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CONTRACEPTION. 1992 Aug; 46(2):103-4.WHO formed its Task Force on Methods for the Regulation of Male Fertility in 1972. Its charge is developing safe, effective, reversible, and affordable contraceptive methods for developing countries. The research focus is on suppression of sperm production. The research strategy consists of 3 parts: suppression of secretion of the pituitary gonadotropin hormones, recouping circulating androgen to physiological levels without prompting spermatogenesis, and determining the functional ability of residual sperm if treatment does not bring about azoospermia in all cases. A task Force study reveals that men of various ethnic groups respond to testosterone contraceptives differently. Other clinical research involved an androgen with a progestogen such as DMPA. Since steroids are basically inexpensive to produce they may prove to be beneficial and affordable to national family planning programs in developing countries. Gonadotropin releasing hormone (GnRH) antagonists proved to be relatively effective in suppressing gonadotropins and sperm production in animals. Scientists working on developing GnRH antagonists should strive to formulate a reversible contraceptive with no side effects which requires limited injections. The Task Force carried out a study in bonnet monkeys with the GnRH agonist buserelin in which buserelin suppressed spermatogenesis for 3 years and, after treatment, testicular function was entirely restored. Subsequent mating trials indicated they were fertile. The Task Force planned to follow the study with a GnRH antagonist. The 1st international gathering on GnRH analogues in China served to bring together scientists the world over to meet and to collaborate in developing new drugs for contraceptive use.
Advances in Steroid Biochemistry and Pharmacology. 1979; 7:1-8.Due to the numerous adverse side effects of steroidal contraceptives which continuously arise and result in potential decreases in the benefit-to-risk ratio, new chemical and biologic strategies need to be designed and implemented to assure continued success in the contraceptive area. Novel contraceptive stragegies include both new chemical classes and their receptive biologic targets. 4 basic pharmacologic approaches subserve female contraception: inhibition of ovulation; inhibition of fertilization; inhibition of implantation; and interruption of established implantation. Many diverse compounds have been evaluated in regard to a male contraceptive, but problems of toxicity and loss of libido have made the search difficult. The problem is further complicated by the task of trying to eliminate the hundreds of millions of sperm that are constantly being produced and which are in different stages of the spermatogenic cycle. This task calls for chronic dosing and the accompanying problem of eventual liver involvement and hypertrophy of the secondary accessory sex organs. An interesting area supported by the World Health Organization is the identification of plants and the isolation of their active principles for fertility regulating purposes. The United States National Institute of Health supports 3 major and separate programs related to contraception: 1) synthesis and testing of anti-ovulatory agents; 2) synthesis and testing of male contraceptive agents; and 3) peptide antagonists of LH-RH (luteinizing hormone-releasing hormone) as ovulation inhibitors. The following categories represent areas of research that might prove fruitful: LH-RH agonists; LH-RH antagonists; non-natural synthetic products; inhibin; and plant extracts. These categories are reviewed.
Design of studies for the assessment of drugs and hormones used in the treatment of endocrine forms of female infertility.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagen, Denmark, Scriptor, 1977. p. 135-154The lack of uniformity in diagnostic selection of women for treatment of infertility, in choice of therapy, in monitoring of therapy, and in follow-up, frequently does not allow a meaningful comparison of results reported from different centers. To design studies assessing effectiveness of therapy of endocrine forms of female infertility, it is essential to consider: 1) mechanism controlling reproductive functions (e.g., process of ovulation); 2) cause(s) responsible for infertility (mechanical factors, ovarian failure, and pituitary failure); and 3) the mechanism of action of agents used for therapy (e.g., gonadotropins stimulate gonadal function, clomiphene stimulates gonadotropin secretion, and ergoline derivatives inhibit prolactin secretion). Patients selected for therapy should be grouped according to etiology: 1) hypothalamic-pituitary failure; 2) hypothalamic-pituitary dysfunction; 3) ovarian failure; 4) congenital or acquired genital tract disorder; 5) hyperprolactinemic patients with a space-occupying lesion in the hypothalamic-pituitary region; 6) hyperprolactinemic patients with no space-occupying lesion; and 7) amenorrheic women with space-occupying lesion. Ideally, an infertile couple should be diagnosed and treated as a unit.