Medical Hypophysectomy Research Articles

Hormonal Therapies in Cancers.

The hormonal therapy for cancer has become a household name and the series of experiments performed leading to the discovery of hormones use in the treatments of breast cancer. The hormones like antiestrogen, aromatase restrictors, antiandrogens, and use of extremely strong luteinizing hormone-releasing hormone agonists to perform a "medical hypophysectomy" because of their ability of causing desensitization in the pituitary gland have proven their value in the treatment of cancers over the last two decades. Millions of women still use hormonal therapy for menopause symptoms. Estrogen plus progestin or estrogen separately utilized as a menopause hormonal therapy throughout the world. Women receiving different premenopausal and postmenopausal hormonal therapies are on higher risk of having ovarian cancer. The risk of ovarian cancer did not increase with the increase of duration of hormonal therapy. Postmenopausal hormone use was found to be inversely related to major colorectal adenomas.

Traditional Approaches to Androgen Deprivation Therapy

For most of the past 25 years, 1 of the favored approaches to treating prostate cancer has been the suppression of circulating testosterone with luteinizing hormone-releasing hormone (LHRH) agonists. LHRH agonists produce a downregulation of LHRH receptors and an uncoupling of the LHRH signal transduction mechanism. This leads to a marked reduction in the secretion of bioactive hormones stimulating testosterone production and eventual induction of a reversible, but transient and incomplete, state known as “selective medical hypophysectomy.” The treatment with LHRH agonists has proved effective in many settings; however, the dosage and timing strategies depend critically on the patient's disease risk and progression. More recent investigations have suggested that a newer, quicker acting, pure gonadotropin-releasing hormone antagonist might be a preferable treatment approach. It remains a fundamental truth, however, that hormonal therapy is both overused and more toxic than generally appreciated. Therefore, a complete understanding of the indications and applications of this approach is essential for the practice of evidence-based medicine.

Serum luteinizing hormone, follicle-stimulating hormone and oestradiol pattern in women undergoing pituitary suppression with different gonadotrophin-releasing hormone analogue protocols for assisted reproduction

Gonadotrophin-releasing hormone analogues (GnRH-a) are used widely in controlled ovarian stimulation (COS) cycles for assisted reproduction. At present, there is great debate about the influence of exogenous hormone activity on the hypothalamus–pituitary axis following pituitary desensitization. The objective of this comparative study was to investigate the pattern of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and oestradiol in women undergoing ovarian stimulation with different GnRH-a preparations. We retrospectively analysed 201 women, aged between 27 and 43 years, who were referred consecutively to our infertility clinic between January 2002 and January 2003. All women had no endocrinopathies or occult ovarian failure as assessed by day-3 hormone profile. Women were enrolled in one of the following COS protocols: depot triptorelin long protocol (n = 38), buserelin long protocol (n = 101) or buserelin short protocol (n = 62). Recombinant FSH was used to induce ovulation. Treatment was monitored by transvaginal ultrasound scan and serum measurement of FSH, LH and oestradiol. Among the women initially included, 30 had cancelled cycles due to poor ovarian response. Serum LH levels were significantly higher in the short-protocol group compared with the long-protocol groups (p < 0.001). The number of follicles, oocyte yield, number of grade-I embryos and fertilization rate were significantly lower in the short-protocol group than in the long-protocol groups. These findings showed that LH concentrations are significantly higher in women undergoing reversible medical hypophysectomy with a GnRH-a short protocol than in women treated with a long protocol. The hypothesis of an LH ceiling is confirmed.

The role of gonadotropins in follicular development and their use in ovulation induction protocols for assisted reproduction

