How is fsh transported to the ovary

Generally, variation is maximal and intermenstrual intervals are longest in the years immediately after menarche and immediately before menopause, when ovulation occurs less regularly. The menstrual cycle begins and ends with the first day of menses day 1.

The menstrual cycle can be divided into phases, usually based on ovarian status. The ovary proceeds through the following phases:. Luteal postovulatory—see figure The idealized cyclic changes in pituitary gonadotropins, estradiol E2 , progesterone P , and uterine endometrium during the normal menstrual cycle The idealized cyclic changes in pituitary gonadotropins, estradiol E2 , progesterone P , and uterine endometrium during the normal menstrual cycle Amenorrhea the absence of menstruation can be primary or secondary.

Primary amenorrhea is failure of menses to occur by age 15 years in patients with normal growth and secondary sexual characteristics The endometrium Endometrium Hormonal interaction between the hypothalamus, anterior pituitary gland, and ovaries regulates the female reproductive system.

In the early follicular phase first half of the follicular phase , the primary event is. 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.

Early in the follicular phase, when estradiol levels are low, the vaginal epithelium is thin and pale. Later in the follicular phase, as estradiol levels increase, squamous cells mature and become cornified, causing epithelial thickening.

During the luteal phase, the number of precornified intermediate cells increases, and the number of leukocytes and amount of cellular debris increase as mature squamous cells are shed. From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world.

The results were showed that r-hLH helped in:. Promoting dose-associated increase in the secretion of estradiol and androstenedione by r-hFSH-induced follicles. Enhancing ovarian sensitivity to FSH as observed in the number of patients who developed follicles following FSH administration.

Based on the findings, the researchers recommended that 75 IU r-hLH is effective in most of the women by facilitating maximal endometrial growth and optimal follicular development, which is defined as:. This might be due to excessive or inconsistent LH activity from the hCG component in hMG may affect ocyte maturation in the latter half of the ovarian stimulation cycle, giving rise to the differences in numbers of oocytes retrieved and success of pregnancy. Optimal follicle development with subsequent ovulation requires the complex interaction of FSH, LH and their complementary activities.

Thus, ART outcome can be improved with optimization of FSH dose in various patient populations and supplementation of LH in various subgroups discussed above. Biomarkers to ascertain women who are in need of exogenous LH need to be sought. With the increasing evidence of pharmacogenetic approaches, it is likely that the choice of ART regimen will be also guided by patient's genetic makeup.

We suggest that before deciding on use of exogenous LH, it is crucial to identify patients who would benefit the most from LH supplementation and assess the cost-benefit ratio in the use of exogenous LH. Further research is needed to arrive at a clear and uniform consensus on dosage, timing and patient population who would benefit the most with LH supplementation.

The authors are grateful to acknowledge Knowledge Isotopes www. Conflict of Interest: This review article is the result of a series of advisory board meetings supported by Merck Specialties Private Limited.

National Center for Biotechnology Information , U. J Hum Reprod Sci. Author information Article notes Copyright and License information Disclaimer. Address for correspondence: Dr. E-mail: moc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3. This article has been cited by other articles in PMC. Abstract Luteinizing hormone LH in synergy with follicle stimulating hormone FSH stimulates normal follicular growth and ovulation.

Open in a separate window. Figure 1. Figure 2. Follicle stimulating hormone threshold and recruitment window. Concept of luteinizing hormone therapeutic window The concept of the LH therapeutic window has been explained in brief in Figure 3.

Figure 3. Optimizing follicle stimulating hormone dosing Various studies suggest four parameters of FSH administration management involved in the risk of multifollicular development: a the choice of the FSH starting dose,[ 34 , 35 ] b the duration of the starting, dose before stepping up or stepping down,[ 34 , 36 ] c the rate of increase in FSH dose at each increment[ 37 ] and d the reduction of the FSH dose once a follicle has been selected. Exogenous luteinizing hormone supplementation LH is important in regulating steroidogenesis throughout follicular development; adequate LH is particularly important for oocyte maturation.

Poor responders and low ovarian reserve Many factors are linked to a decreased ovarian response and hence, it is difficult to identify poor responders. Role of luteinizing hormone in polycystic ovary syndrome PCOS The detrimental impact of endocrinological disorder, which is linked to hyper-secretion of LH and ovulatory dysfunction, is attributed to increased LH levels.

