Folliculogenesis is regulated through the complex interaction of hormones produced by the hypothalamus, pituitary gland, and ovaries. Among these hormones, estradiol, together with progesterone and inhibins, plays a key regulatory role in the hypothalamic–pituitary–ovarian axis
Η Luteinizing hormone (LH) ) and follicle-stimulating hormone (FSH) are secreted by the anterior pituitary gland in response to gonadotropin-releasing hormone (GnRH) and play a central role in follicular development and ovulation. Specifically, LH stimulates androgen production by the ovarian theca cells. These androgens are then transported to the granulosa cells, where they are aromatized into estrogens. LH is also essential for folliculogenesis and the ovulatory process, while FSH primarily promotes the growth and maturation of ovarian follicles.
The coordinated action of both LH and FSH is essential for steroidogenesis, follicular development, granulosa cell proliferation, the initiation of ovulation, and the maintenance of the corpus luteum.
Insufficient production or impaired action of LH and FSH has a detrimental effect on gametogenesis and ovarian steroid hormone production, thereby compromising female fertility.
The causes of reduced LH and FSH production—such as Kallmann syndrome, intensive physical exercise, nutritional disorders, diabetes mellitus, thyroid disease, psychological stress, and pituitary disorders or necrosis (including prolactinoma and Sheehan syndrome)—have been extensively studied and well documented. However, comparatively less attention has been given to the clinical consequences of impaired gonadotropin action. It is now well established that both the production and biological activity of these hormones are closely linked to human reproduction and represent an area of considerable clinical importance in assisted reproductive medicine.
The biological activity of LH and FSH is influenced by several factors, including the frequency and amplitude of GnRH secretory pulses, the different LH and FSH isoforms, genetic polymorphisms of the gonadotropins and their receptors, and the intracellular signaling pathways that mediate their effects.
In assisted reproductive medicine, the biological activity of gonadotropins and the ovarian response to exogenously administered gonadotropins are also influenced by individual demographic and clinical characteristics, including age, coexisting medical conditions, prior use of oral contraceptives, and ovarian stimulation protocols involving GnRH analogues. Furthermore, a growing body of evidence suggests that anti-Müllerian hormone (AMH) plays an important role in the neuroendocrine regulation of reproduction and in modulating the actions of LH and FSH. AMH has been shown to increase the frequency of LH pulsatile secretion while reducing follicular sensitivity to FSH, decreasing aromatase activity, and downregulating LH receptor expression in granulosa cells.
GnRH agonists and antagonists, which are used during controlled ovarian stimulation to prevent the premature LH surge and, consequently, premature ovulation, allow the retrieval of a greater number of oocytes. However, their use also induces a temporary suppression of endogenous LH and FSH secretion.
In most cases, the residual circulating levels of LH remain sufficient to support steroidogenesis in the theca cells. However, LH levels that fall substantially below physiological baseline may adversely affect the outcome of assisted reproductive treatment, particularly in certain groups of women.
More specifically, in the field of assisted reproductive medicine, a combination of factors—including advanced maternal age, which appears to influence GnRH pulsatility and consequently LH secretion, and genetic variations in gonadotropins and their receptors, which affect gonadotropin activity—may further exacerbate the temporary suppression of LH and FSH induced by GnRH analogues. This, in turn, may contribute to a suboptimal ovarian response during controlled ovarian stimulation.
Several studies have shown that co-administration of FSH and LH during controlled ovarian stimulation may improve treatment outcomes in women with a temporary deficiency of LH and FSH resulting from the use of GnRH agonists or antagonists.
The co-administration of LH and FSH appears to be particularly beneficial in specific subgroups of women who are more likely to develop a temporary deficiency of these gonadotropins following GnRH analogue administration. These include women of advanced reproductive age and those who exhibit a lower-than-expected ovarian response to controlled ovarian stimulation.
As previously discussed, advancing maternal age is associated with alterations in GnRH pulsatility. Consequently, the functional capacity of the gonadotropin axis may be further compromised by the administration of GnRH analogues, potentially affecting the ovarian response during assisted reproductive treatment.
Recent evidence suggests that the co-administration of LH and FSH during controlled ovarian stimulation in women aged 35–39 years may improve implantation and live birth rates. With regard to poor ovarian response, reduced LH and FSH activity may result from defects at the level of the gonadotropin receptors or in their downstream signaling pathways, leading to a diminished response to ovarian stimulation treatment.
Finally, the beneficial effect of adding LH to FSH therapy in selected groups of women—particularly those of advanced reproductive age and those with a lower-than-expected ovarian response—may also be attributed to the positive role of LH in promoting successful embryo implantation within the uterus.
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Suggested reading
Alviggi C, Conforti A, Esteves SC, Andersen CY, Bosch E, Bu ̈hler K, . Ferraretti AP, De Placido G, Mollo A, Fischer R. et al. Recombinant luteinizing hormone supplementation in assisted re. productive technology: a systematic review. Fertil Steril 2018a;109: . 644–664
Bosch Ε, Alviggi C, Lispi M, Conforti A, Hanyaloglu A.C, Chuderland D, Simoni M, Raine-Fenning N, Cre ́pieux P, Kol S, Rochira V, D’Hooghe T, Humaidan P,Reduced FSH and LH action: implications for medically assisted reproduction,Human Reproduction, Vol.36, No.6, pp. 1469–1480, 2021
Hill MJ, Levens ED, Levy G, Ryan ME, Csokmay JM, DeCherney AH, . Whitcomb BW. The use of recombinant luteinizing hormone in . patients undergoing assisted reproductive techniques with ad- . vanced reproductive age: a systematic review and meta-analysis. . Fertil Steril 2012;97:1108–1114.e1.
Humaidan P, Bungum L, Bungum M, Andersen CY. 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 . Oxf Engl 2002;17:2016–2021
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