During the 1960s, hypogonadotropic patients with polycystic ovary syndrome and those with clomiphene citrate resistance were the first to achieve pregnancy after urinary human menopausal gonadotropin (hMG) administration plus preovulatory human chorionic gonadotropin injection, with cumulative pregnancy rates ranging from 40% to 80% after six to 12 treatment cycles. Ever since, dramatically more progress has been achieved regarding methods and medication in assisted conception techniques, involving both a rapidly increased number of subfertile couples, as well as many practitioners in obstetrics and gynecology. The purpose of this review was to highlight the most crucial historical steps of this remarkable process, by emphasizing the role of gonadotropins in ovulation induction protocols according to the various clinical categories of subfertile patients. In the late 1970s, urinary hMG was the most widely used gonadotropin for ovarian stimulation during in vitro fertilization-embryo transfer for assisted reproduction. The often concurrent problems of premature luteinizing hormone (LH) surges and premature luteinizations, and thus cancellations of the cycles, were efficiently overcome by ‘reversible medical hypophysectomy’, performed by gonadotropin releasing hormone (GnRH) analogs, introduced in 1982. According to its initiation and duration, GnRH analog use was divided into three protocols: the long, most widely used, protocol, which was the best for suppression of endogenous, high tonic LH levels, especially in polycystic ovary syndrome and normogonadotropic patients; and the short and ultra-short protocols, which were mainly used in poor responders to ovarian stimulation treatment, older or hypergonadotropic patients with ovarian failure, because of the well-known ‘flare-up phenomenon’. Recently, GnRH antagonists, which directly do not permit GnRH action by binding to the GnRH gonadotropic cell receptors, have been used, but no final results from large, multicenter clinical trials that are still being undertaken have yet been achieved. Various sub-products of urinary hMG have been produced since the 1980s, with the intention of eliminating most or all of the LH, such as a form with a 3 : 1 proportion ratio between follicle stimulating hormone (FSH) and LH, as well as a form resulting in the removal of almost all of the LH, the ‘pure’ urinary FSH. Finally, in the mid-1990s, recombinant pure FSH was produced in vitro from hamster ovarian cell cultures. The theoretical basis for the broad use of pure urinary FSH and recombinant FSH is that the very low endogenous LH levels after pituitary desensitization are sufficient for proper theca steroidogenesis; still, data in the literature and clinical experience may be controversial upon that issue. From the clinical point of view, clinicians nowadays tend to stimulate polycystic ovary syndrome patients with recombinant FSH plus the application of GnRH analogs in along protocol. However, in poor responders, patients in whom ovulation is resistant to clomiphene citrate, those older than 40 years or hypergonadotropic patients with ovarian failure, urinary hMG, because endogenous LH levels are obviously not sufficient for proper steroidogenesis in the theca cells of the follicles of these patients, is necessary in add to the administration of GnRH analogs in a short or ultra-short protocol. Regarding normogonadotropic women (the majority of patients), most authors agree with the long-protocol application of GnRH analogs. In these patients, it is not certain whether recombinant FSH alone is sufficient for the best possible induction or whether exogenous LH administration in the form of urinary hMG still remains necessary.

The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers

The use of agonistic analogues of luteinizing hormone releasing hormone (LHRH) is an established therapy for hormone-dependent metastatic pre-menopausal breast cancer. Their mechanism of action in this disease is the suppression of ovarian oestrogen production (medical castration). In the treatment of post-menopausal metastatic breast cancer, LHRH agonists also have some effect, although minor, probably through a suppression of ovarian androgen production. Convincing evidence has been accumulated that LHRH analogues can directly inhibit the proliferation of breast cancer cells in vitro. The clinical impact of these findings, however, is still controversial. Experimental data and several pilot clinical trials suggest that in epithelial ovarian cancer and sex-cord-stromal tumours of the ovary, LHRH agonists might have antitumour activity through the suppression of gonadotrophin secretion (selective medical hypophysectomy). Phase III clinical trials, evaluating this hypothesis, are in progress. Direct antiproliferative effects of LHRH analogues on epithelial ovarian cancer cells have been demonstrated in vitro. In endometrial cancer, experimental and early clinical results support the concept of a direct antiproliferative activity of LHRH analogues. Recently, potent antagonistic analogues of LHRH, devoid of relevant side-effects have become available for clinical testing. These new antagonists might be superior to agonistic LHRH analogues with respect to the rapidity and efficacy of selective medical hypophysectomy and medical castration. Modern LHRH antagonists might also permit a better exploitation of direct antitumour effects. A further therapeutic improvement in gynaecological oncology might result from a combination of LHRH agonists or antagonists with other peptide hormone analogues such as agonists of somatostatin or antagonists of bombesin/gastrin releasing peptide which have antitumour activity. Since 50% of breast cancers and 80% of epithelial ovarian cancers and endometrial cancers have high affinity binding sites for LHRH, cytotoxic LHRH analogues might provide a targeted chemotherapy, which would be more efficacious and less toxic than conventional regimens.