Role of luteinizing hormone LH supplementation is important in older and poor-responding patients because they usually receive higher FSH doses for COS, show higher progesterone levels at the end of stimulation and subsequently, their endometrium receptivity diminishes. Dosing of luteinizing hormone In , the European Study Group conducted the first randomized efficacy clinical study to investigate the safety and tolerability of r-hLH supplementation in hypogonadotropic hypogonadal women WHO group 1 anovulation.

The results were showed that r-hLH helped in: Promoting dose-associated increase in the secretion of estradiol and androstenedione by r-hFSH-induced follicles. Increasing the successful luteinization of follicles on exposure to hCG. Shoham Z. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Fertil Steril. Ovarian response and pregnancy outcome related to mid-follicular LH levels in women undergoing assisted reproduction with GnRH agonist down-regulation and recombinant FSH stimulation.

Hum Reprod. Lower apoptosis rate in human cumulus cells after administration of recombinant luteinizing hormone to women undergoing ovarian stimulation for in vitro fertilization procedures. LH supplementation in down-regulated women undergoing assisted reproduction with baseline low serum LH levels. Gynecol Endocrinol. Current opinion on use of luteinizing hormone supplementation in assisted reproduction therapy: An Asian perspective. Reprod Biomed Online. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: An age-adjusted analysis.

Curr Med Res Opin. Vaskivuo T. Regulation of Apoptosis in the Female Reproductive System. Brown JB. Pituitary control of ovarian function - Concepts derived from gonadotrophin therapy. Role of angiotensin II on follicle development and ovulation.

Anim Reprod. Williams Textbook of Endocrinology. Philadelphia: Saunders Elsevier; PA: Saunders Elsevier; Regulation of steroidogenesis in bovine preovulatory follicles. J Anim Sci. Luteinization, however, occurs in a small percentage of the cases with raised LH. The importance of LH suppression during ovarian stimulation induction has not been clarified because data in the literature are conflicting Westergaard et al.

LH secretion is also suppressed during the luteal phase of stimulated cycles Messinis and Templeton, b ; Tavaniotou et al. It seems that the suppression of gonadotrophin secretion during ovarian stimulation is a continuous process starting in the follicular phase and ending up in a disrupted luteal phase. The two feedback mechanisms are important determinants of the relationships between the ovaries and the hypothalamic-pituitary system.

The ovarian steroids, E 2 and progesterone, are the principal mediators of the suppressing effect on gonadotrophin secretion during the normal menstrual cycle.

Evidence has been provided that for FSH secretion non-steroidal substances, such as inhibin A and B, also play an important role. E 2 is the main component of the positive feedback mechanism that induces the midcycle endogenous LH surge. Further research is required to clarify the specific role of each of the steroidal and non-steroidal substances in the context of the feedback mechanisms. J Clin Endocrinol Metab 79 , — European Cetrorelix Study Group.

Hum Reprod , — Clin Endocrinol Oxf 47 , — Endocrinology , — Exp Gerontol 36 , — J Reprod Fertil , — Hum Reprod 10 , — J Clin Endocrinol Metab 74 , — J Clin Endocrinol Metab 88 , — In Burger HG ed. Ares Serono Symposium, Rome, Italy, pp. Borm G and Mannaerts B Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial.

The European Orgalutran Study Group. Hum Reprod 15 , — Gynecol Endocrinol 6 , — Clin Endocrinol Oxf 49 , Climacteric 3 , 17 — Recent Prog Horm Res 57 , — Biol Reprod 52 , 88 — Byrne B , Fowler PA and Templeton A Role of progesterone and nonsteroidal ovarian factors in regulating gonadotropin-releasing hormone self-priming in vitro.

J Clin Endocrinol Metab 81 , — Br J Obstet Gynaecol 84 , — J Clin Endocrinol Metab 47 , — Hum Reprod 19 , — Clin Endocrinol Oxf 60 , — J Clin Endocrinol Metab 91 , — Danforth DR and Cheng CY Purification of a candidate gonadotropin surge inhibiting factor from porcine follicular fluid.

Fertil Steril 70 , — Daw E Luteinising hormone LH changes in women undergoing artificial menopause. Curr Med Res Opin 2 , — Hum Reprod Update 8 , — Fertil Steril 77 , — Clin Endocrinol Oxf 20 , — Hum Reprod 17 , — Hum Reprod 16 , — Google Scholar.

