S. Franks

MULTIFOLLICULAR OVARIES: CLINICAL AND ENDOCRINE FEATURES AND RESPONSE TO PULSATILE GONADOTROPIN RELEASING HORMONE

By means of pelvic ultrasonography, a multifollicular ovarian appearance was observed in women with weight-loss-related amenorrhoea. Multifollicular ovaries (MFO) are normal in size or slightly enlarged and filled by six or more cysts 4-10 mm in diameter; in contrast to women with polycystic ovaries (PCO), stroma is not increased. Unlike PCO patients, women with MFO were not hirsute and serum concentrations of luteinising hormone and follicle stimulating hormone were normal and decreased, respectively. The uterus was small indicating oestrogen deficiency. In MFO, treatment with gonadotropin releasing hormone (LHRH) induced ovulation in 83% of cycles and there were seven pregnancies in 8 women; in PCO, only 40% of cycles were ovulatory and there were eleven pregnancies (8 women) but six of these aborted. In MFO ovarian morphology reverted to normal in ovulatory cycles, whereas in PCO the polycystic pattern persisted despite the presence of a dominant follicle. MFO may represent a normal ovarian response to weight-related hypothalamic disturbance of gonadotropin control.

DIFFERENCES IN CLINICAL AND ENDOCRINE FEATURES BETWEEN OBESE AND NON‐OBESE SUBJECTS WITH POLYCYSTIC OVARY SYNDROME: AN ANALYSIS OF 263 CONSECUTIVE CASES

Two hundred and sixty‐three women with ultrasound‐diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI > 25 kg/m2‐). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non‐obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5α‐reductase activity, were higher in obese than in non‐obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8‐h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio‐availability of androgens to peripheral tissues and enhanced activity of 5α‐reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.

Evidence for a single gene effect causing polycystic ovaries and male pattern baldness

OBJECTIVE Polycystic ovary syndrome is one of the most common endocrine disorders but its aetiology remains unknown. It is highly prevalent within families, suggesting a genetic basic for the syndrome, but the mode of inheritance is unclear. The purpose of this study was to determine the mode of inheritance of polycystic ovary syndrome, within the families of affected individuals, by classic segregation analysis.

Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology. The aims of this study were to identify whether ovarian thecal cell steroidogenesis is abnormally regulated in PCOS by measuring steroid responses to a single dose of hCG before, and during, suppression of endogenous LH levels by a GnRH analogue (GnRHa).

The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries

OBJECTIVE Insulin insensitivity is a recognized feature of polycystic ovary syndrome (PCOS) but previous studies have suggested that circulating insulin concentrations are normal in hyperandrogenaemic women with regular cycles. The aim of this study was to examine the relationship between insulin sensitivity and menstrual pattern in women with PCO.

Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I.

The purpose of this study was to investigate the effect of calorie restriction on serum concentrations of sex hormone binding globulin (SHBG) in women with normal or polycystic ovaries (PCO) and to examine the possible role of insulin and insulin‐like growth factor‐I (IGF‐I) in mediating changes in SHBG levels. Six normal subjects with mean (SD) body mass index (BMI) 25.5 (2.2) and five subjects with PCO (BMI 36.1 (3.7)) were studied before and after 2 or (PCO only) 4 weeks of a very low calorie diet (330 kcal/day; Cambridge Diet). In both normal women and patients with PCO there was a twofold increase in SHBG concentrations after 2 weeks and this was sustained in the PCO subjects for a further 2 weeks. The rise in SHBG was accompanied by a fall in free testosterone concentrations. There were parallel changes in serum insulin and IGF‐I concentrations which decreased during the diet and there were significant negative correlations of SHBG with insulin in both normal subjects (r =−0.62) and women with PCO (r =−0.60). In addition, serum concentrations of an insulin‐dependent small molecular weight (34 kDa) binding protein for IGF‐I (IGF‐BPI) increased significantly during dieting in both groups and were negatively correlated with serum insulin (controls, r =−0.56; PCO, r =−0.68) and positively correlated with serum SHBG levels (controls, r = 0.69; PCO, r = 0.63).

Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries

OBJECTIVE Polycystic ovary syndrome (PCOS) is characterized by hyperinsulinaemia and insulin resistance. Previous reports of lipid abnormalities in the syndrome have produced conflicting results which may, in part, be related to the lack of appropriate controls for the obese women with PCOS. Only one study has related lipid levels to insulin sensitivity. The objective of this study was to assess lipids and lipoproteins in women with PCOS, to compare the results with weight matched controls, and to relate the findings to indices of insulin secretion and action, and to menstrual history.

A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

A randomized controlled trial of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion

The value of medroxyprogesterone acetate (MPA) and of psychotherapy in the treatment of lower abdominal pain due to pelvic congestion was assessed in a randomized controlled trial. Eighty‐four women with abnormal pelvic venography were assigned to one of four treatment groups: MPA alone, MPA plus psychotherapy, placebo alone, and placebo plus psychotherapy. Women were treated for 4 months and thereafter followed up regularly for 9 months with pain assessments, pelvic ultrasound scanning, and hormone measurements. During treatment, MPA showed a significant benefit in terms of a reduction in visual analogue scale pain score, with 73% of women reporting at least 50% improvement compared with 33% of those treated with placebo. At 9 months after the end of therapy there was no overall significant effect of MPA or psychotherapy, but there was an interaction between MPA and psychotherapy, with 71 % of the women in this group showing a ≥50% reduction in pain score. Therapy with MPA is a useful first‐line therapy for women with pain associated with demonstrable pelvic congestion.

Body size from birth to adulthood as a predictor of self-reported polycystic ovary syndrome symptoms.

OBJECTIVE: To study the association between body size from birth to adulthood and self-reported symptoms of polycystic ovary syndrome (PCOS), particularly hirsutism and menstrual disturbances.DESIGN: Longitudinal, population-based study of a cohort of women born in 1966 in northern Finland. The study population included 2007 women who were not pregnant and did not use hormonal contraception. Of these 528 (26%) had self-reported symptoms of PCOS.RESULTS: Weight at birth, gestational age, being small for gestational age or growth retardation at birth were not associated with PCOS symptoms at 31 y. An increased risk of PCOS symptoms was observed among women with abdominal obesity (waist/hip ratio >85th percentile) at 31 y who had normal weight in adolescence and were overweight (body mass index (BMI) 25.0–29.9 kg/m2) or obese (BMI>30.0 kg/m2) at 31 y (relative risk (RR) (95% CI) 1.44(1.10–1.89)), and among women with abdominal obesity who were overweight or obese at both 14 and 31 y (1.71 (1.30–2.24)). A total of 30% and 41% of the women with PCOS symptoms in these groups could be attributed, respectively, to overweight, obesity and abdominal obesity at 31 y.CONCLUSIONS: These results suggest that obesity in adolescence and in adulthood, and also weight gain after adolescence, particularly in the presence of abdominal obesity, are associated with self-reported PCOS symptoms in adulthood. Thus, based on the results from intervention studies treating PCOS and the results of this study, the prevention of obesity and abdominal obesity is important among young women.