Roles of FSH and testosterone in the initiation of spermatogenesis in prepubertal rats medically hypophysectomized by a GnRH antagonist.

Experimentally induced medical hypophysectomy in prepubertal rats through treatment of GnRH antagonist for 3 weeks, initiated on the 20th day of age, markedly decreased testicular weight by 85% of that of the controls. Quantitative assessment of spermatogenesis in testicular semithin preparations revealed a significant reduction in the numbers of preleptotene (27.2 +/- 1.6 to 15.6 +/- 0.52) and pachytene (25.8 +/- 0.96 to 5.35 +/- 0.26) spermatocytes and complete absence of any spermatids after the treatment. By contrast, round stage 7 and elongated spermatids were observed in many tubules of the testis in the age-matched control rats. At the end of GnRH antagonist treatment, the blood levels of LH were undetectable, while testosterone and FSH were decreased to 12 and 44% of the controls, respectively. Supplementation of either FSH (ovine FSH 20 micrograms/rat day-1) or testosterone (30 micrograms/rat day-1) enhanced the testicular weight (68%) and the circulatory levels of these hormones, but failed to support quantitatively normal spermatogenesis, which was, however, qualitatively improved. The number of maturing spermatids were comparatively higher in the testosterone-supplemented group that in the FSH-administered group. The latter group had otherwise the highest number of degenerating germ cells per tubule (mean 4.8 +/- 0.1). Testicular weight and stage-specific germ cell counts were restored to normalcy only in rats supplemented with both FSH and testosterone, the critical concentrations of which were important in the initial stages of spermatogenesis. Testosterone alone had a positive effect in terms of germ cell development, while FSH without testosterone was detrimental to the maturing germ cells.

10 The use of GnRH agonists with hMG for induction or stimulation of ovulation

To induce ovulation is to provoke follicular maturation and rupture in a patient who would not otherwise ovulate. To stimulate ovulation is to interfere with normal physiological ovarian regulation in order to intensify ovulatory phenomena. In the first case there is a pathological condition which prevents the patient from ovulating spontaneously, and drugs are used to try to correct this condition or to activate the ovary which would otherwise remain quiescent. The aim is to obtain maturation of one follicle which will release one oocyte ready to be fertilized. In the second case, the aim is to obtain several mature oocytes for in vitro fertilization. Both techniques use the same drugs in various regimens. Gonadotrophinreleasing hormone (GnRH) agonists have also been used, but their effects vary widely depending on whether the need is to induce or to stimulate ovulation. GnRH agonists can create a state of reversible medical hypophysectomy, suppressing the greatest part of endogenous follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion (Kenigsberg et al, 1984; Fraser and Sandow, 1985; Monroe et al, 1985). Their use, together with direct stimulation of the ovary by gonadotrophins, makes it possible to conduct follicular and oocyte maturation under exogenous influence only, with no risk of interference from possibly detrimental endogenous phenomena.

Biological basis of follicle growth.

Ovarian stimulation therapy is notoriously difficult to manage, partly because of the individual variability in response to exogenous hormones and hormone antagonists. The varied underlying pathophysiological conditions necessitating ovulation induction therapy were in great part causative of the different responses between patients. However, in-vitro fertilization therapy has provided a wider experience, particularly with ovarian stimulation in endocrinologically normal women. From these data, there is much inherent variability of response to exogenous gonadotrophins evident, even in these 'normal patients'. Furthermore, individual response types tend toward a consistent pattern from cycle to cycle, suggesting a constancy of physiological status, as opposed to a stoichastic response. In this study, we are seeking ways of reducing individual variability of responses to gonadotrophin therapy based on understanding the physiological origin. Our first objective is to identify the source of individual variability in the hypothalamic--pituitary ovarian axis. We developed a new experimental primate model, the reversible 'medical hypophysectomy', achieved by administration of a gonadotrophin-releasing hormone (GnRH) antagonist to negate endogenous gonadotrophin secretion. The second objective is to assess the validity of our model for medical hypophysectomy. Effective doses and regimens of the GnRH antagonist applications are determined. The third objective is to study the differential actions of follicle-stimulating hormone (FSH) treatment alone versus combined FSH/luteinizing hormone (LH) therapy on the ovary. In summary, it is concluded: (i) individual variation in ovarian response to gonadotrophin therapy in monkeys is, in large part, supra-ovarian in origin, although failure to respond to gonadotrophins was not negated by GnRH antagonist treatment. Furthermore, a milieu approaching 'medical hypophysectomy' using a potent GnRH antagonist deserves consideration as a clinically applicable strategy to reduce variability among responders, thereby improving patient management. (ii) In our monkey model, the GnRH antagonist promptly produced a relatively hypogonadotrophic state that was reversible. These findings have implications for both fertility and anti-fertility research. (iii) The two-cell theory requiring co-ordinate action of both FSH and LH to achieve ovarian steroidogenesis culminating in a dynamic oestrogen production, may be re-examined. Indeed, the importance credited to the ratios of these gonadotrophins is surely open to question.

