|( * ) Jornal Brasileiro de Ginecologia, 95 (3): 63 – 64, 1985 JBGCA8/3 645|
As gonadotrofinas hipofisárias atuam no folículo ovariano em alvos bem determinados: o LH age sobre o estrona e a teca interna dando início à esteroidogênese, que atinge a etapa C-19 (androgênios); o FSH na granulosa promove a aromatização que os transforma em C-18 (estrogênios). Diferente de outras glândulas endócrinas, todavia, o ovário não mostra uma estrutura histológica permanente, e o aparelho folicular está em renovação constante, com um grupo de folículos que se desenvolve até a maturação de um deles (ovulação) e em seguida involui sob a forma de corpo amarelo, marchando para a atresia.
O equilíbrio entre o estímulo gonadotrófico e a secreção de esteróides ovarianos assume, por esta razão, uma característica particular face aos demais sitemas de controle hipofisário. Propomos que o evoluir dos folículos e consequente ovulação é de certa forma um fato inerente ao seu desenvolvimento, e que o pico dito “ovulatório”do LH não é realmente a causa, mas uma consequência da ovulação. Procuramos mostrar que tal raciocínio pode ser feito aceitando-se os níveis dos principais hormônios envolvidos, FSH, LH e Estradiol como descritos até o presente, sem nada necessitar de alterações forçadas ou indevidas. E ainda, que nas condições envolvendo os níveis desses hormônios na pré-menopausa e na síndrome de ovário policístico, é possível aduzir argumentos favoráveis à sustentação do novo conceito.
| The real
moment of ovulation in human species, even after the introduction of ultra-sonographic
screening, is still a controversial matter. Papers suggesting a positive
feed-back action of estrogens on LH secretion are not conclusive: Baldwin
& cols. (1) , Everett (2) , Jewelewicz (3) , Lemay & cols. (5)
, Reichlin , Yen & cols. (6) .
the recent concepts about hypophysis-ovary balance within the menstrual
cycle. They imply the acceptance of a double role of feed-back by
estrogens, sometimes negative, sometimes positive, leaving all of the complexities
not fully understood. There appears to be another way of interpreting
the levels of the main hormones involved, as they are presently determined,
but with a completely different explanation. The graph shows plasmatic
levels of FSH, LH and estradiol obtained with routine RIA methods, and
although in a semischematic way (for a 30 days cycle), we can verify that
it is in agreement with what has been described by the majority of work
in this area.
The secretion of LH is steady: in women, as in men, it establishes itself individually in direct dependence upon androgen levels. We must admit that this includes adrenal C-19 steroids. Thus, in the limits of normality, there is a constitucional pattern of LH and C-19 steroids. The sexual difference, accepting an identical adrenal pattern in both sexes, would be determined through the particular answers of Leydig cells on one side, and their correspondents on the ovary on the other. As correspondents, in this case, we have stroma cells participating in cycle steroidogeneses, and hilar cells (well-known as identical to Leydig cells) probably with a minimal but regular production of C-19 steroids.
The secretion of FSH is steady in men, but cycle in women. The reason for the difference is obviously found in the Gonad: while FSH in the testicle regulates spermatogenesis, a continuous function, the same hormone produces in the ovary growth and maturation of the follicles. This continues until one ruptures (ovulation), a fact that repeats itself at intervals, regularly in the human species. In women, the production of FSH evolves in an ondulatory way, that is, rises and falls rhythmically dependant upon estradiol levels produced under its stimulus in the follicular apparatus. The first elevation is premenstrual, when the development of the follicles begins for the next cycle. This is the only period (about five days) during which, in normal women, the level of FSH is superior to LH. From this moment on, FSH decreases slowly until the point where estradiol reaches its maximum secretion by simple negative feed-back (on graph, around 14th day).
Under FSH stimulus a specific group of follicles develops and one of these follicles is destined for total maturation and ovulation by a completely unknown mechanism. A detectable presence of FSH in follicular fluid has been found, but not for LH. LH stimulates the production of androgens in theca cells, while FSH induces the aromatization of these C-19 steroids into estrone and estradiol in granulosa cells. Estradiol in turn increases FSH binding to granulosa cell receptors, thus magnifying their sensitivity to FSH. It is the granulosa that has the capacity to synthetize estrogens, the final step of steroidogenesis.
Estradiol, that was at its lowest levels during the previous pre-menstrual phase, rises in parallel with the growth of the follicular apparatus initiating all the peripherical transformations that are characteristic of the proliferative phase, particularly the aspect of maximum expansion of the endometrium. On reaching full capacity this enables the secretory changes of the second half of the menstrual cycle. The elevation of estradiol, slow and gradual, results in the proportional decrease of FSH.
At a specific moment, which corresponds with full maturation of the follicle, estradiol is at its highest rates when ovulation and the consequent colapse of the dominant follicle take place. There is then an abrupt decline in estradiol synthesis, falling to basal levels for some time. At this moment the second peak of FSH occurs, therefore, post-ovulatory. Its stimulating effect rebuilds the estradiol synthesis. The reconstruction of the follicle and the luteinization that changes it into a yellow body re-establish steroidogenesis. From now on the main steroid product is progesterone, which is the simplest sexual steroid and requires minimum enzimatic action for its secretion. Estradiol rises again, but here its numbers only reach about 2/3 of its pre-ovulatory peak. In the luteinic phase estradiol decreases to its basal levels significantly before progesterone. Estradiol does not disappear completely (as progesterone practically does), because in the pre-menstrual phase, as has been mentioned, the growth of the follicles has already begun to prepare the following cycle.
