Which cells secrete oestrogen

If the loss of follicle stimulating hormone occurs after puberty, there will be a similar loss of fertility. About Contact Events News. Search Search. You and Your Hormones. Students Teachers Patients Browse. Human body. Home Hormones Follicle stimulating hormone. Follicle stimulating hormone Follicle stimulating hormone is produced by the pituitary gland.

It regulates the functions of both the ovaries and testes. Lack or insufficiency of it can cause infertility or subfertility both in men and women. Alternative names for follicle stimulating hormone FSH; follitropin pharmaceutical preparations What is follicle stimulating hormone?

How is follicle stimulating hormone controlled? What happens if I have too much follicle stimulating hormone? What happens if I have too little follicle stimulating hormone? Specific proteins will be discussed in this section, outlining the relevant research in this area and how each factor may contribute to theca growth and function. Activin promoted the development of preantral follicles in sheep Thomas et al. Studies on isolated human thecal cells cultured in vitro showed that activin suppressed androgen and progesterone production Hillier et al.

It has been suggested that granulosa cells secrete inhibin to control the amount of androgen synthesized by theca cells as substrates for estrogen synthesis in granulosa cells Hillier et al. Thus, activins have direct effects on thecal cell function, and are regulated by the extracellular antagonists inhibin and follistatin Findlay , Welt et al.

In some species, an indirect effect of activins may occur through stimulation of granulosa cell proliferation or preantral follicle development Li et al. Activin can act by upregulating FSH receptors and aromatase gene expression in granulosa cells, and is involved in promoting estradiol production Nakamura et al.

Furthermore, since estradiol may suppress activin expression, this forms a possible interaction between activin and estrogen signaling during folliculogenesis Kipp et al. Increased estradiol and inhibin production by the putative preovulatory follicle s would act to suppress activin production through estradiol, and block activin action at the theca through inhibin, thus enhancing thecal androgen production. Inhibin alone increased androgen production from human thecal cells in culture and also blocked the inhibitory effect of added activins Hillier et al.

During folliculogenesis, BMPs are released at specific time points and act in either an autocrine or paracrine manner to modulate growth, differentiation, and function of follicular cells.

BMP expression patterns have been investigated in rodents, ruminants, and primates, and observations suggest that species-specific differences occur for some molecules reviewed by Shimasaki et al.

BMP6 is produced by oocytes, but its function appears to differ between rodents and ruminants Otsuka et al. In sheep Souza et al. Human theca-derived tumor cells show reduced androstenedione production in vitro when treated with BMP4, and this effect is enhanced in the presence of cAMP agonists Dooley et al. Taken together, observations indicate that BMPs may act directly on theca to inhibit androgen production and also function to regulate the expression of factors from granulosa cells that act in a paracrine manner on thecal steroidogenesis.

GDF9 is primarily produced specifically by the oocyte McNatty et al. Mutations of the GDF9 gene lead to arrested folliculogenesis at the primary stage in mice, sheep, and humans Shimasaki et al.

Follicles from GDF9 null mice and sheep Thoka lack supporting thecal cells indicating a role for GDF9 in the regulation of thecal recruitment, differentiation, and proliferation, but this appears to be dependent on the stage of follicle development Dong et al. The level of proliferation appeared higher in theca cells from small follicles compared to those from large follicles, and this may be related to higher levels of the putative GDF9 receptor, ALK5, in theca cells from small follicles.

Thus, in small follicles, GDF9 could enhance proliferation, yet have no effect on promoting differentiation of thecal cells. GDF9 increased androgen production in rat thecal cells Solovyeva et al. Alternatively, the difference may be due to luteinization of the cells in culture. GDF9 may also act in an indirect manner to modulate theca cell function, perhaps through regulating SCF expression Dong et al. GDF9 also stimulated inhibin production Hayashi et al.

These findings indicate that recruitment of putative theca-like cells can occur in the absence of GDF9, but differentiation of these cells does not appear to occur. GDF9 appears to have an indirect function on thecal cells, perhaps by promoting granulosa cell proliferation. Both TGFB1 and TGFB2 are present in theca cells from follicles at the small preantral stage of development onwards and in stromal tissue and vascular systems in sheep ovaries, but not in granulosa cells or oocytes Juengel et al.

Furthermore, latent TGFB-binding proteins, which affect the bioavailability of TGFBs in tissues, are localized to the ovarian cortical stroma and theca externa of bovine antral follicles Prodoehl et al. TGFB1 has been reported to suppress androgen synthesis from human and rat thecal cells Fournet et al. These results are not clear-cut, but it appears that in the human at least, TGFB has a similar role to activin and BMPs in suppressing androgen production.