Hot flushes during Gn-RH analogue administration despite normal serum oestradiol levels

Five out of 6 normally-menstruating women who were treated with a potent gonadotropin-releasing hormone (Gn-RH) agonist in order to achieve medical hypophysectomy developed hot flushes despite having normal oestradiol (E 2) levels. The Gn-RH agonist was administered subcutaneously for 6 days and then intranasally for a further 14 days. A dose of 2 mg of E 2 benzoate was injected intramuscularly once a week for 2 consecutive weeks. This combined treatment resulted in low peripheral gonadotropin levels but normal serum E 2 concentrations. Four (4) women developed mild to moderate hot flushes and there was 1 case of flushes severe enough to necessitate cessation of treatment. The flushes occurred in the second week of Gn-RH analogue treatment when the level of serum luteinizing hormone (LH) was low and the pituitary was unresponsive to provocative tests, despite the fact that the patients' E 2 levels were normal (mean 250 ± 25 pg/ml). It is suggested that neither LH pulsatility nor low peripheral E 2 levels are mainly responsible for the development of hot flushes. It is possible that Gn-RH, a hypothalamic decapeptide, may play a major role or act as a mediator in the aetiology of hot flushes.

Pituitary and ovarian suppression rate after high dosage of gonadotropin-releasing hormone agonist

Ten infertile menstruating women were treated with daily injections of gonadotropin-releasing hormone agonist (GnRH-a). The GnRH-a (Buserelin; Hoe 766, Hoechst-AG, Frankfurt/Main, West Germany) was administered subcutaneously (SC) from day 9 of the cycle for 6 days, and intranasally (1.2 mg) for 15 days. Before treatment, all ten women had a normal response to Buserelin challenge test and the GnRH test, and seven of the ten responded to estradiol (E2) benzoate test (2 mg intramuscularly). The SC administration of Buserelin (1.5 mg) for 6 days resulted in suppression of pituitary activity. Continuous treatment with Buserelin (1.2 mg for 3 weeks) was effective as demonstrated by decreasing serum E2 levels to below 20 pg/ml, and in the absence of ovarian follicles in ultrasonographic scanning. Three days after cessation of Buserelin treatment, the pituitary again responded to the GnRH test. Thus, the authors concluded that the administration of Buserelin in very high doses can induce medical hypophysectomy within 6 days, but over 3 weeks of suppression therapy are required to abolish ovarian findings. Desensitization of the pituitary was reversible within 3 days of cessation of the treatment.

Induction of ovulation with luprolide acetate and human menopausal gonadotropin

Four women with unexplained infertility and two anovulatory oligomenorrheic women who experienced repeated premature luteinization when treated with human menopausal gonadotropin (hMG) or gonadotropin-releasing hormone (GnRH) were given the gonadotropin-releasing hormone agonist (GnRHa), luprolide acetate, in order to effect medical hypophysectomy. This was followed by hMG for induction of ovulation. Four of the six patients had hMG-only cycles, which were compared with the luprolide acetate/hMG cycles. The luprolide acetate/hMG cycles resulted in normal folliculogenesis with presumptive ovulation. In luprolide/hMG cycles, significantly more hMG was needed for induction of ovulation than in hMG-only cycles. Premature luteinization was abolished with luprolide acetate treatment.

Abolishment of the positive feedback mechanism: a criterion for temporary medical hypophysectomy by LH-RH agonist.