Ovulation is an intrinsic ovarian phenomenon, occuring somewhere between the estradiol peak and the FSH peak. Meanwhile the estradiol curve reflects itself in the gonadotrophic function, and exclusively by only one negative feed-back. There is no need to imagine another feed-back (positive) and create an unecessary complication for a dual behaviour of estradiol. Simply, the abrupt fall of estradiol suddenly releases a hypothalamic stimulus by the discharge of the Gonadotrophin Releasing Hormone (GnRH). In the use of GnRH in tests for pituitary reserve the gonadotrophins are stimulated simultaneously, but in terms of avaible RIA methods, the values of LH are always significantly higher than those of FSH. We understand then that this is in fact a physiological pattern: the LH peak is about five times greater than the FSH one. The ovulatory peak of LH is not the cause, but a consequence of ovulation.
After this rapid peak LH returns to its basal line, then, besides the effect produces on stroma cells, it will also act on the rupture follicle. It is questionable whether it is really the only reason for luteinization, but it is surely connected with yellow body function. The granulosa cells receiving vascularization after the rupture of the follicle become able to promote the first steps of steroidogenesis from circulating cholesterol, synthesizing progesterone. At the same time they lose their capacity of aromatization and in a few days stop producing estrogens. We also know that secretion of progesterone is followed by the presence of 17-CH-progesterone, the best indicator of an ideal luteinization, and afterwards, the various C-19 steroids.
There is absolutely no change in LH effects, but there is in the target organ resulting in more progesterone secretion. The rise of FSH permits, for some time, the aromatase activity necessary for the production of estrogens. Progesterone and estradiol then decrease as the luteinic phase ends. Thus, having a recognized period of useful life, the yellow body in its last days produces only progesterone in ever decreasing amounts. The estradiol that is found from a certain point on results from new developing follicles, as mentioned above. Considering the yellow body function in this way enables us to understand that it is a structure condemned to a very limited, reasonably fixed duration, and it does not need the presence of supposed luteolytic agents to justify the end of its activity. In addition to this, we understand that a productive normal yellow body is only possible when preceded by a normal mature follicle with normal estradiol secretion.
The study of the final period of ovarium activity permits the collection of some data to be considered. In pre-menopause the ovary is in decline and this usually affects the stroma cells first, the producers of C-19 steroids, even though avaible primordial follicles still exist. When this happens, the first steroid to show reduced levels is testosterona (followed by estradiol) and the consequent gonadotrophic rise is predominantly of LH. In post-menopause when estradiol reaches its lowest levels, the rise of FSH is then clearly and always larger than that of LH. The existence of elevated levels of LH explains the hiper-activity of the adrenal reticular layer, and also the elevated urinary 17-KS in spite of low rates of testosterone.
In the field of pathology we can also obtain corroborating information. In the policystic ovarian syndrome it was demonstrated in vitro that the follicles are not adequately able to convert androgens into estrogens. When gonadotrophins are added to the culture medium, FSH intensifies the production of estradiol in the granulosa cells, while LH has no effect whatsoever. If there is such normal behaviour in the FSH – estradiol relationship, the defect must arise because follicles fail to grow normally. This probably happens because of an imbalance of FSH/LH during the menstrual cycle, with too much LH being secreted. The condition than becomes self-perpetuating as the resulting steroid imbalance upsets follicles growth and the feed-backs to the pituitary gland. As a result we find high (more than 30 miliUI/ml) and always steady levels of blood LH in the policystic ovarian syndrome.
In closing, it should be stated that this is only a first approach, and of course nothing but a few correlations were considered. It seems clear that if the idea is accepted, a great number of pathophysiologic problems will be studied in a new perspective, and possibly new explanations for our old difficulties in this field of endocrinology will arise.
1. Baldwin D., Baldwin DM, Ramiez VD & cols. – Pituitary responsiveness to LHRH in short-term ovariectomized rats given a single injection of estrogen. Fed Proc, 33: 212, 1973.
2. Everett JW – Progesterone and estrogen in the experimental control of ovulation time and others features of the estrous cycle in the rat. Endocrinology, 43: 389, 1948.
3. Jewelewicz R, Ferin M & Vandle Wiele RL – Active immunization to 17-beta-estradiol and its effects upon the reproductive cycle of the rhesus monkey. Fertil and Steril, 25: 290, 1974.
4. Lemay A, Labrie F, Raymond JP & cols. – Action lutéotique de la LH-RH chez la femme. C.R. Acad Sci (Paris), 286: 527, 1978.
5. Reichlin S – The control of the hypophysiotropic secretions of the brain. Arch Int Med, 135: 1350, 1975.
6. Yen SSC, Vandenberg
G, Tasi CC & Siler T – Causal relationship between the hormonal
variables in the menstrual cycle – in Ferin, M. & cols. (Eds.).
Biorhythms and Human Reproduction, p. 219. J. Wiley &
Sons, N. York, 1974.