The hedgehog pathway has recently been shown to intersect with pathways involved with FGF receptor 2, BMPs, and other regulatory networks Katoh Theca cells appear to be modulated by hedgehog signaling with the expression of hedgehog target genes Ptch1 , Ptch2 , Hip1 , and Gli1 all present within theca cells Wijgerde et al. Hedgehog proteins are expressed in the granulosa cells, but oocytes are unable to respond since they do not contain the necessary receptors.

Hedgehog target genes are expressed in the pre-thecal cell compartment, and are therefore possible markers of pre-thecal cells and potentially involved in inducing theca cell differentiation. In cultured bovine thecal cells, sonic hedgehog-induced cell proliferation and androstenedione production see Fig. In a transgenic mouse model, the hedgehog pathway was dominantly activated, and these mice displayed defective thecal development with reduced or absent smooth muscle actin normally seen in the thecal layer of growing follicles Ren et al.

The dominant activation of the hedgehog pathway therefore appears to block the differentiation of precursor cells into muscle cells that are normally located in the outer thecal layers, and are perhaps required for ovulation. A common trend appears to be emerging where the TGFB superfamily members are involved in fine tuning the modulation of androgen biosynthesis and steroidogenic enzyme gene expression. It makes sense that these two independent pathways influence the expression of completely separate groups of genes; otherwise, they would simply utilize the same pathway for the same effects.

If the two pathways do in fact activate separate sets of genes, then these genes appear to be having similar effects on steroidogenesis. These contrasting results in different species coincide with the observed effects on androgen production, where in rat theca cells, GDF9 enhanced androgen synthesis Solovyeva et al.

There may be important species-specific differences in the function of GDF9 in particular, and this may also be the case with other TGFB superfamily members and therefore requires closer investigation. There are also important species differences between rodents and humans with regard to stem cells.

By studying each factor in isolation, one is able to infer a specific function and role in ovarian folliculogenesis. However, we know that in vivo this is clearly not the case, and many different factors at varying, tightly controlled, concentrations all work synergistically to control the very delicate balance between the life and death of an ovarian follicle.

The level and pattern of gene expression are vital factors; moreover, crosstalk between pathways and the presence of antagonists are additional levels of control for folliculogenesis and are yet to be fully elucidated. Classically, it was thought that the oocyte was passively carried along the developmental process, and its maturation was controlled entirely by the production of endocrine hormones and surrounding somatic cell factors influencing the follicle as a whole.

The latest concept in reproductive biology is that the oocyte itself is actively involved in regulating the surrounding somatic cells in order to provide an environment suitable for its own maturation.

With this new and exciting theory in mind, it is possible that the oocyte itself is responsible for sending the signal for primordial follicle activation and thecal cell recruitment. However, since oocytes produce only limited factors, it is most likely that the interaction and communication between the oocyte and its somatic cells control the follicle development as a whole, and when one component fails, the entire process is halted.

Nevertheless, thecal cells are vital for folliculogenesis in the ovary. They are specialized cells that are recruited to surround an activated follicle and provide structural support at first, and then by proliferating and differentiating, and acquiring a capillary network, they have become essential components of developing follicles.

Their primary function is to synthesize androgens which act as substrates for estrogen production in granulosa cells, which is crucial for the pituitary—gonadal axis and endocrine control of reproduction. Androgen production is largely under the control of LH produced by the pituitary and transported to thecal cells via the blood stream. Theca cells have been somewhat forgotten more recently, where topical research has focused on granulosa cells and oocytes, but these specialized cells have a highly significant role in follicular function and are crucial for normal follicular development.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. We would like to thank Ted Pinner for preparation of the figures, and Bruce Campbell for useful discussions. Endocrine Reviews 6 — doi Molecular and Cellular Endocrinology — doi Endocrinology 98 — doi Biology of Reproduction 24 — doi Journal of Animal Science 76 — Fertility and Sterility 40 — Obstetrics and Gynecology 64 73S — 80S.

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The interrelationships among the three steroids may also reveal the maturation of granulosa tissue after the gonadotropin surge table 3. For example, in follicles from which an oocyte was not recovered, testosterone levels correlated with estradiol; perhaps this reflects the lack of granulosa maturation which requires the presence of the oocyte. When an oocyte was recovered and subsequently fertilized, estradiol correlated with progesterone levels but not testosterone. The relationship between follicular size and oocyte maturation has been debated for some time.