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976). Copenhagan, Denmark, Scriptor, 1977. 72-87.Recent evidence has shown that spermatogenesis and steroidogenesis are not independent testicular functions, but rather represent a feedback mechanism. Spermatogenesis in mammals can be divided into 3 stages: 1) mitotic replication of stem cells, the spermatogonia; 2) the meiotic process involving primary and secondary spermatocytes; and 3) spermiogenesis--a complex series of cytological changes resulting in transition of conventional cell into a spermatozoon. These cytological changes include 1) elaboration of the acrosomal cap by the Golgi complex; 2) change in nuclear position from central to eccentric; 3) formation of axial filament and its associated organelles from Golgi-adjacent centrioles; and 4) rearrangement of the cytoplasm of spermatids toward the abaacrosomal pole of the spermatid. The kinetics of spermatogenesis show a biological constant for most species in duration of time for conversion from spermatogonia to sperm (64 days in humans). It is generally agreed that luteinizing hormone and follicle stimulating hormone are required for initiation of spermatogenesis at puberty in humans and rats, though controversy exists over whether both hormones are necessary for maintenance. The action of increasing doses of testosterone in suppressing and then stimulating spermatogenesis suggests that a high local concentration of testosterone is required for the spermatogenic process. Evidence supports high androgen concentration within the seminiferous tubules, but its entry route is still speculative. Relationship of Sertoli cell to spermatogenesis and hormonal interrelationship between the testis and hypothalamo-hypophyseal unit are discussed. Sperm maturation is attributed to: 1) inherent ability of sperm to mature, and 2) specialized environment of the epididymis.
In: Diczfalusy, E., ed. Regulation of human fertility. (Proceedings of the WHO Symposium on Advances in Fertility Regulation, Moscow, USSR, November 16-19, 1976) Copenhagan, Denmark, Scriptor, 1977. p. 21-71This chapter reviews the hormonal changes which occur during the menstrual cycle. During the last days of the preceeding menstrual cycle, plasma levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) increase. Follicular phase is characterized by gradually increasing estrogens. A few days preceding the LH surge, some little understood changes in estradiol, LH, and 17-hydroxyprogesterone, on one hand, and ACTH, cortisol, and aldosterone, on the other, occur. Evidence indicates that the estradiol peak occurs first, followed by a simultaneous rise and fall in LH and 17-hydroxyprogesterone values. The peak period of LH is about 32-44 hours long, during which time a rise in progesterone levels takes place. Other pituitary and steroid hormones (human chorionic gonadotropin, ACTH, prolactin, testosterine, androstenedione, cortisol, and aldosterone) show elevated levels during the periovulatory period. Ovulation occurs 16-48 hours after LH peak. The period following LH surge is characterized by rapidly increasing levels of progesterone, 17-hydroxyprogesterone, and 20-alpha-dihydroprogesterone, accompanied by moderately increasing estrogen levels to form the typical luteal-phase hormonal pattern. A luteal increase occurs also in levels of several other hormones, ranging from renin activity to angiotension, or from pregninolone to aldosterone. The last part of the luteal phase is characterized by rapidly declining levels of peripheral hormones. The perimenstrual phase around onset of heavy bleeding is characterized by gradually decreasing levels of progesterone, 20-alpha-hydroprogesterone, estradiol, and testosterone, associated with an incipient rise in LH and FSH levels.
Cyproterone acetate (CPA) a potential male contraceptive: further studies on the interactions with endocrine parameters.
Berlin, Germany, WHO-CCCR, . 11 p.This unpublished paper is the transcript of a conference proceeding, but the figures referred to textually are not included in the document. This study evaluated the effects of medium dose cyproterone acetate (CPA), 10-30 mg/day, on gonadotropin and peripheral androgen levels. On the average, luteinizing hormone (LH) concentrations were about 35% lower during CPA administration; similar observations were made for follicle stimulating hormone (FSH). CPA medication resulted in a significant reduction of LH response to LH-releasing hormone (RH); FSH increments following LH-RH stimulation were considerably smaller than those of LH and were hardly distinguishable from spontaneous FSH fluctuations. LH-RH double stimulation resulted in a slow but continuous rise of T without distinct peaks of borderline significance. CPA administration caused a highly significant elevation of serum prolactin in 7/10 males. In summary, medium dose CPA exerted the following effects on the hypothalamo-pituitary-testicular axis during the 1st 12 weeks of administration: 1) suppression of basal LH, FSH, T, and dihydroT; 2) abolition of the spiking phenomenon of androgen secretion; 3) suppression of LH-RH mediated secretion of LH and FSH; and 4) elevation of basal prolactin.