Data on the mechanism of action of inhibin are lacking in women, and information is derived only from studies in animals. It has been suggested that in the context of the negative feedback mechanism, inhibin acts directly on the pituitary without affecting GnRH secretion, although it may reduce the GnRH-induced FSH secretion de Kretser et al.
Especially, activin A has been shown to be secreted by rat anterior pituitary cells in culture Liu et al. Follistatin is also secreted from rat pituitary cells Liu et al. The role of another non-steroidal substance named anti-Mullerian hormone AMH is less clear. In women, AMH is expressed in the granulosa cells of follicles from the primordial to the antral stage until the size of 4—6 mm Weenen et al.
Although it appears that serum levels of AMH on cycle day 3 of normally cycling women decline with increasing age de Vet et al. This is derived from experiments in women that have shown that after ovariectomy, performed in the midluteal phase, both E 2 and progesterone concentrations decreased significantly within the first 24 h, while those of FSH and LH increased gradually Alexandris et al.
Although these data underlie the importance of these two steroids in the control of gonadotrophin secretion in the luteal phase, they do not specify the role of each of them. The latter has been further investigated in a recent study Messinis et al.
When, however, the midluteal concentrations of progesterone were also maintained with the exogenous administration of this steroid, the increase in FSH and LH values was prevented Messinis et al. This suggests that it is the combined action of E 2 and progesterone that mediates the negative feedback effect of the ovaries on gonadotrophin secretion during the luteal phase of the cycle. Whether progesterone alone could express a similar action has not been investigated, although under experimental conditions the negative feedback effect of progesterone is apparent in the presence of estrogen Soules et al.
During the luteal phase, the frequency of GnRH pulses decreases, while the amplitude increases Filicori et al. Although this could be due to the high progesterone concentrations Soules et al. Apart from the steroids, no other ovarian substances have been detected to specifically suppress basal LH secretion in women.
For FSH, however, inhibin may participate in the negative feedback mechanism during the luteal phase but does not affect LH secretion. This is derived from data in both animals and women. Infusion of inhibin A into rhesus macaques starting at midluteal phase resulted in a progressive decline in FSH levels Stouffer et al. A recent study in women has shown a significant decline in inhibin A values within the first 12 h from ovariectomy performed in the luteal phase that was followed by a gradual but significant increase in serum FSH concentrations Muttukrishna et al.
Although in that study E 2 and progesterone levels also declined, a negative correlation between the values of inhibin A and FSH was found. In the same study, inhibin B levels did not change significantly after ovariectomy, suggesting that this protein is not a regular component of the negative feedback mechanism during the luteal phase of the cycle Muttukrishna et al.
Nevertheless, previous data have demonstrated that normally cycling premenopausal women with raised FSH values in the early follicular phase had during the luteal phase inhibin A, and during the follicular phase inhibin B, concentrations significantly lower than in women with normal FSH levels Danforth et al. These data provide evidence that both forms of inhibin participate in the control of FSH secretion in women with inhibin A being important during the luteal phase and inhibin B during the follicular phase of the cycle.
The role of activin and follistatin in the control of human gonadotrophin secretion during the luteal phase is, as in the follicular phase, not clear. Measurement of follistatin in the circulation of women has not shown any significant alterations throughout the whole menstrual cycle Khoury et al.
FSH starts to increase 2—3 days before the onset of the menstrual period, although recent data have shown that the initial rise occurs 4 days before menses Miro and Aspinall, FSH remains elevated during the early follicular phase and returns to the basal value in midfollicular phase Mais et al.
The described changes in FSH levels were measured by immunoassays, but when a specific in vitro bioassay was used, increased signal was detected earlier, i. The intercycle rise of FSH appears to be controlled by ovarian substances Figure 1. Before the onset of the FSH rise, a gradual but significant decline in the levels of inhibin A, E 2 and progesterone takes place Roseff et al.
It is assumed, therefore, that the intercycle rise of FSH starts in late luteal phase as a result of the reduced activity of the negative feedback mechanism that suppressed FSH secretion during the early- and midluteal phases.
Inhibin B does not participate in this mechanism. However, from the time FSH levels reach a peak at the onset of menstruation, inhibin B levels increase gradually and significantly Groome et al. It is possible that the increasing concentrations of inhibin B under the influence of FSH during the early follicular phase Welt et al.
Hormonal dynamics during the luteal-follicular transition. The FSH intercycle rise is the result of the reduced activity of the negative feedback mechanism due to the decrease in estradiol E 2 , inhibin A and progesterone P4 concentrations in late luteal phase.
