Jens A. Gudmundsson

Variants in DENND1A Are Associated with Polycystic Ovary Syndrome in Women of European Ancestry

CONTEXT A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry. OBJECTIVE The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry. DESIGN This was a case-control study. SETTING The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States. PATIENTS Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively. INTERVENTION There were no interventions. MAIN OUTCOMES Main outcomes were allele frequencies for seven variants in PCOS cases and controls. RESULTS Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria. CONCLUSIONS We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Inhibition of ovulation by intranasal nafarelin, a new superactive agonist of GnRH

Thirty healthy female volunteers used a new superactive stimulatory analog of the hypothalamic gonadotropin-releasing hormone (GnRH) for inhibition of ovulation and contraception during 3 months. The potent GnRH agonist nafarelin (D-Nal(2)6-GnRH) was administered intranasally in a daily dose of 125 micrograms to 15 women and 250 micrograms to 15 women. The treatment inhibited ovulation in all women during the 89 months of therapy. No pregnancies occurred during 59 treatment months in which no additional contraceptives were used. The mean estradiol concentration decreased during the 3-month treatment within the normal range for the early to mid-follicular phase of the menstrual cycle. The results suggest that the GnRH agonist nafarelin has a potential for contraception by inhibition of ovulation in women.

Intranasal peptide contraception by inhibition of ovulation with the gonadotropin-releasing hormone superagonist nafarelin: six months' clinical results *

Forty-seven woman volunteers used a new highly potent stimulatory analog of the hypothalamic gonadotropin-releasing hormone (GnRH) for contraception. The superagonist nafarelin acetate, D-Nal(2)6-GnRH, was administered intranasally in one daily dose of 125 micrograms to 25 women and 250 micrograms to 22 women. Ovulation was consistently inhibited during 261 of 262 treatment months. No pregnancy occurred during 222 months in which no additional contraceptives were used. The mean plasma estradiol level after 6 months of treatment was 162 pmol/l. The predominant bleeding pattern was oligomenorrhea. Three women on the lower dose and six women on the higher dose discontinued the trial prematurely, mainly because of hot flushes. No serious side effects were reported. Ovulatory menstruations returned after a median time of 43 days after discontinuation of therapy. Daily intranasal nafarelin treatment for inhibition of ovulation proved to be an effective and rapidly reversible method of contraception.

Endometrial morphology after 6 months of continuous treatment with a new gonadotropin-releasing hormone superagonist for contraception*

Light and electron microscopic studies were performed on endometrial curettage specimens from 27 women after 6 months of contraceptive treatment with continuous intranasal gonadotropin hormone-releasing hormone (GnRH) superagonist. The GnRH superagonist nafarelin acetate (D-Nal[2]6-GnRH) was used in single daily doses of 125 or 250 micrograms. Ovulation was inhibited during all but one of the 159 treatment months. No pregnancies occurred. In 6 women with fairly regular bleedings, the endometrium displayed weak to normal proliferation. Twenty women developed oligomenorrhea or amenorrhea, 16 of them had inactive endometrium, 1 had weakly proliferative endometrium, and 3 endometrial biopsies were too sparse for adequate evaluation. One woman reported repeated episodes of heavy uterine bleedings. The endometrial biopsy from this woman showed weak proliferation. No signs of endometrial hyperplasia were observed. Generally, the electron microscopy showed signs of low metabolic activity and weak protein synthesis. Thus, long-term continuous treatment with nafarelin acetate for inhibition of ovulation does not appear to have untoward effects on the endometrium.

A New Superagonist of GnRH for Inhibition of Ovulation in Women

This paper presents the initial results from a study that used a new superagonist of gonadotrophin-releasing hormone (GnRH), naferelin acetate, for the inhibition of ovulation. The superagonist was administered by nasal spray daily for 12 weeks to 20 women with regular menstrual periods. Radioimmunoactive estradiol and progesterone were assayed weekly, and there were regular check ups and daily recordings of basal body temperature. None of the subjects had a normal ovulatory menstrual cycle during 57 treatment months. During the 1st 8 weeks, 7 women had menstrual-like bleeding, 8 had oligomenorrhea, and 5 were amenorrheic. No pregnancies occurred during the study, nor were there any clinical symptoms or signs of estrogen deficiency. These preliminary findings suggest that nafarelin is a potent antifertility drug with potential use for contraception. The antireproductive properties of the agonist are also of interest for treatment of tumors, gynecologic disorders such as endometriosis and polycystic ovarian disease, and precocious puberty.

A new superagonist of GnRH for inhibition of ovulation in women

Thousands of analogues of GnRH have been synthesized since the structure of this hypothalamic gonadotrophin-releasing hormone became known in 1971 (6). The purpose of this enourmous task has been: l/ to develop more potent and long-acting molecules than GnRH itself for use in infertility and 2/ to develop antagonistic analogues of GnRH for use in contraception. The biological potency of the GnRH residue lies in the first part of the decapeptide. The amino acids histidine and tryptophan in positions 2 and 3 play a functional role in the biological activity of GnRH. The amino acids in positions 1 and from 4-10 seem to be involved in the binding to the GnRH receptor. Glycine in position 6 and 10 are most critical for preserving conformation.

Characterizing Discrete Subsets of Polycystic Ovary Syndrome as Defined by the Rotterdam Criteria: The Impact of Weight on Phenotype and Metabolic Features

A lack of standard criteria for diagnosing polycystic ovary syndrome (PCOS) has made it very difficult to compare phenotypes around the world. A workshop held recently in Rotterdam attempted to reconcile the differences by adding ultrasonography to expand the diagnostic criteria. PCOS is diagnosed if two of three findings are present: irregular menses (IM); clinical or biochemical hyperandrogenism (HA); and/or polycystic ovary morphology (PCOM) on pelvic ultrasound study, all in the absence of a disorder that can cause the same symptoms. The four possible diagnostic subgroups of PCOS are IM/HA/PCOM, IM/HA, HA/PCOM, and IM/PCOM. The phenotypic features of women in these subgroups were compared in a large population of women with PCOS residing in Boston and in Iceland. Of the 481 women evaluated, 71% met criteria for IM/HA/PCOM. Another 2% had IM/HA; 18% had HA/PCOM; and 9% had IM/PCOM. Virtually all women with IM/HA also had PCOM. Women with IM/HA and normal ovarian morphology differed from those with PCOM only by being older and having higher levels of follicle-stimulating hormone. Because follicle counts and the frequency of PCOM decline with advancing age in women with PCOS, the IM/HA/PCOM and IM/HA groups were combined and designated IM/HA. Ferriman-Gallwey scores and androgen levels were highest in the IM/HA and HA/PCOM groups. Ovarian volumes were higher in all subgroups compared to control women without PCOS. Women in the IM/HA subgroup had the highest body mass index (BMI) values and circulating insulin levels. Insulin resistance was most frequent in the IM/HA subgroup, but there were no group differences in fasting glucose or glycosylated hemoglobin levels, or in the frequency of type 2 diabetes. Women in the IM/HA and IM/PCOM subgroups had the largest ovarian volumes and the most follicles on ultrasound study. These parameters were greater in all groups of women with PCOS than in the control subjects. This study shows that women with PCOS defined by HA are most severely affected. They also have the highest BMIs, suggesting that weight gain or intrinsic insulin resistance may worsen symptoms of PCOS or lead to irregular cycles in women with HA at baseline. Further studies will be needed to learn whether phenotypic differences influence such long-term sequelae as infertility and cardiovascular disease.