Sandra P.T. Tho

Adult-onset amenorrhea: a study of 262 patients

A series of 262 patients with amenorrhea of adult onset are reported. Hypothalamic suppression followed by inappropriate positive feedback, and then hyperprolactinemia and ovarian failure are the most frequently encountered etiologies. Other etiologies are diverse and numerically less frequent. Amenorrhea after use of oral contraceptives, or postpill amenorrhea, occurred in 77 (29%) of all patients. The average age of presentation, prior menstrual history, associated morbidity, and subsequent reproductive potential of each diagnostic group are reported. Adult-onset amenorrhea has a less significant impact on future wellbeing than was reported for a similar-sized group of patients whose amenorrhea developed as a result of pubertal aberrancy.

Evidence for a partial deletion in the androgen receptor gene in a phenotypic male with azoospermia

Androgen resistance is thought to vary phenotypically from a normal female to an infertile male. Previous evaluation of infertile males has been limited to androgen receptor-binding affinity. The androgen receptor gene has been isolated, cloned, and studied extensively in patients with complete androgen insensitivity syndrome, but no comparative data are available on infertile males. To address this matter, the androgen receptor gene was studied in seven azoospermic males by use of the polymerase chain reaction and Southern blot hybridization. A partial gene deletion was found in one patient. This study provides the first molecular evidence of an abnormality in the androgen receptor gene in a phenotypic male with azoospermia.

Etiologic factors of recurrent abortion and subsequent reproductive performance of couples: Have we made any progress in the past 10 years?

OBJECTIVES We hypothesize that the diagnostic yield and pregnancy outcomes of patients with recurrent abortion have improved over the past 10 years. STUDY DESIGN The study was performed in an academic medical center. Diagnoses and outcomes for group A, a published series of 100 patients investigated for recurrent abortion in the section between 1968 and 1977, was compared with those for group B, the 131 patients seen between 1987 and 1991. A standardized protocol was followed, enhanced by new techniques and autoimmune investigations in the latter group. Results were compiled retrospectively. Descriptive statistics and chi 2 analysis were used. RESULTS No cause could be found in 37% of patients in group A compared with 24% of couples in group B (p less than 0.05). No clear difference could be shown in the subsequent outcomes of pregnancies. CONCLUSIONS Our ability to establish a cause of recurrent abortion has improved slightly over the past 15 years. The gain is not yet reflected in successful pregnancy rates. Multicenter trials are indicated.

Paternal somatic and germ-line mosaicism for a sex-determining region on Y (SRY) missense mutation leading to recurrent 46,XY sex reversal

OBJECTIVE To determine the etiology for recurrent 46,XY sex reversal in a family with two Swyer siblings. DESIGN Deoxyribonucleic acid (DNA) from peripheral lymphocytes and sperm were analyzed for duplication of the dosage sensitive sex locus (DSS) and for mutations in sex-determining region on Y (SRY). SETTING An academic teaching hospital. PATIENTS A family consisting of mother, father, and five phenotypic daughters, of which two were 46,XY sex-reversed females. INTERVENTION Deoxyribonucleic acid (DNA) extraction, polymerase chain reaction (PCR), Southern blotting, dosage densitometry, single-strand conformation polymorphism (SSCP), and sequencing. MAIN OUTCOME MEASURE Comparison of control and subject DNA. RESULTS Deoxyribonucleic acid (DNA) analysis of SRY in genomic DNA from the 46,XY sex-reversed siblings revealed identical missense mutations (T-->G) in both sisters. Analysis of the SRY gene in paternal lymphocyte and sperm DNA revealed mosaicism for wild and mutant (T-->G) SRY sequences. SRY analysis of sperm DNA also demonstrated the same mosaicism for the T-->G missense mutation. CONCLUSION A postembryonic SRY mutation gave rise to paternal mosaicism for two distinct cell populations (SRY+/SRY-). The presence of a wild type SRY in the somatic cell line may account for a normal pattern of male sexual differentiation, whereas the presence of a mutated SRY in the germ line resulted in two 46,XY sex-reversed offspring. These results confirm a proposed mechanism for the condition of recurrent 46,XY sex-reversed females.

Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes

OBJECTIVE To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype. DESIGN Retrospective review of patient records; cytogenetic and molecular analysis. SETTING Tertiary medical center setting. PARTICIPANT(S) Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes. INTERVENTION(S) Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient. MAIN OUTCOME MEASURE(S) Clinical phenotype versus genotype. RESULT(S) Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone. CONCLUSION(S) The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

Familial gonadotropin-releasing hormone resistance and hypogonadotropic hypogonadism in a family with multiple affected individuals