The FSH increase is terminated by the rising E 2 and inhibin B levels produced by the dominant follicle. The diagram, regarding the pattern of hormonal changes, is based on data presented in two references Messinis et al. Although this makes sense, a study in women has shown that maintenance of midluteal concentrations of E 2 during the intercycle period postponed the intercycle rise of FSH despite a decline in inhibin concentrations Le Nestour et al.
Furthermore, following the selection of the dominant follicle in the normal cycle, serum FSH declined as E 2 levels increased van Santbrink et al. It is suggested from these results that E 2 is possibly more important than inhibin in regulating the FSH window. More recent data in women treated with the anti-estrogenic compound, tamoxifene, have confirmed the greater role of E 2 over inhibin in the negative control of FSH secretion during the luteal phase and the luteal-follicular transition with inhibin B being more important as the follicular phase progresses Welt et al.
The role of progesterone in the control of the intercycle rise of FSH is less clear, although this hormone may participate via an effect on GnRH secretion. Progesterone is believed to reduce the frequency and increase the amplitude of LH pulses during the luteal phase of the cycle Soules et al.
Therefore, the withdrawal of the progesterone effect in late luteal phase increases the frequency of GnRH pulses McCartney et al. This is possibly one of the reasons that the increase of LH during the intercycle period is less discernible. In any case, however, the frequency of GnRH pulses contributes to but is not solely responsible for the intercycle rise of FSH in women Welt et al. Another mechanism that might contribute to the intercycle rise of FSH includes activin A.
The concentrations of this protein, despite limitations in the existing methodology, start to increase from the midluteal phase, preceding through the intercycle rise of FSH Muttukrishna et al. Also, aged but normally cycling women with raised FSH values in the early follicular phase had increased concentrations of activin A in the luteal phase Muttukrishna et al. Similarly, a significant increase in serum activin A levels over age has been reported in healthy post-menopausal women Baccarelli et al.
In terms of the role of other forms of activin, such as activin B and activin AB, there are no data in the literature regarding their concentrations in the circulation of women.
It has been known for years that E 2 is the main component of the positive feedback effect of the ovaries on the hypothalamic-pituitary system Ferin et al. The interaction between E 2 and GnRH is important for the expression of the endogenous gonadotrophin surge at midcycle Hoff et al. Experiments in women involving the i. Under these circumstances, the reserve is converted to the acutely releasable pool before gonadotrophins are secreted.
During the i. Although this reflects increased number of GnRH receptors in the gonadotrophs Laws et al. In addition, data in rats have shown that GnRH controls LH biosynthesis by increasing glycosylation and polypeptide synthesis of LH, while E 2 facilitates LH secretion by lowering the concentrations of GnRH needed to stimulate these two processes Ramey et al.
The biphasic pattern of LH response to GnRH has been also shown in vitro using rat pituitary cells in a perifusion system Evans et al.
When GnRH experiments were performed during the human menstrual cycle, it was found that the pituitary sensitivity and reserve as well as the self-priming effect were augmented in the late follicular phase as compared to the early follicular phase Wang et al.
This augmentation of LH secretion as a response to repeated injections of GnRH in an estrogenic environment is related to the rate with which LH molecules are discharged from the pituitary Sollenberger et al.
It has been found that the pituitary sensitivity to GnRH, estimated as the min response to a single i. This suggests that the sensitizing effect of E 2 on the pituitary is inhibited during the early- and midfollicular phases and is facilitated in the late follicular phase of the normal menstrual cycle. Alternatively, the ovaries during the early- and midfollicular phases produce a substance that is able to antagonize the sensitizing effect of E 2 on the pituitary gonadotrophs.
Experiments that were performed in healthy estrogen-deprived post-menopausal women support this assumption Dafopoulos et al. In particular, two simulated follicular phases with a luteal phase in between were created in these women with the exogenous administration of E 2 and progesterone.
Immediately after the end of the simulated luteal phase, the response of LH to GnRH was similar to that in the early follicular phase of the normal menstrual cycle. However, from that point onwards, i.
These data are compatible with the hypothesis of a missing ovarian substance in the case of post-menopausal women because their ovaries are not functioning. In Group 1, estrogen-deprived post-menopausal women were treated with exogenous estradiol valerate and progesterone to induce concentrations of these two steroids similar to those in the follicular phase and the luteal phase of the normal menstrual cycle. Two simulated follicular phases and one luteal phase in between were induced.
Days 32—42 correspond to the second simulated follicular phase immediately after the simulated luteal phase.
The different pattern of LH changes is interpreted as indicating that the ovaries Group 2 produce a substance gonadotrophin surge-attenuating factor that in the early follicular and midfollicular phases prevent the increase in pituitary sensitivity to GnRH. This substance was not produced in Group 1 as the ovaries were not functioning.
