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The Role of Gonadotrophin Releasing Hormone in the Investiga- Tion and Treatment of Hypogonadism

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The Role of Gonadotrophin Releasing Hormone in the Investiga- Tion and Treatment of Hypogonadism Postgrad Med J: first published as 10.1136/pgmj.61.713.195 on 1 March 1985. Downloaded from Postgraduate Medical Journal (1985) 61, 195-200 Review article The role of gonadotrophin releasing hormone in the investiga- tion and treatment of hypogonadism Adrian Gossagel and Sheila Duncan2 Department ofMedicine' andDepartment ofObstetrics/Gynaecology2, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7A U UK. Introduction Normal progression through puberty and mainten- inhibitory feedback effects of sex-steroids and so the ance offertility depends on the integral functioning of release of Gn-RH and consequently FSH and LH is the hormonal circuit linking the hypothalamus, not inhibited until higher plasma concentrations of pituitary and gonads shown in Figure 1. The hypoth- sex-steroids are reached. An early manifestation of alamic factor - gonadotrophin-releasing hormone this change is the incremental development ofpulsatile (Gn-RH) was isolated and its structure determined in release of LH with maximal activity at about 0300 h 1971 (Schally et al., 1971). This releasing hormone acts (Boyar et al., 1972). In healthy pre-pubertal children on cells within the anterior pituitary and stimulates the gonadotrophins are present at low plasma concen- copyright. their secretion of the gonadotrophins, follicle trations but both FSH and LH will rise in response to stimulating hormone (FSH) and luteinizing hormone Gn-RH. At puberty the LH response becomes greater (LH). Gonadotrophin-releasing hormone is given for than that ofFSH (Roth et al., 1972). The pre-pubertal therapeutic as well as for diagnostic purposes and plasma levels ofLH and FSH respond to variations in there is now considerable clinical experience ofits use. the low plasma levels ofsex steroids but this regulatory This article discusses the clinical use of Gn-RH in the influence appears not to become dominant until investigation and treatment of infertility and delayed puberty. puberty and the clinical application of the develop- The pulses of gonadotrophins occur in response to ment of long-acting synthetic analogues. hypothalamic pulses of Gn-RH. Once established the http://pmj.bmj.com/ pulses of FSH and LH occur with a frequency of 2-4 per 6 h in men. In women they occur more closely to Hormonal changes of normal puberty hourly intervals during the follicular phase of the menstrual cycle, a pulse rhythm described as circhoral The first recognised hormonal change preceding by Knobil (1980), but during the luteal phase the puberty is an increase in the adrenal output of frequency and amplitude of the pulses and the mean androgenic steroids (Ducharme et al., 1976; plasma level of LH reduces, probably due to the on September 23, 2021 by guest. Protected Sizonenko & Paunier, 1975). The hormonal stimulus influence of progesterone (Soules et al., 1984). causing the increase in adrenal androgen production has not been identified but there is evidence for a shift in emphasis of the adrenal enzymes, resulting in Hypotamic hypogonadism greater production of androgens (Kelnar & Brook, 1983). The increase in plasma dehydroepiandros- Many of the patients who lack hypothalamic Gn-RH terone occurs before LH and FSH begin to rise and will present with delayed puberty or sometimes later adrenal androgens may be important for the 'matur- with infertility. There may be a congenital inability to ing' of the hypothalamus. As puberty progresses the detect smells, sometimes with additional midline de- hypothalamus seems to become less sensitive to the fects such as cleft palate, a condition known as Kallmann's syndrome (Kallmann et al., 1944). These Adrian Gossage M.D., M.R.C.P.; Sheila Duncan M.D., individuals will have persistently low or undetectable F.R.C.O.G. plasma levels ofLH and FSH and there will not be any Accepted: 25 July 1984 increase in plasma levels in response to the standard C The Fellowship ofPostgraduate Medicine, 1985 Postgrad Med J: first published as 10.1136/pgmj.61.713.195 on 1 March 1985. Downloaded from 196 A. GOSSAGE & S. DUNCAN a Hypothalamus GN - RH I+ve; Pituitary ve- { ~~~~~~~~Progesterone t ~~F.S.H. L.H. and Oestrogen/ \estrogen ve Ovary in Ovary in Testosterone follicular phase luteal phase androgens inhibin b Hypothalamus copyright. GN - RH Pituitary y http://pmj.bmj.com/ - y Qestradiol - ye Inhibin / \ F.S.H. L.H. (I.C.S.H.) Testosterone on September 23, 2021 by guest. Protected Testosterone 0 0 + ye ~,Sertoli cells Leydig cells Figure 1 (a) Female; (b) Male. The hypothalamus releases pulses ofgonadotrophin-releasing hormone (Gn-RH) which stimulate the pituitary to release pulses of the gonadotrophins: luteinising hormone (LH) and follicle stimulating hormone (FSH) (LH in the male was previously termed interstitial-cell-stimulating hormone ICSH). FSH stimulates the maturation ofgonadal germ cells. In the female FSH is predominant during the follicular phase ofthe cycle and stimulates the production ofoestrogens. During the luteal phase in females LH is predominant and stimulates the production ofprogesterone. In the male, LH stimulates the production oftestosterone. The pituitary production ofLH and FSH lessen as the levels ofgonadal steroids and inhibin rise. The LH surge predisposing to ovulation is dependent on the prior rise in plasma levels of oestrogens but with a fall in oestrogen levels just preceding the release of LH. Postgrad Med J: first published as 10.1136/pgmj.61.713.195 on 1 March 1985. Downloaded from ROLE OF GN-RH IN HYPOGONADISM 197 test doses of 100 lAg i.v. ofGn-RH. The frequency and Whilst the pituitary of females is receiving pulsatile amplitude of the hypothalamic pulses of Gn-RH can stimulation by the hypothalamic Gn-RH it should be also be reduced by illness, resulting in delayed puberty. capable ofmaking a positive response and release LH Delayed development of the pulses of Gn-RH is also following the administration of oestrogens (Knobil, thought to be the explanation for the delayed menar- 1980). This capability will be absent if the stimulation che occurring in marathon runners and ballet dancers by Gn-RH has not begun or has ceased. In general, (Warren, 1980), and a reversion to the pre-pubertal amenorrhoeic patients who have absent or impaired pattern is found in anorexia nervosa and secondary responses to Gn-RH will not respond to clomiphene amenorrhoea with low body weight syndromes. (Ginsburg et al., 1975) or oestrogens. Amenorrhoeic patients who do respond to administration of oes- tradiol by an increased pituitary secretion of LH will Investigation of hypogonadism still have pulsatile rhythms ofLH secretion (El Sheikh et al., 1983) and hence, presumably, pulses of Gn-RH It is difficult to distinguish between simple delay of secretion. puberty, due to slow development of the gonadotro- Ifgonadotrophins are lacking or reduced the ovary phic axis, and lack ofgonadotrophins due to pituitary or testis will remain underdeveloped. Consequently or hypothalamic disease states. A test with a single the hormonal response to an administered stimulus to bolus of Gn-RH will not reliably separate the two the gonad will be less than that ofgonadal tissue from groups (Roth et al., 1972), although it has been a normal person and an interval is needed during reported that the ratio of FSH to LH is increased in which the response to successive doses of the stimulus those with hypothalamic hypogonadism (Crowley et will increase. Both ovarian and testicular tissues are al., 1980). A poor response may occur in both delayed able to up-regulate and down-regulate their receptors puberty and hypothalamic hypogonadism, the mag- for the gonadotrophins (Conti et al., 1976). nitude and pattern of response being related to the In conclusion, Gn-RH will provide a valuable degree of prior exposure to Gn-RH. Following ex- contribution in the assessment of hypogonadal posure to Gn-RH, further provocation tests with patients but often further tests are necessary and boluses of Gn-RH show that the LH response be- continued stimulation by Gn-RH may be needed to copyright. comes more marked whereas the FSH response shows clarify the diagnosis. little enhancement (Roth et al., 1972). This alteration in FSH and LH response resembles the normal physiological pattern at puberty. Treatment ofinfertility by Go-RH Hypogonadism due to intrinsic pituitary failure is demonstrated by complete lack of gonadotrophin It had always been expected that the isolation and response despite repetitive infusions of Gn-RH subsequent synthesis and availability of Gn-RH (Snyder et al, 1979). Investigation of patients with would allow clinicians to help patients with delayed http://pmj.bmj.com/ delayed puberty and hypothalamic hypogonadism puberty and infertility. Gn-RH has however proved has also been explored by continuous infusion of difficult and unpredictable in clinical use. Continuous Gn-RH. The normal post-pubertal response to a 4 h infusion of Gn-RH to normal subjects for prolonged continuous infusion of Gn-RH is biphasic (Bremner periods will raise plasma levels ofLH and FSH but this & Paulsen, 1974). There is an initial surge of LH response begins to attenuate after about 5 h and is lost response which begins to decline at 40 min but then after a few days. However a pulsatile infusion of Gn- increases again at 90 min and the new raised level is RH results in an increase in FSH and LH levels that is sustained for the remainder of the 4 h. Bremner and sustained (this was studied in rhesus monkeys for 7 on September 23, 2021 by guest. Protected colleagues (1977) reported that the typical response for weeks (Belchetz et al., 1978)). The use of pulsatile pre-pubertal children, hypothalamic-hypogonadal prolonged infusions ofGn-RH allows the patient with patients and patients with anorexia nervosa is mono- hypothalamic deficiency to synthesize and release phasic; the initial response with FSH is relatively FSH and LH.
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