Gonadotropin surge-attenuating factor

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Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. [1] GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. [1] During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. [2] At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. [1] In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. [3] GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion. [4]

Contents

Molecular structure and characteristics

GnSAF is a large molecule consisting of subunits that has the same structure as the carboxyl terminal fragment of human serum albumin (HAS). [5] [6] [7] However, HSA, in its complete form, does not exhibit any GnSAF activity. [8]

The smallest biologically active fraction of GnSAF found in human follicular fluid is a peptide of molecular mass 12.5 kDA. [7] The activity of other subunits has not yet been clarified, but it has been confirmed that more than one protein contributes to the attenuating effect of GnSAF. [9]

Since GnSAF is found in very low concentrations in the human follicular fluid, GnSAF in women has been difficult to isolate, sequence and conclusively characterise. [9]

Synthesis of GnSAF

GnSAF is produced in the granulosa cells of the small sized antral follicles, which have the highest concentration of GnSAF. [10] Concentrations of GnSAF bioactivity is inversely proportional to follicle size. [2] Upon synthesis, GnSAF is released into peripheral circulation. [11]

Follicle-stimulating hormone (FSH) from the anterior pituitary stimulates and prolongs GnSAF biosynthesis in growing small antral follicles in the ovary. [12] FSH induces expression and transcription of exons 12 and 13 of the HSA gene found in granulosa cells. [13] During the early and mid-follicular phase, FSH is secreted to promote growth and proliferation of the granulosa cells, which increases GnSAF concentrations. [14] Once the dominant ovarian follicle has been selected at mid-follicular phase, the non-dominant follicles undergo atresia. [15] Without the presence of small follicles during the late follicular phase, GnSAF concentrations steadily decline to its lowest levels observable in the ovarian cycle. [15] Additionally, the rate of GnSAF biosynthesis by the granulosa cells of the remaining dominant follicle decreases as the follicle approaches maturation. [16] During the transition between luteal phase and follicular phase, GnSAF gradually increases from the late luteal phase and onwards due to the recruitment of follicles and concomitant rise of FSH. [5]

The time-course production of GnSAF depends on the serum FSH concentrations. [17] [18] Higher serum concentrations of FSH increases the potency of the attenuating effects of GnSAF on release of LH. [18] However, there is a limit to how much FSH can stimulate GnSAF production: FSH doses above 450 IU do not elicit any more increases in GnSAF bioactivity. [18]

Function

GnSAF antagonises the positive feedback effects of estradiol on GnRH-induced LH release during the follicular phase. [19] GnSAF inhibits the stimulatory role of estradiol in increasing GnRH-induced de novo synthesis of GnRH receptors in the pituitary. [20] [21] GnRH receptor mRNA levels are low in the presence of high GnSAF bioactivity, which limits the availability of binding sites for GnRH at the pituitary and decreased pituitary sensitivity to GnRH. [20] [21] [22] The moderated GnRH pulse amplitude and frequency is sufficient for maintaining low blood concentrations of LH and protects against premature LH surges and LH hypersecretion. [19] [23]

GnSAF also inhibits LH synthesis after the transcription stage and limits stored LH in the pituitary. [24] Whilst the pulse amplitude of LH is reduced by GnSAF, [12] constitutive production of LH is unaffected by GnSAF. [25]  

Effects on the ovarian cycle in women

Follicular phase

GnSAF prevents a pre-ovulatory surge in LH during this time, allowing sufficient time for the dominant follicle to mature before ovulation. [3] [10]

At the start of the follicular phase, high serum FSH concentrations stimulate the development and proliferation of the granulosa cells of the small antral follicles, resulting in a steady increase in GnSAF biosynthesis. [14] The relatively high GnSAF bioactivity dampens the response of the pituitary gland to GnRH by antagonising the sensitising effects of estradiol on the pituitary gland. [22] [25] The GnRH pulse, in the presence of GnSAF, is not frequent or potent enough to stimulate LH secretion from the anterior pituitary above basal levels. [26]

Diagram of the hormones released by the hypothalamic-pituitary-ovarian axis during the early and late follicular phase of the human ovarian cycle. Broken lines represent absence of action and size of the arrows indicates relative concentrations of the hormone. Effects of GnSAF on early and late follicular phase.png
Diagram of the hormones released by the hypothalamic-pituitary-ovarian axis during the early and late follicular phase of the human ovarian cycle. Broken lines represent absence of action and size of the arrows indicates relative concentrations of the hormone.

