Christine P. West

Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial

A randomized, double-blind, placebo-controlled trial of cotreatment with biosynthetic, human sequence, growth hormone (GH), and human menopausal gonadotropins (hMG) for induction of ovulation was performed in 16 women with amenorrhea and anovulatory infertility. Patients were randomly allocated to treatment with hMG + GH (24 IU on alternate days, total dose 144 IU) or hMG + placebo. Those who received placebo were given GH in a subsequent course of treatment. On cotreatment with GH compared with placebo, there was a significant reduction in the required dose of hMG, duration of treatment, and the daily effective dose of gonadotropins. Serum insulin-like growth factor-I (IGF-I) rose during treatment with GH but not with placebo. We conclude that growth hormone augments the response of the human ovary to stimulation by gonadotropins. These results suggest a role for the use of GH in induction of ovulation.

Shrinkage of uterine fibroids during therapy with goserelin (Zoladex * ): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot

Thirteen premenopausal women with uterine fibroids were treated for a maximum of 6 months with a long-acting agonist of luteinizing hormone-releasing hormone (LH-RH), goserelin (Zoladex depot, ICI Pharmaceuticals, Macclesfield, UK) 3.6 mg, administered subcutaneously every 28 days. A 55% reduction (range, 38% to 84%) in uterine volume assessed by ultrasound was obtained. The greatest reduction (30%) was apparent within the first treatment cycle regardless of whether treatment was started in the early follicular or the luteal phase. Fibroid regression was inversely correlated with urinary estrogen concentration. Treatment was well tolerated and only one subject withdrew from the study before its scheduled completion. Following cessation of therapy, ovulatory menstruation returned within 3 months in the majority of the subjects, but this was accompanied by a rapid regrowth of the fibroids. This medical approach to the management of fibroids merits further investigation but as yet cannot be regarded as an alternative to surgery.

The binding of epidermal growth factor to the human uterus and leiomyomata in women rendered hypooestrogenic by continuous administration of an LHRH agonist

Summary. The binding of epidermal growth factor (EGF) to human myometrium and leiomyomata was assessed in a group of women rendered hypo‐oestrogenic with the LHRH agonist Zoladex (ICI118630). The results were compared with those obtained with tissues from women with normal cycles. Tn normal women, the specific binding of radiolabelled [125I] EGF to both myometrial and fibroid homogenates did not vary during the menstrual cycle, but the specific binding of [125I] EGF to fibroid in women treated with LHRH agonist was significantly less than in the untreated group. Since the hypo‐oestrogenic state induced by the agonist is associated with a decrease in fibroid size, the results suggest that the effect of oestrogen on fibroid tissue may partly be mediated by EGF.

Treatment with the gonadotrophin releasing hormone-agonist goserelin before hysterectomy for uterine fibroids

Objective To investigate the effect of the gonadotrophin releasing hormone (GnRH)‐agonist goserelin, given by monthly subcutaneous injection for three months prior to total abdominal hysterectomy for uterine leiomyomata, on the pre‐operative symptoms, difficulty of operation and operative blood loss.

SUPPRESSION OF OVARIAN ACTIVITY BY ZOLADEX DEPOT (ICI 118630), A LONG-ACTING LUTEINIZING HORMONE RELEASING HORMONE AGONIST ANALOGUE

A long‐acting LHRH agonist, Zoladex depot 3–6 mg, was administered as a monthly s.c. injection to seven premenopausal volunteers for a maximum of 6 months, starting in the luteal phase of the cycle. Transient stimulation of gonadotrophin release was observed 24 h after the initial depot, followed by sustained suppression of plasma LH, while FSH levels returned to the normal range. Plasma oestradiol concentrations fell to early follicular phase values within 14 d. Twice‐weekly monitoring of urinary oestrone‐3‐glucuronide and pregnanediol demonstrated inhibition of ovulation and almost complete suppression of ovarian follicular activity throughout therapy. All the subjects became amenorrhoeic. Mean plasma testosterone concentrations were also significantly reduced while androstenedione remained within the pretreatment range. SHBG concentrations were not significantly reduced. After cessation of therapy, postovulatory menstruation occurred within 80 d of administration of the last depot.

A double-blind study comparing a new non-ergot, long-acting dopamine agonist, CV 205-502, with bromocriptine in women with hyperprolactinaemia

Twenty‐two hyperprolactinaemic women were randomly allocated to two groups and treated with bromocriptine or the new, non‐ergot, long‐acting dopamine agonist, CV 205‐502. The study was double‐blind for 6 months. Four patients in the bromocriptine group, but none in the CV 205‐502 group, discontinued the study because of adverse reactions. Adverse reactions in those receiving the new drug were milder and more transient than with bromocriptine. With once‐daily doses of 0.075 mg CV 205‐502, eight of 11 women achieved normal PRL concentrations after 8 weeks treatment (median (95% confidence limits), 352 (70‐987) mU/1) compared with two of nine receiving a divided daily dose of 5 mg bromocriptine (1802 (1205‐4438) mU/1) (P < 0.002). With doses of 0.075‐0.15 mg of CV 205‐502, 10 of 11 women achieved normal PRL concentrations at 24 weeks compared with three of the remaining seven women on doses of 5‐10 mg of bromocriptine. Regular menstrual bleeding was restored and galactorrhoea relieved in the majority of patients, with marginally greater efficacy with CV 205‐502. CV 205‐502 is highly effective for the long‐term treatment of hyperprolactinaemia. It is better tolerated than bromocriptine, is effective in a once‐daily dose, appears to be safe, and provides a valuable alternative to the dopamine agonist drugs in use today.