Evans WS , Boykin BJ, Kaiser DL, Borges JL and Thorner MO Biphasic luteinizing hormone secretion in response to gonadotropin-releasing hormone during continuous perifusion of dispersed rat anterior pituitary cells: changes in total release and the phasic components during the estrous cycle.

Evans LW , Muttukrishna S and Groome NP Development, validation and application of an ultra-sensitive two-site enzyme immunoassay for human follistatin. J Endocrinol , — Fertil Steril 79 , — Hum Reprod 18 , — Farnworth PG , Robertson DM, de Kretser DM and Burger HG Effects of 31 kilodalton bovine inhibin on follicle-stimulating hormone and luteinizing hormone in rat pituitary cells in vitro: actions under basal conditions.

Endocrinology 94 , — Endocrinology , 50 — J Clin Endocrinol Metab 62 , — Foster DL and Ryan KD Endocrine mechanisms governing transition into adulthood: a marked decrease in inhibitory feedback action of estradiol on tonic secretion of luteinizing hormone in the lamb during puberty. Endocr Rev 17 , — J Reprod Fertil 90 , — Mol Hum Reprod 8 , — Reproduction , — Baillieres Clin Obstet Gynaecol 2 , — Biol Reprod 22 , — J Clin Endocrinol Metab 87 , — J Clin Endocrinol Metab 85 , — J Clin Endocrinol Metab 44 , — J Clin Endocrinol Metab 49 , 8 — J Clin Endocrinol Metab 57 , — Hum Reprod 20 , — Johansson ED and Wide L Periovulatory levels of plasma progesterone and luteinizing hormone in women.

Acta Endocrinol Copenh 62 , 82 — Fertil Steril 54 , — Hum Reprod 21 , — Endocrinology 92 , — Hum Reprod 11 , — Kelner KL and Peck EJ Jr Differential sensitivity of estrogen target tissues: implications for estrogen regulation of serum luteinizing hormone. J Neurosci Res 11 , 79 — Fertil Steril 65 , — Keye WR Jr and Jaffe RB Strength-duration characteristics of estrogen effects on gonadotropin response to gonadotropin-releasing hormone in women. Effects of varying duration of estradiol administration.

J Clin Endocrinol Metab 41 , — J Clin Endocrinol Metab 80 , — Kishi H , Okada T, Otsuka M, Watanabe G, Taya K and Sasamoto S Induction of superovulation by immunoneutralization of endogenous inhibin through the increase in the secretion of follicle-stimulating hormone in the cyclic golden hamster. J Endocrinol , 65 — J Clin Endocrinol Metab 89 , — Knobil E The neuroendocrine control of ovulation.

Hum Reprod 3 , — Koppenaal DW , Tijssen AM and de Koning J The effect of gonadotrophin surge-inhibiting factor on the self-priming action of gonadotrophin-releasing hormone in female rats in vitro. Effects upon sexual hormone levels. Contraception 31 , — Fertil Steril 44 , — J Clin Endocrinol Metab 43 , — J Clin Endocrinol Metab 46 , — Clin Endocrinol Oxf 46 , — Periovulatory changes in relation to the LH surge. Acta Endocrinol Copenh 84 , — J Clin Endocrinol Metab 77 , — Lee WS , Smith MS and Hoffman GE Progesterone enhances the surge of luteinizing hormone by increasing the activation of luteinizing hormone-releasing hormone neurons.

Legan SJ and Tsai HW Oestrogen receptor-alpha and — beta immunoreactivity in gonadotropin-releasing hormone neurones after ovariectomy and chronic exposure to oestradiol. J Neuroendocrinol 15 , — Fertil Steril 62 , — Br J Obstet Gynaecol 85 , — Biochem Biophys Res Commun , — Endocr J 43 , 39 — Endocr J 43 , — J Clin Endocrinol Metab 52 , — Am J Physiol , — J Clin Endocrinol Metab 64 , — J Clin Endocrinol Metab 49 , — Marshall JC and Kelch RP Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction.

N Engl J Med , — Proc Soc Exp Biol Med , 1 — McCartney CR , Gingrich MB, Hu Y, Evans WS and Marshall JC Hypothalamic regulation of cyclic ovulation: evidence that the increase in gonadotropin-releasing hormone pulse frequency during the follicular phase reflects the gradual loss of the restraining effects of progesterone. J Clin Endocrinol Metab 83 , — McNatty KP , Smith DM, Makris A, Osathanondh R and Ryan KJ The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro.