Adapted from Dafopoulos et al. Such a substance could be gonadotrophin surge-attenuating factor GnSAF that in superovulated women reduces the pituitary response to GnRH and attenuates the endogenous LH surge Messinis et al. Another candidate could be progesterone, but this is not likely because when normal women were treated with the antiprogestagen, mifepristone, both the pituitary sensitivity and reserve were significantly attenuated as compared to control cycles of the same women Kazem et al.
It is clear from these data that when the progesterone activity is neutralized, the pituitary sensitivity is decreased, and therefore, the lack of progesterone in the post-menopausal women would be expected to result in a decrease and not in an increase in the pituitary responsiveness to GnRH during the administration of E 2. In other words, progesterone in the follicular phase of the normal cycle, although in low concentrations, probably sensitizes the pituitary to GnRH and in that way facilitates the E 2 positive effect.
In agreement with this notion are data in rats in which the sensitizing effect of progesterone on the GnRH self-priming in pituitary monolayers was abolished by coincubation with mifepristone Byrne et al. Even, in the absence of progesterone, according to data in rats, GnRH self-potentiation requires a cross-talk with the progesterone receptor Waring and Turgeon, As has been shown in several studies, E 2 is the predominant factor that triggers the onset of the endogenous LH surge during the normal menstrual cycle provided a threshold level is exceeded for a certain period of time Karsch et al.
Even supraphysiological levels of E 2 induced by the exogenous administration of estrogen are able to stimulate an LH surge Messinis et al. The extent to which other ovarian hormones, such as progesterone, participate in the positive feedback mechanism at midcycle is less clear.
Experiments in women have shown that progesterone can induce a positive feedback effect only after pretreatment with estrogen, even when the appropriate threshold for E 2 has not been reached Chang and Jaffe, ; March et al. At midcycle, the shift in steroidogenesis represents the ability of the preovulatory follicle to produce more progesterone than E 2 McNatty et al.
There has been debate, however, in the literature as to whether the progesterone secretion and, therefore, its concentrations in the circulation increase a little while before the onset of the midcycle LH surge Johansson and Wide, ; Thorneycroft et al. In one study, in which blood samples were taken from normal women every 2 h for 5 days during the periovulatory period, a clear increase in progesterone concentrations was demonstrated before the real onset of the surge Hoff et al.
It is possible, therefore, that at midcycle the role of progesterone is permissive. In experiments performed in women, the administration of progesterone advanced the onset of an E 2 -induced LH surge Chang and Jaffe, ; Liu and Yen, ; Messinis and Templeton, Also, in rats progesterone enhanced E 2 -induced GnRH secretion from the medial basal hypothalamus Miyake et al.
Although the role of circulating progesterone in the positive feedback mechanism in women requires clarification, data in ovariectomized estrogen-treated progesterone receptor knockout mice have shown that activation of these receptors is necessary for the expression of the GnRH self-priming effect and the generation of the E 2 -induced gonadotrophin surge Chappell et al. Additional information in ovariectomized and adrenalectomized rats indicates that neuroprogesterone synthesized in the hypothalamus under the influence of E 2 is an obligatory mediator of the positive feedback mechanism that is induced by this steroid Micevych et al.
Furthermore, data in rats have shown that estrogens induce de novo synthesis of progesterone from cholesterole in the hypothalamus, which plays a role in the onset of the LH surge Soma et al. It is possible, therefore, that progestestogenic mechanisms involving the progesterone receptor participate in the E 2 positive feedback mechanism, regulating thus the LH surge onset. The site of action of E 2 for the positive feedback effect is both the hypothalamus and the pituitary Xia et al.
A preovulatory surge of GnRH has been detected in the ewe Moenter et al. In women, while data are lacking, one study has shown an increase in plasma immunoreactive GnRH, as a result of estrogen administration, that precedes the increase of LH and FSH Miyake et al. It is likely, therefore, that the primary site of the positive feedback effect is the pituitary and that GnRH plays a permissive role Knobil, A recent study has shown that in rats a direct action of E 2 on the anterior pituitary is obligatory for the positive feedback effect on LH secretion Yin et al.
Progesterone seems also to exert the positive feedback effect via the hypothalamus Terasawa et al. The mechanism of the E 2 positive effect on gonadotrophin secretion is via the estrogen receptors ER. Both types exist in the gonadotrophs Mitchner et al. A study using human follicular fluid as a source Pappa et al. In one of them Tavoulari et al. Different clones were obtained that in the in vitro bioassay system of rat pituitary cells were able to reduce the GnRH-induced LH secretion demonstrating, therefore, GnSAF bioactivity Tavoulari et al.
