclonal gammopathy. When the patient's serum was added to radioiodinated human follicle-stimulating hormone (125I-hFSH)-bovine testis membrane-receptor complex solubilized by detergent, followed by the addition of antihuman immunoglobulin G ((anti-hIgG), the preformed complex was precipitated. No such precipitation was seen when normal human or rabbit serum, serum from a patient with polyostotic fibrous dysplasia, or serum from other patients with polyclonal gammopathies were utilized. The patient's serum did not precipitate free 125I-hFSH. Detergent-solubilized testis receptor not complexed to hFSH, as well as highly purified radioiodinated receptor were also precipitated when this serum was added followed by anti-hIgG. Our results indicate that serum from the patient contained antibodies to FSH testis receptor. It is possible that antibodies to gonadal receptors may exist in other patients, although it is not yet possible to assume a causal relationship between the presence of receptor antibodies and gonadal failure.

Active immunization of four adult rhesus monkeys with highly purified ovine follicle-stimulating hormone (FSH) over 4 1/2 years resulted in the production of specific FSH antibodies. While luteinizing hormone and testosterone secretion were not affected, sperm counts were in most instances reduced to or below the lower normal range. On a few occasions, azoospermia or high sperm counts were observed. Although the antibodies produced neutralized the biologic activity of FSH throughout, spermatogenesis gradually returned, as evidenced by testicular histologic characteristics. However, the diameter of the seminiferous tubules remained decreased, and the germinal epithelium was depleted. No adverse side effects could be demonstrated in the immunized animals, e.g., immune complexes in either serum or tissues and resultant tissue damage. These results show that although active immunization with FSH may not result in an effective method of male fertility control, long-term immunization against a circulating hormone may not result in deleterious side effects.

Recently, a model for early pregnancy in the rhesus monkey was developed which involved administration of a 10-day treatment regimen of human chorionic gonadotropin (hCG). The current studies were designed to determine whether monkeys produced antibodies in response to this hCG regimen and, if so, to characterize the specificity of the antibodies and their effects on subsequent menstrual cycles. Based on Sephadex chromatography and immunoglobulin precipitation with protein A, serum collected from hCG-treated monkeys contained binding components for 125I-hCG. Binding was specific for human gonadotropins (hCG, human luteinizing hormone [LH], human follicle-stimulating hormone [FSH]) and did not cross-react with macaque LH/FSH. Shortening the hCG regimen to less than or equal to 6 days did not result in significant binding. The 10-day hCG regimen did not alter subsequent menstrual cycles, but attenuated 17 beta-estradiol production in response to human menopausal gonadotropin. In conclusion, the 10-day regimen of hCG treatments used to simulate early pregnancy in rhesus monkeys induced the production of serum components with characteristics of hCG antibodies. These antibodies did not alter the regulation of the menstrual cycle, but attenuated the response to exogenous human gonadotropins.

Ovulation induction in the postpartum rhesus monkey was attempted with the use of purified human pituitary gonadotropins for assessment of (1) whether this procedure could be used to provide a source of luteal tissue; (2) the extent of ovarian responsiveness to gonadotropic stimulation; (3) factors that might facilitate ovulation induction during the peurperium; and (4) factors that might be a contributory cause of induction failure. Twenty rhesus monkeys were treated with purified human follicle-stimulating hormone (hFSH) and human luteinizing hormone (hLH) twice daily, beginning on days 0, 10, or 20 postpartum, with or without prior administration of bromocriptine. Laparotomies were performed during the midluteal phase. Ovaries were examined, and all corpora lutea were removed. Neither the day of beginning the gonadotropin treatment nor bromocriptine administration had a significant effect on the success rate of ovulation induction, which averaged 60% overall. Inductions begun during July had a significantly (P less than 0.025) lower success rate than those started at other times of the year. Antibodies to hFSH and hLH were detected in serum from monkeys that had undergone ovulation induction. Antibodies to hFSH, but not hLH, were associated with significantly reduced induction success (P less than 0.05). Plasma estradiol rose in response to gonadotropin treatment, and the induced follicular phase averaged 13.6 +/- 0.7 days. In all animals judged to have ovulated, corpora lutea were observed at laparotomy, and plasma concentrations of progesterone were significantly elevated (13.8 +/- 3.8 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Ovarian resistance to exogenously administered gonadotropins and elevated serum gonadotropins, especially follicle-stimulating hormone (FSH), are considered virtually diagnostic of ovarian failure. However, similar clinical findings can be caused by circulating antibodies to gonadotropins which can neutralize the biologic activity of exogenously administered gonadotropins and can also cause falsely high gonadotropin determinations by routine double-antibody radioimmunoassay (RIA). We have used a primate model with anti-FSH antibodies to demonstrate that an acute course of combined estrogen-progestin therapy will suppress the pituitary secretion of FSH, which is markedly elevated in ovarian failure, while the false FSH elevations caused by circulating anti-FSH antibodies are not reduced by steroid negative feedback. Thus, gonadotropin (RIA) determinations before versus during an acute course of estrogen and progesterone therapy can distinguish true ovarian failure from the presence of circulating anti-gonadotropin antibodies.

Neonatal rats secrete considerable amounts of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) between 5 and 15 days of age. Antisera to LH and FSH were injected during this 11-day period in an attempt to study the importance of gonadotropins for functional development of the gonads. Autopsies at 15 days of age revealed normal ovarian follicular histology after either antiserum treatment, but antiserum to LH significantly retarded differentiation of interstitial tissue. Uterine weights were increased, and some of the serum samples showed elevated FSH levels following the antiserum treatments. The testes of antiserum-treated rats were heavier at 15 days of age, while accessory sex organ weights were unchanged. Vaginal opening after antiserum treatment was more variable than in controls, but tended to be earlier. The first appearance of penile serum was not significantly changed. Both males and females were fertile as adults. Important limitations to the use of chronic antiserum injections were found in immature rats. The antisera were present for at least 34 days after injection. The ways in which this pool of antiserum might have influenced the results are discussed.

The biologic (B) and immunologic (I) properties of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in three commercial urinary gonadotropin preparations and in the first international standard preparation of human urinary gonadotropins before and after fractionation by isoelectrofocusing (IEF). Significant differences were found in the IEF profiles of both bioactive and immunoreactive LH and FSH and in the B/I ratios of the preparations studied. The observed differences in the molecular composition of LH and FSH seem to be attributable to the purification procedures employed. The possible influence of these differences on the in vivo potencies, circulating half-lives, and clinical effects of gonadotropin preparations are discussed.