The tonic FSH and LH pulses sufficiently stimulate the theca cells of the follicle to produce androgen substrates for granulosa cell aromatase and induces cytochrome P450 enzymes that can produce progesterone later in the luteal phase. [3] Androgen substrates from the theca cells are used by the enlarging granulosa cells to produce more estradiol. [3]

At mid-follicular phase, GnSAF bioactivity gradually declines as the dominant follicle is established and the small subordinate follicles undergo atresia. [15] The development of the dominant follicle and regression of small non-dominant follicles is supported by increasing estradiol secretion. [15]

Towards the end of the follicular phase, GnSAF bioactivity is at its lowest due to the absence of small antral follicles. [1] Estradiol secretion from the dominant follicle exponentially increases and exceeds a threshold which switches estradiol feedback on GnRH pulse frequency from negative to positive. [12] [15] Pituitary sensitivity to GnRH is restored. [2] [4]

Mid-cycle

The absence of GnSAF lowers the threshold for GnRH pulse frequency and amplitude required to stimulate the anterior pituitary to secrete LH. [19] Concurrently, GnRH pulse frequency and amplitude increases, which allows LH secretion significantly higher than basal levels. [23] The LH secretion most noticeable as a LH surge lasting 48 to 72 hours in the middle of the ovarian cycle. [3] Meiosis in the dominant follicle resumes and follicle ruptures shortly after the LH surge. [27] Ovulation can only occur if GnSAF is absent and the mid-cycle LH surge occurs. [3] [27]

Luteal phase

Immediately after the LH surge and subsequent ovulation, estradiol concentrations drop and the corpus luteum develops. [23]

Towards the end of luteal phase, GnSAF production in the small antral follicles increases steadily. [18] FSH does not stimulate GnSAF production in the corpus luteum, so GnSAF bioactivity is low after ovulation, until the intercycle rise in FSH occurs. [16]

Relationship between GnRH and GnSAF

GnRH and GnSAF are functionally antagonistic over the control of LH secretion in the hypothalamic-pituitary axis. [15] In the presence of GnSAF, endogenous pulses of GnRH from the hypothalamus still persist, in approximately one hour intervals. [23] Due to this large time interval between consecutive GnRH pulses, GnSAF effectively limits the effects of GnRH on the anterior pituitary. [23] GnSAF acts on the gonadotropic cells of the pituitary to neutralise the second messenger pathway responsible for transducing GnRH signalling in the gonadotropes. [28] The effectiveness of downstream actions of GnRH, such as calcium mobilisation and the protein kinase C system, are reduced by GnSAF. [28] These antagonistic effects of GnSAF on GnRH keeps the anterior pituitary in a low responsiveness state, which prevents acute elevations of serum LH concentrations until GnSAF bioactivity declines. [28]

When estradiol concentrations are high in the late follicular phase, GnRH pulse frequency and amplitude increases and overrides the attenuating effects of GnSAF. [23] Frequent and consecutive exogenous administration of GnRH at submaximal doses is sufficient in overcoming the neutralizing effects of GnSAF. [29] This is because estradiol lowers the GnRH pulse frequency and amplitude required to stimulate the biosynthesis and secretion of LH. [30]

Associated disease states and abnormalities

Abnormal GnSAF bioactivity has been associated with premature surges in LH and LH hypersecretion. Optimal and timely changes in serum LH concentrations are crucial to ensuring the viability of oocytes and implantation after fertilization. [15] [23] For successful implantation of a zygote, the mid-cycle LH surge after the decline of GnSAF and ovulation must correspond with uterine receptivity. [23] Hypersecretion of LH contributes to cycle disturbance, infertility and increased chances of miscarriage. [31]

GnSAF has been implicated in polycystic ovary syndrome (PCOS), one of the most common ovarian disorders responsible for causing anovulatory infertility. [32] Approximately 40% of women with PCOS display higher GnRH pulse frequency and tonic hypersecretion of LH due to hypersecretion of androgens from the polycystic ovary. [3] [32] [33] Androgens are readily metabolized to estradiol in the ovaries. [33] The supraphysiological concentrations of estradiol maintains high pituitary responsiveness to GnRH, permitting the hypersecretion of LH. [34]