Ann N Y Acad Sci , 35 — Messinis IE Ovulation induction: a mini review. Messinis IE and Templeton A The effect of pulsatile follicle stimulating hormone on the endogenous luteinizing hormone surge in women. Clin Endocrinol Oxf 25 , — Messinis IE and Templeton AA Endocrine and follicle characteristics of cycles with and without endogenous luteinizing hormone surges during superovulation induction with pulsatile follicle-stimulating hormone.

Hum Reprod 2 , 11 — Messinis IE and Templeton AA Disparate effects of endogenous and exogenous oestradiol on luteal phase function in women. J Reprod Fertil 79 , — J Reprod Fertil Suppl 36 , 27 — Messinis IE and Templeton A Blockage of the positive feedback effect of oestradiol during prolonged administration of clomiphene citrate to normal women. Clin Endocrinol Oxf 29 , — J Reprod Fertil 87 , — Messinis IE and Templeton AA Effects of supraphysiological concentrations of progesterone on the characteristics of the oestradiol-induced gonadotrophin surge in women.

J Reprod Fertil 88 , — J Reprod Fertil 92 , — Messinis IE , Templeton A and Baird DT Endogenous luteinizing hormone surge during superovulation induction with sequential use of clomiphene citrate and pulsatile human menopausal gonadotropin. J Clin Endocrinol Metab 61 , — Messinis IE , Templeton A and Baird DT Endogenous luteinizing hormone surge in women during induction of multiple follicular development with pulsatile follicle stimulating hormone.

Clin Endocrinol Oxf 24 , — Clin Endocrinol Oxf 35 , — Hum Reprod 7 , — Clin Endocrinol Oxf 39 , 45 — J Reprod Fertil 97 , — Clin Endocrinol Oxf 38 , — Clin Endocrinol Oxf 44 , — Messinis IE , Milingos S, Zikopoulos K, Hasiotis G, Seferiadis K and Lolis D Luteinizing hormone response to gonadotrophin-releasing hormone in normal women undergoing ovulation induction with urinary or recombinant follicle stimulating hormone.

Hum Reprod 13 , — Neuroendocrinology 78 , 29 — Miro F and Aspinall LJ The onset of the initial rise in follicle-stimulating hormone during the human menstrual cycle.

Hum Reprod 20 , 96 — Mitchner NA , Garlick C and Ben-Jonathan N Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Mitwally MF and Casper RF Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 75 , — Acta Endocrinol Copenh , — J Clin Endocrinol Metab 56 , — Increase in serum gonadotropins in response to estradiol.

J Clin Endocrinol Metab 34 , — Changes in serum gonadotropins in menstruating women in response to oophorectomy.

J Mol Endocrinol 6 , — Mol Cell Endocrinol , 45 — Science , — J Clin Endocrinol Metab 69 , 67 — Is follistatin-induced suppression of FSH secretion mediated via changes in activin availability and does it involve changes in gonadotropin-releasing hormone secretion? Biol Reprod 66 , — Hum Reprod 14 , — Fertil Steril 73 , — Plant TM and Shahab M Neuroendocrine mechanisms that delay and initiate puberty in higher primates.

Physiol Behav 77 , — J Clin Endocrinol Metab 76 , — Richardson DW , Gordon K, Billiar RB and Little AB Chronic hyperestrogenemia: lack of positive feedback action on gonadotropin-releasing hormone-induced luteinizing hormone release and dual site of negative feedback action. Rivier C and Vale W Effect of recombinant activin-A on gonadotropin secretion in the female rat. Rivier C , Rivier J and Vale W Inhibin-mediated feedback control of follicle-stimulating hormone secretion in the female rat.

J Clin Endocrinol Metab 69 , — Recent Prog Horm Res 26 , 1 — J Clin Endocrinol Metab 35 , — Am J Obstet Gynecol , — Fertil Steril 71 , — Shaw RW Tests of the hypothalamic-pituitary-ovarian axis.

Clin Obstet Gynaecol 3 , — Fertil Steril 64 , — J Clin Endocrinol Metab , — Sopelak VM and Hodgen GD Blockade of the estrogen-induced luteinizing hormone surge in monkeys: a nonsteroidal, antigenic factor in porcine follicular fluid. Fertil Steril 41 , — J Clin Endocrinol Metab 58 , —