Estrogenic action of tamoxifen in women treated with luteinizing hormone-releasing hormone agonists (goserelin)—lack of shrinkage of uterine fibroids

Six premenopausal women with uterine fibroids were treated with a combination of tamoxifen, 20 mg/d, and goserelin, 3.6mg every 28 days, for a total of 24 weeks. Results were compared with those from six women, matched for pretreatment uterine volume, who had been treated with goserelin alone. During combined therapy, plasma and urinary estrogen concentrations were significantly lower than during goserelin alone, whereas sex hormone binding globulin concentrations were significantly higher. Plasma luteinizing hormone and follicle stimulating hormone (FSH) concentrations were both suppressed, in contrast with results during goserelin alone when FSH levels remained within the pretreatment range. None of the women on combined therapy bled in response to the endocrine changes of the initial treatment cycle. Despite this profound pituitary-ovarian suppression, there was no significant change in uterine volume during combined therapy. These results suggest that tamoxifen is acting as an estrogen agonist in women rendered hypoestrogenic with luteinizing hormone-releasing hormone agonists.

9 Fibroids and menorrhagia

Summary Fibroids are an important cause of menorrhagia, resistant to conventional methods of medical treatment. The mechanism of their effect on menstrual blood loss is poorly understood but may involve abnormalities of local venous drainage, enlargement of the uterine cavity and abnormalities in prostaglandin production. Their cause remains unknown although it has long been assumed that they are oestrogen-dependent. In the past, study of their aetiology, prevention and treatment has received scant attention. Recent developments including measurement of tissue receptors for steroids and growth factors, non-invasive methods of monitoring fibroid growth and the use of LHRH agonists have enabled further study of their nature and of their response to therapy although much work remains to be done. The majority of women with uterine fibroids associated with menorrhagia are treated by hysterectomy although developments in endoscopic surgery have enabled a more conservative approach in some circumstances. LHRH agonists are the only medical agents which cause substantial shrinkage of fibroids although regression is not permanent. These agents are of value in short-term relief of symptoms and are likely to be a useful adjunct to surgery by reducing both uterine volume and bloodflow. However, because of the consequences of prolonged ovarian suppression, they are not suitable for long-term use unless there are medical contraindications to surgery. It remains to be seen whether their use in low-dose regimens or in combination with other agents will provide a successful, safe and cost-effective alternative to hysterectomy in women whose primary problem is heavy menstrual loss. They do however offer a means of conserving reproductive function in women wishing to retain this option.

A COMPARATIVE STUDY OF SINGLE‐DOSE GROWTH HORMONE THERAPY AS AN ADJUVANT TO GONADOTROPHIN TREATMENT FOR OVULATION INDUCTION

One intramuscular injection of biosynthetic human growth hormone (24 IU), administered on the first day of gonadotrophin treatment for ovulation induction, significantly augmented the ovarian response to gonadotrophic stimulation in seven patients. Compared with a protocol involving six injections of 24 IU of GH given on alternate days to the same patients, the smaller dose had an intermediate but highly significant effect in reducing the amount, duration of treatment and daily effective dose of hMG needed to induce ovulation. The difference between the effect of the one‐dose and six‐dose protocols was small. The action of growth hormone on the human ovary, probably mediated by insulin‐like growth factor‐1 (IGF‐1), appears effective in enhancing the response to gonadotrophin therapy even when given in a single dose.

Tamoxifen prolongs luteal phase in premenopausal women but has no effect on the size of uterine fibroids

Tamoxifen (20 mg per day) was administered for at least 3 months to six premenopausal women with uterine fibromyomata. In all the women there was an increased variability in the length of the menstrual and ovarian cycle associated with a significant lengthening of the luteal phase (16.9 ± 3.5 vs 12.5 ± 1.5 days, mean ± SD, P < 0.02). The concentration of oestradiol and progesterone in plasma and their metabolites in urine (oestrone glucuronide and pregnanediol) increased reflecting multiple follicular development and ovulation. There was a significant rise in the concentration of FSH during the luteal phase of the cycle (8.0 ± 2.9 vs 2.0 ± 1.7 U/I, P < 0.01). There was no change in the size of the uterine leiomyomata. These results demonstrate that the antioestrogen tamoxifen results in an increased secretion of gonadotrophins by antagonizing the effects of oestradiol at the hypothalamus and anterior pituitary. The lengthening of the luteal phase suggests oestradiol may play a role in the mechanism of luteal regression either locally or via feedback effect on gonadotrophins.