Chemistry: molecular biology and microbiology – Kit
Reexamination Certificate
1995-05-05
2002-12-10
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Kit
C514S002600, C514S015800, C514S021800, C530S313000
Reexamination Certificate
active
06492177
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the treatment of polycystic ovarian disease (PCOD), and in particular a treatment for infertility associated therewith.
2. Related Prior Art
PCOD is a complex syndrome comprising a disorder of multiple etiologies involving a vicious circle of imbalance between various interdependent endocrine and peripheral structures. The syndrome is characterised by a variety of symptoms, some or all of which may be present in any one individual. These include menstrual abnormalities, hyperandrogenism, infertility and bilateral polycystic ovaries. Observations on the levels as well as the secretion and metabolism of the sex hormones helps to identify the pathophysiology of the syndrome.
Recently, several reports appeared showing that polycystic ovary diseases may be connected with acanthosis nigricans and insulin resistance. (For instance see: Kahn C R, Flier J S, Bar R S, Archer J A, Gordon P, Martin M M, Roth J: “The syndrome of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man.” New Engl J Med 294:739, 1976; Burghen G A, Givens J R, Kitabachi A E: “Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease.” J. Clin. Endorinol. Metab. 50:113, 1980; and Shapiro A G: (1981). “Pituitary adenoma, menstrual disturbance, hirsutism and abnormal glucose tolerance.” Fertil Steril 35: 226, 1981.) This indicates clearly that PCOD may be linked with insulin action and its control.
It also became apparent that growth factors (GF) play a modulating role in the ovarian response to gonadotropic stimulation as described by Adashi E A, Resnick C E, Svoboda M E, van Wyk J J: “Somatomedin C enhances induction of LH receptors by FSH in cultured rat granulosa cells.” Endrocrinol. 116:2369, 1988. Homburg et al (“Growth hormone facilitates ovulation induction by gonadotropins,” Clin. Endocrinol. 29:113, 1988) demonstrated that the addition of growth hormone (hGH) to menopausal gonadotropin (hMG) therapy reduced the amount of gonadotropins required for ovulation induction. Blumenfeld & Lunenfeld (“The potentiating effect of growth hormone on follicle stimulation with human menopausal gonadotropins in a panhypopituitary patient”. Fertil. Steril. 25:238, 1989) demonstrated that patients with panhypopituitarism require excessive amounts of gonadotropins which can be reduced by concomitant administration of growth hormone. Menashe et al (“Does endogenous hormone reserve correlate to ovarian response to menopausal gonadotropins?” Isr. J. Med. Sci. 25:296, 1889) showed that anovulatory women with reduced growth hormone reserve (as established by the clonidine growth hormone reserve test) needed significantly more gonadotropins to induce follicular maturation and ovulation than women who were clonidine positive.
Urdl, in “Polycystic ovarian disease: Endocrinological parameters with specific reference to growth hormone and somatomedin-C.” Arch. Gynecol. Obstet. 243:13, 1988, studied 33 women with polycystic ovarian disease and in 18 of them observed decreased hGH levels and increased Somatomedin-C (Sm-C) values. Pekonen et al in “Decreased 34K insulin-like growth factor binding protein in polycystic ovarian disease”. Fertil. Seteril. 51:972, 1989, found that patients with PCOD had decreased levels of human insulin-like growth factor-1 binding protein (hIGFBP-1).
All these observations indicate definitely that growth hormone and other growth factors as well as their binding proteins may play an important role in pathophysiology of PCOD.
Growth hormone (GH) stimulates the systemic release of insulin-like growth factor-1 (ICF-1) from the liver. GH and probably other growth factors binding protein is also produced by the liver. Moreover, Leung and co-workers in “Growth hormone receptor and serum binding protein: purification, cloning and expression.” Nature 330:537, 1987, showed that the growth hormone receptor from rabbit liver and the growth hormone binding protein from rabbit serum having the same amino-terminal amino-acid sequence indicating that the binding protein corresponds to the extracellular hormone-binding domain of the liver receptor. It is becoming clear that the liver must play an important role in both normal and abnormal function of the ovaries.
At this stage the inventor believes that PCOD is connected with higher levels of free IGF-1 (Somatomedin C). Since Somatomedin C increases the ovarian response to gonadotropins, this may explain the excessive production of androgens by the luteinising hormone (LH) responsive structural ovarian components. Furthermore, it also explains the hyper-responsiveness of the ovarian follicular elements to follicle stimulating hormone (FSH) stimulation. If so, one pathophysiological basis of the PCOD could be explained as follows: the increased levels of free IGF-1 result in excessive follicular stimulation on the one hand and in overproduction of androgens leading to follicular atresia on the other hand.
PCOD has been treated by several schemes. Since the syndrome is associated with increased levels of androgen, one treatment is to remove a section of androgen-producing tissue (ovarian wedge vesection) but this has now been replaced wherever possible by hormonal therapy. Administration of glucocorticoid reduces excessive androgen production mostly of adrenal origin and has been used with relative success in the management of PCOD treatment originating from adrenal disease. Antiestrogens such as clomiphene citrate have also been used. Luteinising hormone releasing hormone analgoue has been shown to suppress PCOD by Chang et al in J. Chem. Endomet. Metab. 56:897 (1983).
Woodruff et al in U.S. Pat. No. 5,102,868 propose to treat PCOD by inhibiting maturation of follicles by administering activin to the ovary of a female PCOD sufferer. The activin composition is administered directly to the ovary or the immediate surrounding area. Activin is a member of family of growth and differentiation factors which includes also transforming growth factors and is a dimer of inhibin &bgr; subunits. It has been shown to have follicle stimulating hormone releasing activity, suppresses androgen production, and inhibits progesterone production. Its activity in showing the rate of follicular maturation of PCOD patients is due to its activity as an intragonadal down-regulator of reproductive function.
Human menopausal gonadotropin (hMG) (eg a 50:50 mixture in I.U. of follicle stimulating hormone (FSH) and luteinising hormone (LH)) and urofollitrophin (FSH substantially free of LH) have been used to treat infertile PCOD patients. Urofollitrophin may be preferred as these patients are prone to hyperstimulation by LH. All gonadotropin therapy is subject to the risk of ovulation of multiple follicles and hyperstimulation. It has also been proposed to suppress endogenous secretion of gonadotropins by administration of a gonadotropin releasing hormone (GnRH) analogue prior to administration of exogenous gonadotropins and this does have some benefits as described by Coutts et al in Exerpta-Media Int. Congress Series 652:608, 1984.
However since hIGFBP-1 and the level of free or bond IGF-1 are not affected by GnRH analogues, it is also logical that in this group of PCOD patients, the basic ovarian response to hMG or hFSH (urofollitrophin) stimulation is not significantly changed by pituitary down regulation.
It has been proposed to use as a contraceptive regimen the administration of luteinising hormone releasing hormone (LHRH) analogues as these have been found to block ovulation. Crowley in U.S. Pat. No. 4,762,771 discloses that LHRH analgoue administration alone leads to side effects of estrogen deficiency and proposes overcoming these by administering estrogen simultaneously with the LHRH analogue and, in a latter stage of the menstrual cycle, adding also a progestrational steroid. The method is designed to inhibit ovulation.
SUMMARY OF THE INVENTION
According to the present invention there is provided method of treating PCOD in which a gonadotropin releasin
Applied Research Systems ARS Holding NV
Gucker Stephen
Kunz Gary L.
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