Superovulation is common in women who take medications such as clomiphene citrate, an anti-estrogenic oral medication used to treat infertility. [22] Superovulation is induced in women to increase chances of fertilization and conception in assisted reproductive techniques. [22] In naturally superovulating women, the mid-cycle LH surge is significantly lower compared to that of normal ovulating women due to the presence of GnSAF in the late follicular phase fluid. [17] [35] The high basal GnSAF bioactivity is due to a greater number of small follicles, the site of GnSAF biosynthesis. [36]

Possible uses in medicine

An alternative to using GnRH analogues in IVF treatments could be short-term administration of GnSAF. [37] During IVF, the ovaries are stimulated by raising estrogen concentrations to supraphysiological levels, which prevents the mid-cycle LH surge. [22] [35] Premature LH surges are unfavorable during IVF as it is associated with low oocyte viability and low success rates during IVF treatment. [22] GnSAF could be used to influence ovarian hyperstimulation syndrome. [38] Using GnSAF would potentially eliminate the need to use human chorionic gonadotropin. [38]

Administration of GnSAF could also be used to prevent ovulation and replace exogenously administered steroids that are often perceived as being risky, [39] or to delay the naturally premature LH surge observed in some hyperstimulated or infertile women. [15] GnSAF could form part of a contraceptive drug [37] or in treatments for infertility that target LH hypersecretion or abnormal ovarian cycles. [15]

Related Research Articles

<span class="mw-page-title-main">Menstrual cycle</span> Natural changes in the human female reproductive system

The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs and the cyclic release of estrogen and progesterone. The uterine cycle governs the preparation and maintenance of the lining of the uterus (womb) to receive an embryo. These cycles are concurrent and coordinated, normally last between 21 and 35 days, with a median length of 28 days, and continue for about 30–45 years.

<span class="mw-page-title-main">Ovulation</span> Release of egg cells from the ovaries

Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized by sperm. In addition, the uterine lining (endometrium) is thickened to be able to receive a fertilized egg. If no conception occurs, the uterine lining as well as the egg will be shed during menstruation.

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Follicle-stimulating hormone</span> Gonadotropin that regulates the development of reproductive processes

Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and luteinizing hormone (LH) work together in the reproductive system.

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/chorionic gonadotropins, human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG), as well as at least two forms of fish gonadotropins. These hormones are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. LH and FSH are secreted by the anterior pituitary gland, while hCG and eCG are secreted by the placenta in pregnant humans and mares, respectively. The gonadotropins act on the gonads, controlling gamete and sex hormone production.

<span class="mw-page-title-main">Granulosa cell</span>

A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Luteal phase</span>

The menstrual cycle is on average 28 days in length. It begins with menses during the follicular phase and followed by ovulation and ending with the luteal phase. Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again.

<span class="mw-page-title-main">Follicular phase</span> Phase of the estrous or menstrual cycle

The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle during which follicles in the ovary mature from primary follicle to a fully mature graafian follicle. It ends with ovulation. The main hormones controlling this stage are secretion of gonadotropin-releasing hormones, which are follicle-stimulating hormones and luteinising hormones. They are released by pulsatile secretion. The duration of the follicular phase can differ depending on the length of the menstrual cycle, while the luteal phase is usually stable, does not really change and lasts 14 days.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

<span class="mw-page-title-main">Gonadotropin-releasing hormone antagonist</span> Class of medications

Gonadotropin-releasing hormone antagonists are a class of medications that antagonize the gonadotropin-releasing hormone receptor and thus the action of gonadotropin-releasing hormone (GnRH). They are used in the treatment of prostate cancer, endometriosis, uterine fibroids, female infertility in assisted reproduction, and for other indications.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

The theca folliculi comprise a layer of the ovarian follicles. They appear as the follicles become secondary follicles.

