Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment.

Human Reproduction Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment Brigitte J.Roozenburg 1 2 Hendricus J.H.M.van Dessel 1 2 Johannes L.H.Evers 0 2 Rob S.G.M.Bots 1 2 0 Department of Obstetrics and Gynaecology, Academic Hospital Maastricht , PO Box 5800, 6202 AZ Maastricht , The Netherlands 1 Division of Fertility, Department of Obstetrics and Gynaecology, St Elisabeth Hospital , Hilvarenbeekseweg 60, 5022 GC Tilburg 2 Franks , S., Adams, J., Mason, H.D. and Polson, D.W. (1985) Disorders in women with polycystic ovary syndrome. Clin. Obstet. Gynaecol., 12, 605-632 3To whom correspondence should be addressed Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate. Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive, expensive, and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome. We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone (an opioid receptor blocker) alone or naltrexone in combination with an antioestrogen. In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed. In conclusion, ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients. Compared to gonadotrophin induction of ovulation, this method is safe, simple and inexpensive. - Anovulation and cycle abnormalities are associated with hypogonadotrophic hypogonadism [World Health Organization (WHO) group I], hypergonadotrophic hypogonadism, or normogonadotrophic status (WHO group II) (Rowe et al., 1993). Most patients with anovulatory subfertility are normogonadotrophic with normal follicle stimulating hormone (FSH) concentrations, but luteinizing hormone (LH) concentrations are raised in some cases. The treatment of first choice is the use of anti-oestrogens, such as clomiphene citrate, during the early follicular phase. Eventually ~30% of normogonadotrophic anovulatory patients will prove to be clomiphene citrate resistant (Franks et al., 1985). Administration of human menopausal gonadotrophins (HMG) is recommended as the next approach for clomiphene citrate resistant anovulation (ESHRE Capri Workshop, 1995, 1996). This treatment provides an acceptable cumulative pregnancy rate but is expensive and potentially hazardous (Navot et al., 1992). Treatments with low-dose step-up or step-down HMG or FSH have been developed to reduce the risk of hyperstimulation and multiple pregnancies, but they are labourintensive (Buvat et al., 1989; Hamilton-Fairley et al., 1991; Fauser et al., 1993) Several groups have used naltrexone, an opioid receptor blocker, in patients with anovulation and cycle abnormalities. Endogenous opioids are among the factors involved in the inhibition of the hypothalamic pulse generator that directs gonadotrophin releasing hormone (GnRH) secretion. Naltrexone establishes chronic blockade of the hypothalamic opioid receptors. Wildt et al. (1993a,b) reported that naltrexone treatment can restore ovulation and normal menstrual cycles in patients with various grades of hypothalamic ovarian failure. In contrast, Armeanu et al. (1992) and Couzinet et al. (1995) could not demonstrate an increase in gonadotrophin secretion or resumption of ovulation in women with hypogonadotrophic hypogonadism after naltrexone treatment. In a group of patients with weight-loss-related amenorrhoea, administration of naltrexone resulted in the restoration of a normal menstrual cycle (Genazzani et al., 1993). In women with polycystic ovarian syndrome LH concentrations were normalized after naltrexone treatment (Lanzone et al., 1993; Cagnacci et al., 1994). We wished to investigate whether patients with subfertility due to normogonadotrophic anovulation, who were clomiphene citrate resistant, ovulated after oral treatment with naltrexone alone or naltrexone in combination with anti-oestrogens. Our goal was to keep the treatment as simple and efficient as possible and to avoid side-effects and complications. Materials and methods We based our study on treatment cycles from January 1995 to September 1996 in 22 infertile women with amenorrhoea (n 5 11) or oligomenorrhoea (fewer than six periods a year; n 5 11). Thirteen patients suffered from primary subfertility and nine from secondary subfertility. Exclusion criteria were hyperprolactinaemia, thyroid hormone abnormalities, tubal damage (tested by hysterosalpingography or laparoscopy) and abnormal sperm count (,203106/ml). All patients were normogonadotrophic and previously received, in two cycles, clomiphene citrate (Serophene; Serono Benelux, Amsterdam, The Netherlands) in doses up to 150 mg for 5 days with no signs of ovulation on ultrasound, nor resumption of a regular cycle. Naltrexone treatment was started on the first cycle day of a spontaneous or progestagen-induced menstrual cycle. Naltrexone (Nalorex; Dupont, Nemours, France) was administered orally in a dose of 25 mg twice daily. Regular visits were scheduled for ultrasonic cycle monitoring. Ultrasonograms were obtained using a 5 MHz vaginal European Society for Human Reproduction and Embryology 29 2.4 9 5 219 1.9 probe (Toshiba Medical Systems, Europe BV, Zoetermeer, The Netherlands) from cycle day 9 onwards. When a leading follicle (.10 mm diameter) was detected, ultrasonographic monitoring was performed every other day until ovulation had occurred. Progesterone concentrations were determined 1 week later. Progesterone was estimated in a commercially available heterogeneous competitive magnetic separation immunoassay (Bayer, Tarrytown, NY, USA). The total variation coefficient is between 2.8 and 13.8%). If the patient did not respond to naltrexone alone, 100 mg of clomiphene citrate for 5 days was added to the continuous naltrexone therapy. If ovulation was demonstrated, the present treatment was continued using basal body temperature chart (BBT) instead of ultrasound detection of ovulation. Up to six cycles per patient were included in this study. Ovulation was considered to have taken place in the case of ultrasonographic signs of ovulation, and/or elevated midluteal progesterone (.30 nmol/l), and/or biphasic BBT, and/or resumption of a regular menstrual cycle and if pregnancy occurred. Naltrexone was discontinued in the case of a positive pregnancy test or when patients had no follicular growth after 21 days of combined naltrexone and clomiphene citrate treatment. Hormone assays Baseline hormone samples were drawn at day 1, 2, 3 or 4 of a spontaneous or progestagen-induced menstrual bleeding. All hormones were assayed by commercially available kits. Plasma LH and FSH concentrations were determined in a het (...truncated)