All fragments of HSA were expressed in the nucleus of the granulosa cells, and only the promoter and the C-terminal fragment were expressed in the cytoplasm Karligiotou et al. Although GnSAF bioactivity is particularly evident during ovarian stimulation, it is possible that this factor plays a physiological role during the normal menstrual cycle affecting gonadotrophin secretion.
Studies in women during the natural cycle have suggested that GnSAF is produced during the luteal-follicular transition under the influence of the intercycle rise of FSH Messinis et al. A hypothesis has been developed that the activity of GnSAF in the circulation is high during the early- and midfollicular phases, and this maintains the pituitary in a state of low responsiveness to GnRH Messinis and Templeton, ; Fowler et al.
However, in the late follicular phase, there is a decline in GnSAF bioactivity that facilitates the sensitizing effect of E 2 on the pituitary and the full expression of the midcycle LH surge Messinis et al. Activity of gonadotrophin surge-attenuating factor GnSAF during the normal menstrual cycle in relation to inhibin A, inhibin B, estradiol E 2 and progesterone P4 patterns.
A hypothesis on the physiological role of gonadotrophin surge-attenuating factor GnSAF during the normal menstrual cycle.
This factor is produced mainly by small growing follicles, and therefore, its activity is high in the early- to mid-follicular phase. The activity of GnSAF is reduced in the late follicular phase and at midcycle, facilitating thus the sensitizing effect of E 2 on the pituitary and the full expression of the endogenous LH surge.
That GnSAF activity is higher in the early- and midfollicular phases than in the late follicular phase is also supported by in vitro studies demonstrating GnSAF activity in human follicular fluid particularly of small- and medium-sized follicles rather than of large follicles Fowler et al. According to this hypothesis, the role of GnSAF in humans is to control the amplitude and not the onset of the LH surge.
In fact, an endogenous LH surge occurs invariably as a response to the positive feedback effect of E 2 either in the early- or in midfollicular phases of the normal menstrual cycle, but this surge is attenuated as compared to midcycle Taylor et al.
Therefore, E 2 and GnSAF seem to interact at the pituitary gonadotrophs with the former expressing a sensitizing effect and the latter an antagonistic effect.
Of the other ovarian hormones, progesterone seems also to play a role in the control of the amplitude of the LH surge. Under experimental conditions in normally cycling or in post-menopausal women, exogenous progesterone amplified the LH surge that was induced by the administration of exogenous estrogen Liu and Yen, ; Messinis and Templeton, Data in rats have shown that this action of progesterone is mediated via an enhanced activation of GnRH neurons Lee et al.
The midcycle LH surge normally has a duration of 48—72 h Hoff et al. The factors, however, that control the termination of the endogenous LH surge during the normal menstrual cycle have not been clarified.
After the onset of the LH surge, E 2 concentrations decline. It is rather unlikely that the withdrawal of the E 2 effect terminates gonadotrophin secretion, because termination also occurred in experiments in which high estrogen concentrations were maintained during the LH surge Liu and Yen, In addition, animal studies have shown that E 2 is important for triggering the LH surge but is not required after its onset Evans et al. Serum progesterone levels in women increase gradually from the onset to the end of the LH surge and continuously, thereafter, during the luteal phase of the cycle Hoff et al.
It is possible that the rising progesterone levels contribute to the termination of the LH surge via a negative feedback effect. Experimental data in women have shown that when an LH surge was induced with the exogenous administration of E 2 , LH values declined following the peak but went down to the presurge level only after the administration of progesterone Messinis and Templeton, A recent study has provided more information regarding the mechanism that is responsible for the termination of the endogenous LH surge in women Dafopoulos et al.
You and Your Hormones. Students Teachers Patients Browse. Human body. Home Curriculum topics for students Topics Hormones in human reproduction. Hormones in human reproduction Hormones are the drivers of human reproduction, responsible for sexual development and controlling the menstrual cycle.
As the eggs mature, the cells in the follicle rapidly divide and the follicle becomes progressively larger. Many follicles lose the ability to function during this process, which can take several months, but one dominates in each menstrual cycle and the egg it contains is released at ovulation.
As the follicles develop, they produce the hormone oestrogen. Once the egg has been released at ovulation, the empty follicle that is left in the ovary is called the corpus luteum. This then releases the hormones progesterone in a higher amount and oestrogen in a lower amount. These hormones prepare the lining of the uterus for potential pregnancy in the event of the released egg being fertilised.
If the released egg is not fertilised and pregnancy does not occur during a menstrual cycle, the corpus luteum breaks down and the secretion of oestrogen and progesterone stops.