<span class="mw-page-title-main">Ganirelix</span> Pharmaceutical drug

Ganirelix acetate, sold under the brand names Orgalutran and Antagon among others, is an injectable competitive gonadotropin-releasing hormone antagonist. It is primarily used in assisted reproduction to control ovulation. The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of LH and FSH. Ganirelix is used in fertility treatment to prevent premature ovulation that could result in the harvesting of eggs that are too immature to be used in procedures such as in vitro fertilization.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

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  29. ↑ Messinis, I. E.; Lolis, D.; Zikopoulos, K.; Milingos, S.; Kollios, G.; Seferiadis, K.; Templeton, A. A. (1996). "Effect of follicle stimulating hormone or human chorionic gonadotrophin treatment on the production of gonadotrophin surge attenuating factor (GnSAF) during the luteal phase of the human menstrual cycle". Clinical Endocrinology. 44 (2): 169–175. doi:10.1046/j.1365-2265.1996.589411.x. ISSN   0300-0664. PMID   8849571.
  30. ↑ RAMEY, J. W.; HIGHSMITH, R. F.; WILFINGER, W. W.; BALDWIN, D. M. (1987). "The Effects of Gonadotropin-Releasing Hormone and Estradiol on Luteinizing Hormone Biosynthesis in Cultured Rat Anterior Pituitary Cells*". Endocrinology. 120 (4): 1503–1513. doi:10.1210/endo-120-4-1503. ISSN   0013-7227. PMID   3549263.
  31. ↑ Homburg, R; Armar, NA; Eshel, A; Adams, J; Jacobs, HS (1989). "Influence of serum luteinising hormone concentrations on ovulation, conception, and early pregnancy loss in polycystic ovary syndrome". International Journal of Gynecology & Obstetrics. 28 (4): 1024–1026. doi:10.1016/0020-7292(89)90625-5. ISSN   0020-7292. PMC   1834779 . PMID   3142595.
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  33. 1 2 Balen, Adam H. (2001), "In vitro fertilization and the patient with polycystic ovaries or polycystic ovary syndrome", Polycystic Ovary Syndrome, Cambridge University Press, pp. 177–203, doi:10.1017/cbo9780511545191.012, ISBN   9780511545191
  34. ↑ WANG, C. F.; LASLEY, B. L.; LEIN, A.; YEN, S. S. C. (1976). "The Functional Changes of the Pituitary Gonadotrophs During the Menstrual Cycle". The Journal of Clinical Endocrinology & Metabolism. 42 (4): 718–728. doi:10.1210/jcem-42-4-718. ISSN   0021-972X. PMID   770496.
  35. 1 2 MESSINIS, IOANNIS E.; TEMPLETON, ALLAN; BAIRD, DAVID T. (1985). "Endogenous Luteinizing Hormone Surge during Superovulation Induction with Sequential Use of Clomiphene Citrate and Pulsatile Human Menopausal Gonadotropin". The Journal of Clinical Endocrinology & Metabolism. 61 (6): 1076–1080. doi: 10.1210/jcem-61-6-1076 . ISSN   0021-972X. PMID   3932447.
  36. ↑ MESSINIS, IOANNIS E.; TEMPLETON, ALLAN (1990). "Superovulation Induction in Women Suppresses Luteinizing Hormone Secretion at the Pituitary Level". Clinical Endocrinology. 32 (1): 107–114. doi:10.1111/j.1365-2265.1990.tb03756.x. ISSN   0300-0664. PMID   2110044.
  37. 1 2 Vega, Mario G.; Zarek, Shvetha M.; Bhagwat, Medha; Segars, James H. (2015). "Gonadotropin surge-inhibiting/attenuating factors: A review of current evidence, potential applications, and future directions for research". Molecular Reproduction and Development. 82 (1): 2–16. doi:10.1002/mrd.22439. ISSN   1040-452X. PMC   4710370 . PMID   25581424.
  38. 1 2 Delvigne, A. (2003-01-01). "Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS)". Human Reproduction Update. 9 (1): 77–96. doi: 10.1093/humupd/dmg005 . ISSN   1355-4786. PMID   12638783.
  39. ↑ HODGEN, GARY D.; KENIGSBURG, DANIEL; COLLINS, ROBERT L.; SCHENKEN, ROBERT S. (1985). "Selection of the Dominant Ovarian Follicle and Hormonal Enhancement of the Natural Cycle". Annals of the New York Academy of Sciences. 442 (1 In Vitro Fert): 23–37. Bibcode:1985NYASA.442...23H. doi:10.1111/j.1749-6632.1985.tb37502.x. ISSN   0077-8923. PMID   3925837.


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