The hypothalamic pituitary axis was studied in patients with an abnormal pattern of gonadotropin release during chronic treatment with LH-RH agonist. Two patients had PCOD and the third demonstrated the early luteinization phenomenon. Following a well-defined gonadotropin rise with initiation of LH-RH treatment, no further response was noted. Stabilization of the LH:FSH ratio in PCOD patients was noted after 4 weeks of treatment. Administration of both native LH-RH (100 micrograms) and intravenous pulsatile LH-RH did not evoke any rise in LH. In addition to the above LH-RH challenges, the positive feedback was examined by administration of estradiol benzoate (EB). The study demonstrated that, although the pituitary did not respond to any LH-RH challenge, it may still respond by a rise in LH following EB administration. Both functions of the hypothalamic pituitary axis should be examined in order to determine the state of medical hypophysectomy.

The treatment of postmenopausal women with advanced breast cancer with buserelin.

Repeated administration of long-acting analogues of gonadotrophin-releasing hormone down-regulates the pituitary gonadotrophins and gonadal hormones. The activity of these compounds in premenopausal women with breast cancer has been previously noted. In an attempt to cause a highly selective medical hypophysectomy 18 consecutive postmenopausal women with symptomatic advanced breast cancer were treated with intranasal buserelin in divided dosages of either 600 or 1000 micrograms daily. The pituitary gonadotrophins were suppressed in all patients, without objective evidence of response. This is in contrast with an earlier finding that the long-acting analogues of gonadotrophin-releasing hormone were effective in postmenopausal patients with breast cancer.

Medical hypophysectomy: II. Variability of ovarian response to gonadotropin therapy

In an attempt to control individual variability of ovarian response to gonadotropin therapy, ovulatory monkeys received either "pure" follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG), with or without gonadotropin-releasing hormone (GnRH) antagonist administration. Among females that responded to gonadotropin therapy, the GnRH antagonist reduced (P less than 0.05) the variability of serum estradiol patterns. Surprisingly, after pretreatment and concurrent administration of the GnRH antagonist, FSH alone was as effective as the FSH/luteinizing hormone (LH) mixture (hMG) in stimulating follicular maturation, even when serum LH levels were at or below the limits of detection. The results indicate that in a rapidly reversible hypogonadotropic state approaching a "medical hypophysectomy," concurrent gonadotropin therapy produces a less varied ovarian response. The relative (un)importance of LH in the primate ovarian cycle seems diminished in the face of evidence that FSH alone, or in the presence of vanishingly small amounts of LH, supports follicular maturation and dynamic estrogen biosynthesis.

Medical hypophysectomy: I. Dose-response using a gonadotropin-releasing hormone antagonist

The hypothalamic-pituitary-ovarian axis can be "dissected" in a nonsurgical and reversible fashion by the administration of a potent gonadotropin-releasing hormone (GnRH) antagonist. We created a transient, functional lesion at the level of the pituitary gonadotrope by using a potent GnRH antagonist ([ Ac- pClPhe1 , pClDPhe2 , DTrp3 , DArg6 , DAla10 ]-GnRH). In long-term castrate cynomolgus monkeys, doses of 0.05 to 2.0 mg/kg/day intramuscularly were administered for a total of 32 days. At doses up to 0.2 mg/kg/day, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in circulation were only moderately suppressed; these subjects responded to an estradiol challenge by manifesting an LH elevation or surge within 48 hours. At doses of 0.5 to 1.0 mg/kg/day, FSH and LH secretion was suppressed to or below the limits of assay detection within 7 days, remaining in a severely hypogonadotropic state for the remainder of the treatment interval. Using 2 mg/kg/day, estradiol-positive feedback for midcycle-like LH/FSH surges was fully inhibited. This suppression of gonadotropin secretion was rapidly reversible, in that circulating gonadotropin levels had returned to pretreatment castrate levels within 60 days after termination of GnRH antagonist treatments. These findings suggest that potent GnRH antagonists can effectively create a hypogonadotropic milieu without the initial enhancement of gonadotropin secretion that occurs during initiation of GnRH agonist therapy. "Medical hypophysectomy" through GnRH antagonist administration may permit a more direct and controlled approach to gonadal therapies such as ovulation induction.