Because these hormones are no longer present, the lining of the womb starts to fall away and is removed from the body through menstruation. After menstruation, another cycle begins. The menopause refers to the ending of a woman's reproductive years following her last menstruation. This is caused by the loss of all the remaining follicles in the ovary that contain eggs.
When there are no more follicles or eggs, the ovary no longer secretes the hormones oestrogen and progesterone, which regulate the menstrual cycle. As a result, menstruation ceases. The major hormones secreted by the ovaries are oestrogen and progesterone, both important hormones in the menstrual cycle. Oestrogen production dominates in the first half of the menstrual cycle before ovulation, and progesterone production dominates during the second half of the menstrual cycle when the corpus luteum has formed.
At this time, the gonadotropes in the anterior pituitary contain little LH and FSH, and estrogen and progesterone production is low. As a result, overall FSH secretion increases slightly, stimulating growth of recruited follicles.
The recruited ovarian follicles soon increase production of estradiol ; estradiol stimulates LH and FSH synthesis but inhibits their secretion. During the late follicular phase 2nd half of the follicular phase , the follicle selected for ovulation matures and accumulates hormone-secreting granulosa cells; its antrum enlarges with follicular fluid, reaching 18 to 20 mm before ovulation.
FSH levels decrease; LH levels are affected less. Also, developing follicles produce the hormone inhibin, which inhibits FSH secretion but not LH secretion. Other contributing factors may include disparate half-lives 20 to 30 minutes for LH; 2 to 3 hours for FSH and unknown factors. Levels of estrogen , particularly estradiol , increase exponentially. Estradiol levels usually peak as the ovulatory phase begins. Progesterone levels also begin to increase.
The LH surge occurs because at this time, high levels of estradiol trigger LH secretion by gonadotropes positive feedback. During the LH surge, estradiol levels decrease, but progesterone levels continue to increase.
The LH surge stimulates enzymes that initiate breakdown of the follicle wall and release of the now mature ovum within about 16 to 32 hours. The LH surge also triggers completion of the first meiotic division of the oocyte within about 36 hours. The length of this phase is the most constant, averaging 14 days, after which, in the absence of pregnancy, the corpus luteum degenerates. Progesterone stimulates development of the secretory endometrium, which is necessary for embryonic implantation.
Because progesterone is thermogenic, basal body temperature increases by 0. Because levels of circulating estradiol , progesterone , and inhibin are high during most of the luteal phase, LH and FSH levels decrease. When pregnancy does not occur, estradiol and progesterone levels decrease late in this phase, and the corpus luteum degenerates into the corpus albicans. If implantation occurs, the corpus luteum does not degenerate but remains functional in early pregnancy, supported by human chorionic gonadotropin that is produced by the developing embryo.
The endometrium, which consists of glands and stroma, has a basal layer, an intermediate spongiosa layer, and a layer of compact epithelial cells that line the uterine cavity. Together, the spongiosa and epithelial layers form the functionalis, a transient layer that is sloughed during menses.
After menstruation, the endometrium is typically thin with dense stroma and narrow, straight, tubular glands lined with low columnar epithelium. As estradiol levels increase, the intact basal layer regenerates the endometrium to its maximum thickness late in the ovarian follicular phase proliferative phase of the endometrial cycle. The mucosa thickens and the glands lengthen and coil, becoming tortuous.
Ovulation occurs at the beginning of the secretory phase of the endometrial cycle. During the ovarian luteal phase, progesterone stimulates the endometrial glands to dilate, fill with glycogen, and become secretory while stromal vascularity increases.
Fibrinolytic activity of the endometrium decreases blood clots in the menstrual blood. Because histologic changes are specific to the phase of the menstrual cycle, the cycle phase or tissue response to sex hormones can be determined accurately by endometrial biopsy.
During the follicular phase, increasing estradiol levels increase cervical vascularity and edema and cervical mucus quantity, elasticity, and salt sodium chloride or potassium chloride concentration.
The external os opens slightly and fills with mucus at ovulation. During the luteal phase, increasing progesterone levels make the cervical mucus thicker and less elastic, decreasing success of sperm transport. Menstrual cycle phase can sometimes be identified by microscopic examination of cervical mucus dried on a glass slide; ferning palm leaf arborization of mucus indicates increased salts in cervical mucus. Ferning becomes prominent just before ovulation, when estrogen levels are high; it is minimal or absent during the luteal phase.
Spinnbarkeit, the stretchability elasticity of the mucus, increases as estrogen levels increase eg, just before ovulation ; this change can be used to identify the periovulatory fertile phase of the menstrual cycle.
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