D. W. Polson

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.

OVULATION OF A SINGLE DOMINANT FOLLICLE DURING TREATMENT WITH LOW-DOSE PULSATILE FOLLICLE STIMULATING HORMONE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME

Ten women with clomiphene‐resistant chronic anovulation associated with polycystic ovary syndrome were treated with purified urinary FSH (urofollitro‐phin). The gonadotrophin was given s.c. by pulsatile infusion pump starting at a low dose (1 ampoule or 75 U/d) and increasing by 37‐5 U/d at weekly stages in an attempt to induce ovulation of a single follicle. Seventy percent of the 33 cycles were ovulatory and in 18 of these (78%) a single dominant follicle developed and ovulated. Each of the 10 women ovulated when the optimum dose was reached and five of these women became pregnant. The maximum dose of FSH in uniovulatory cycles was 150 U/d or less. Endogenous LH concentrations which were raised at the onset of treatment were suppressed in the late follicular phase. The rate of follicular growth and gonadal steroid concentrations were consistent with those observed in spontaneous ovulatory cycles. This study demonstrates that by using low‐dose gonadotrophin therapy it is possible to find the‘threshold’ dose of FSH to promote maturation of a single dominant follicle. The high rate of ovulation and pregnancy suggest that this approach is of practical importance in treatment of infertile patients with polycystic ovaries.

THE DISTRIBUTION OF OESTRADIOL IN PLASMA IN RELATION TO UTERINE CROSS‐SECTIONAL AREA IN WOMEN WITH POLYCYSTIC OR MULTIFOLLICULAR OVARIES

The uterine cross‐sectional area (UXA) of women with polycystic (PCO) or multifollicular ovaries (MFO) is significantly larger and smaller, respectively, than those of normal women during the early‐mid‐follicular phase of the menstrual cycle. In the present study the distribution of oestradiol in plasma from normal women and women with PCO or MFO was measured to determine if differences in the available fractions of oestradiol could account for the differences in UXA of women with PCO or MFO. No differences in plasma levels of oestradiol were detected and the concentrations of oestradiol present in a free state or bound to albumin were similar in normal women and women with PCO or MFO. The concentration of oestrone was significantly higher in plasma from women with PCO (516 ± 120 pmo1/1, mean ± SD) than in plasma from women with MFO (389 ± 91 pmo1/1) or normal women (376 ± 89 pmo1/1). Differences in UXA for women with PCO or MFO as compared with normal women cannot therefore be attributed to differences in available oestradiol concentrations. It is possible that abnormalities in oestrogen metabolism within uterine or other tissues may account for the UXA of women with PCO or MFO. Increased plasma oestrone levels in women with PCO may provide more substrate for conversion to oestradiol within the uterus whilst the smaller UXA of women with MFO may reflect both lack of normal cyclical increases of oestradiol and formation of biologically inactive oestradiol metabolites.

OVULATION AND NORMAL LUTEAL FUNCTION DURING LHRH TREATMENT OF WOMEN WITH HYPERPROLACTINAEMIC AMENORRHOEA

Five patients with hyperprolactinaemic amenorrhoea who had been resistant to, or intolerant of bromocriptine were treated with pulsatile LHRH therapy. Ovulation was induced in 9 of 12 treatment cycles. In one patient hyperstimulation occured in the first cycle of treatment but subsequently she ovulated normally on a reduced dose of LHRH. The gonadotrophin and ovarian responses to treatment in ovulatory cycles were normal despite prolactin concentrations that remained elevated throughout treatment and rose still further with resumption of ovarian activity. The length of the luteal phase and the mid‐luteal serum progesterone concentrations were also normal. Pulsatile secretion of progesterone in response to LHRH pulses was observed. These data show that ovulation and normal luteal function can be induced by physiological LHRH replacement in women with persistent hyperprolactinaemia. This confirms that the mechanism of anovulation in hyperprolactinaemic amenorrhoea is disordered LHRH secretion.