Eppig et al [ 27 ] claimed that oocyte developmental competence - as shown by the ability to undergo fertilization and develop to blastocyst stage - was independent of both the size of follicle and the size of oocyte. However, the human oocyte has a size-dependent ability to resume meiosis and complete maturation: larger oocytes, or the oocytes taken from larger follicles, have a higher meiotic maturation rate [ 28 — 30 ].

Furthermore, McNatty et al [ 31 ] demonstrated that the hormone synthesising ability of granulosa cells was also dependent on the size of follicle from which they originated, principally in their aromatizing ability. Serum estradiol is often used as a marker of follicular development [ 5 — 7 , 36 ] and the steroidogenic activity of the incumbent granulosa changes with follicular maturation.

Some studies have suggested that luteinized pre-ovulatory follicular fluid levels of progesterone, estradiol, testosterone - and even the ratio between estradiol and testosterone - is a better indicator of oocyte maturity than follicular size alone [ 37 — 40 ].

Unfortunately, most of these studies showing a significant correlation have grouped follicles into mature and immature sometimes intermediate by criteria based on an arbitrary follicle size cut-off. This will bias results: oocyte maturity is a function of follicular size, whilst steroid production by the follicle is also a function of follicular mass.

If follicles are split simply into large mature or small immature , it is inevitable that higher levels of steroids will be found in those follicles from which there was a higher rate of fertilization.

Any relationship between fertilization outcome and prevailing steroid levels will be a causal function of follicle size. In this study, we examined the molar concentrations and total content of all three steroids in individual follicles. Although most of the steroids are bound to steroid-binding proteins, they are freely released in immunoassays; as such binding has much low affinity than that of an antibody which at equilibrium obliterates the steroid protein-binding effects [ 41 ].

Therefore, the levels of three steroid hormones detected in this study reflect the total amounts of steroids. Results showed that estradiol concentration decreased figure 2a while its total content increased significantly with follicle size figure 2b. Both testosterone and progesterone concentrations remained relatively constant figure 3a , 4a , while their total content increased figure 3b , 4b. Thus individual steroid levels within a follicle are a function of follicular volume.

Furthermore, no significant association between steroid levels and oocyte recovery or fertilization rates was found. This suggests a post-maturity phenomenon, and thus overall this study failed to show a simple linear correlation between fertilization rates and follicular diameter.

This actually further demonstrates the dominance of follicular size in any physiological relationship. This is inconsistent with a study carried out by Haines and Emes, who reported that once a follicle has reached mm in diameter, the fertilization rate remained relatively constant despite progressive follicle growth [ 21 ].

For stimulated cycles, luteinized pre-ovulatory follicular fluid levels of testosterone, progesterone and estradiol do not correlate with oocyte maturity recovery and fertilization rate. In post-luteinized follicles, the steroidogenic ability of granulosa cells is altered to become the dominant cell type producing progesterone.

However, these studies do suggest that the oocyte has an influence on this metabolic switching: Although progesterone is the major de novo synthesised steroid of luteinised granulosa; when an oocyte is present follicular estradiol correlates with progesterone levels.

However, if an oocyte is not present follicular estradiol levels correlate with testosterone and not progesterone levels. Fertil Steril. PubMed Google Scholar. Essential Reproduction. Google Scholar. Article Google Scholar. Am J Obstet Gynecol. Hum Reprod. Conversion of acetateC to estrone and estradiol. J Biol Chem. Conversion of progesteroneC to estrone and estradiol.

Falck B: Site of production of oestrogen on rate ovary as studied in micro-transplants. Acta Physiol Scand. Channing CP, Coudert SP: Contribution of granulosa cells and follicular fluid to ovarian estrogen secretion in rhesus monkey in vivo. Ovarian Follicular Development and Function. Mol Cell Endocrinol. Hillier SG: Sex steroid metabolism and follicular development in the ovary.

Oxf Rev Reprod Biol. J Clin Endocrinolo Metab. Text Book Endocrine Physiology. J Endocrinol. Endocr Rev. Biol Reprod. Bio reprod. J Mol Endocrinol. During the preovulatory phase, cells from large follicles greater than or equal to 8 mm diameter differentiate from an estrogen-secreting state into a P- and, to a lesser extent, an delta 4-secreting one. By contrast, during follicular atresia, granulosa cells continue to synthesize delta 4, but their capacity to synthesize estrogen is substantially reduced.

Furthermore, granulosa cells from atretic follicles are incapable of transforming from an androgen-secreting state into a P-secreting one in tissue culture. During follicular growth, thecal tissue secretes about times more delta 4 than E2.