OBJECTIVE To characterize the phenotype of idiopathic hypogonadotropic hypogonadism due to compound heterozygous GnRHR gene mutations (Arg262Gln/Tyr284Cys). DESIGN Retrospective review. SETTING Tertiary medical center. PATIENT(S) Family containing four siblings (three female and one male) with complete idiopathic hypogonadotropic hypogonadism. INTERVENTION(S) Baseline and stimulated laboratory studies. One patient received GnRH treatment and one received human menopausal gonadotropins. MAIN OUTCOME MEASURE(S) Clinical phenotype vs. genotype is assessed by endocrine studies, karyotype, pedigree, and review of pathology slides of ovarian neoplasm. RESULT(S) With GnRH stimulation, two patients with idiopathic hypogonadotropic hypogonadism had maximum LH < 10 mIU/mL, and two others had peak LH > 10 mIU/mL. With repeated GnRH stimulation 24 hours later, gonadotropin levels in all patients were increased. Stimulation of thyroid-releasing hormone and tests for insulin-induced hypoglycemia were normal. One affected patient did not ovulate after GnRH treatment, but her sister ovulated with gonadotropin treatment. Another affected sibling had bilateral oophorectomy for seromucinous cystadenomas, and her hypogonadotropic state remained after castration. The man with idiopathic hypogonadotropic hypogonadism and his unaffected brother had a ring chromosome 21. CONCLUSION(S) All patients with complete idiopathic hypogonadotropic hypogonadism had the same GnRHR mutations, but clinical presentations and endocrinologic responses were heterogeneous. Gonadotropin levels remained low in patients with idiopathic hypogonadotropic hypogonadism after castration, and ring chromosome 21 was present, suggesting that sequences from this chromosome could affect the idiopathic hypogonadotropic hypogonadism phenotype.

Massive ovarian enlargement in primary hypothyroidism

OBJECTIVE To report a case of ovarian cyst formation and myxedematous infiltration of the ovary in a subject with primary hypothyroidism. DESIGN Retrospective case report. SETTING University hospital. PATIENT(S) A 16-year-old female adolescent with pelvic pain, galactorrhea, irregular menses, and ovarian cysts on pelvic examination. INTERVENTION(S) Laparotomy with bilateral ovarian wedge resection and thyroid replacement therapy. MAIN OUTCOME MEASURE(S) Ovarian histopathology, thyroid function tests, and menstrual history. RESULT(S) Resolution of patients pain, galactorrhea, and resumption of normal menses. CONCLUSION(S) Ovarian cyst formation may accompany primary hypothyroidism in the child with accelerated or delayed sexual maturation. To date, the underlying pathophysiology of the morphological changes in the ovary remain enigmatic. This case report provides the first insight into the actual histologic changes that occur in ovaries of subjects with primary hypothyroidism without secondary ovarian pathology such as torsion. There is clear evidence of myxedematous infiltration into the ovarian stroma without luteinization of the theca interna. These microscopic findings suggest that local changes occurring independent of gonadotropin stimulation may contribute significantly to altered morphology of the ovaries in primary hypothyroidism.

Follicle-stimulating hormone beta gene structure in premature ovarian failure*†

OBJECTIVE To determine whether mutations in the gene for FSH beta are present, and possibly etiologic, in some patients with 46,XX premature ovarian failure (POF). DESIGN DNA samples obtained from 18 study patients with POF and two menopausal fertile controls were studied by Southern blot analysis. DNA sequencing was performed in one patient. SETTING Patients were seen in a reproductive endocrinology clinic and studied in a medical school laboratory setting at the Medical College of Georgia and Tufts University. MAIN OUTCOME MEASURES Restriction fragment sizes on autoradiographs were compared between the study group and controls. DNA sequencing radiographs were compared between one study patient and five controls. RESULTS Fragment sizes obtained with the restriction enzymes EcoRI, DraI, HincII, PstI, KpnI, BglI, BamHI, and BglII were similar size in both study subjects and controls using the probes pFSH beta-1.4 and pFSH beta-1.2. A previously described HindIII polymorphism was present using pFSH beta-1.2, but HindIII fragment sizes were identical in patients with ovarian failure and controls using pFSH beta-1.4. DNA sequencing of the FSH beta gene in one patient was normal. CONCLUSIONS No mutations in the gene for FSH beta were identified in women with POF. DNA sequencing of the exons and promoter region of the FSH beta gene in one woman with POF was normal. This does not entirely exclude the possibility that smaller deletions, insertions, or point mutations of the FSH beta could be etiologic in some women with POF. The HindIII polymorphism does not appear to segregate with 46,XX POF.

Molecular scanning of Yq 11 (interval 6) in men with Sertoli-cell-only syndrome

Data suggesting that probes pDP105/B and 50f2/C,E may identify sequences on distal Yq11 (interval 6) that are critical for spermatogenesis stimulated a study of this region by means of these two probes in azoospermic 46,XY men with biopsy-proved Sertoli-cell-only syndrome. Deoxyribonucleic acid samples from controls and study subjects were digested with the restriction enzymes TaqI, EcoRI, and BamHI. These samples were blotted and hybridized with pDP105/B, 50f2/C,E, and two more proximal Yq11 probes 4B-2 and pAS1. The sequence hydridizing to 50f2/C was absent in one study subject. No deletions were detected with pDP105/B and the two more proximal probes.

The presence of the testicular determining sequence, SRY, in 46,XY females with gonadal dysgenesis (Swyer syndrome)

Subjects with 46,XY gonadal dysgenesis (Swyer syndrome) have a distinctive phenotype. They are normal or tall in stature, lack somatic anomalies, and possess bilateral rudimentary gonads. Critical Yp deletions have been described in some cases, but in the majority no defects at the molecular level have been reported. To verify the presence or absence of SRY, the putative testicular-determining factor gene, specific primers were designed to amplify the conserved region of the SRY gene. Deoxyribonucleic acid from control males (n = 10) and sex-reversed females with the Swyer syndrome phenotype (n = 5) generated the anticipated 310 bp band. This Y-specific band was absent in the deoxyribonucleic acid from control females (n = 9). To search for possible point mutations, the amplified products of all study subjects and one control male were sequenced in both orientations. The base pair sequences were all identical and similar to the previously published report.