BROMOCRIPTINE TREATMENT OF WOMEN WITH CLOMIPHENE‐RESISTANT POLYCYSTIC OVARY SYNDROME

Twenty‐three patients with polycystic ovary syndrome and anovulatory infertility have been treated with bromocriptine. All had previously failed to respond to clomiphene. Twenty had normal serum prolactin concentrations and, of these, four (20%) developed regular ovulatory cycles. All three women with moderate hyperprolactinaemia ovulated regularly on bromocriptine so that, overall, seven of 23(30%) responded, which was a significantly higher proportion than that observed during a control period of no treatment. A further eight women ovulated at least once during the study period but these occasional ovulations were no more common during bromocriptine than with either clomiphene or no treatment. No suppression of LH was noted except during the luteal phase of ovulatory cycles and there was no change in the pattern of pulsatile release of LH. Testosterone and androstenedione concentrations remained elevated and unchanged. We conclude that bromocriptine may be expected to induce ovulation in hyperprolactinaemic women with polycystic ovary syndrome but that there is no clear indication for its use in clomiphene‐resistant patients with normal serum prolactin concentrations.

REDUCED FREQUENCY OF LUTEINIZING HORMONE PULSES IN WOMEN WITH WEIGHT LOSS‐RELATED AMENORRHOEA AND MULTIFOLLICULAR OVARIES

We have studied pulsatile secretion of LH in 10 women with secondary amenorrhoea and multifollicular ovaries (MFO). This group of patients have a history of mild to moderate, or partially recovered weight loss. They have normal basal LH concentrations but evidence of oestrogen deficiency suggesting a hypothalamic abnormality of gonadotrophin regulation. The results of gonadotrophin pulse analysis were compared with those in normal women during the early follicular phase of the cycle. The mean LH concentration during the 8 h study (5.0 ± 0.9 [SD] U/l) was not significantly different from that in normal women (5.7 ± 2.5). There was no difference between the groups in mean LH pulse amplitude (2.1 ± 0.5 in MFO; 2.2 ± 1.3 in normal women). The frequency of LH pulses was, however, significantly lower in women with MFO (2.8 ± 1.6 vs 4–8 ± 1.5, P<0.05). Two women with MFO had LH pulses of normal frequency. One subsequently developed a normal pattern of ovarian follicles. The other showed a sleep‐related rise in LH concentrations during a 24 h profile which was similar to the pattern of gonadotrophin secretion normally observed during late puberty. These results show that women with MFO have a hypothalamic disturbance of gonadotrophin regulation with slowing of LH pulses without a diminution of pulse amplitude.

RECOVERY OF LUTEAL FUNCTION AFTER INTERRUPTION OF GONADOTROPHIN SECRETION IN THE MID-LUTEAL PHASE OF THE MENSTRUAL CYCLE

Ovulation was induced by a pulsatile infusion of GnRH in a patient with hypogonadotrophic amenorrhoea. In order to investigate the effect of short‐term withdrawal of gonadotrophin support in the luteal phase, the pulsatile infusion was stopped 3 d after ovulation and restarted 48 h later. After stopping the pump gonadotrophin and progesterone concentrations fell rapidly to very low levels, but when the infusion was restarted progesterone concentrations returned to normal mid‐luteal values. Menstruation occurred 14 d after the LH surge. We conclude that normal progesterone secretion by the corpus luteum can be restored after temporary withdrawal of gonadotrophin support.

Pulsatile infusion of gonadotrophin releasing hormone (GnRH): investigative and therapeutic applications.

Normal gonadotrophin secretion, and therefore normal ovarian function, depend on delivery to the pituitary of the hypothalamic neuropeptide gonadotrophin releasing hormone (GnRH) in a pulsatile pattern. In the mid-follicular phase of the menstrual cycle, for example, discrete pulses of luteinizing hormone (LH) can be observed at approximately 90 min intervals. Many disorders of ovulation are caused by abnormalities of this natural pulsed signal. We have developed and used a small portable infusion pump to deliver GnRH to women with hypothalamic amenorrhoea; our studies, and those of other groups, have shown that successful ovulation and pregnancy result from such treatment. The results of treatment at St Marys Hospital show that 16 women with hypogonadotrophic amenorrhoea received a total of 31 cycles of treatment with pulsatile GnRH; 25 (81%) of these cycles were ovulatory and 11 of the 14 women who were trying to conceive became pregnant. There was only one multiple pregnancy (twins).

A Spectrum of Disorders of LH Pulsatility in underweight women with Multifollicular Ovaries

In 1974 Boyar reported various abnormalities of pulsatile LH secretion in women with anorexia nervosa (1). In these and subsequent studies, it has been shown that the degree of disturbance of LH secretion is proportional to the extent of weight loss. The most severely underweight patients regress to a “prepubertal” state, with low gonadotrophin levels throughout the day and no detectable pulses (1). As these patients regain weight, the gonadotrophin levels show sleep-related rises, similar to the pattern seen in puberty.