Marina Dimitraki MD., MSc., M.H.A., PhD, EFOG-EBCOG, Gynecologist in Assisted Reproduction, European Fellow of Reproductive Medicine ESHRE/EBCOG
Folliculogenesis is controlled by a complex interaction among hormones in the hypothalamus, anterior pituitary gland and the ovaries. Oestradiol is the hormone most involved in the regulation of hypothalamic-pituitary-goanadal (HPG) axis, together with progesterone and inhibins. Luteneinizing hormone (LH) and follicle stimulating hormone (FSH) are secreted from the anterior pituitary gland in response to GnRH and play a complementary role in follicle development and ovulation. LH stimulates the secretion of androgens in ovarian theca cells, that are transferred to granulose cells to be converted to estradiol (E2) by aromatase and is involved in follicle development and maturation, while FSH stimulates the development of ovarian follicles. The action of both LH and FSH is required for steroidogenesis, follicular growth, granulosa cell growth, ovulation triggering and maintenance of the corpus luteum A deficiency in LH and FSH production or action compromises gametogenesis and gonadal steroid production, thereby reducing female fertility.
Causes of reduced LH and FSH production such as Kallmann syndrome, intensive exercise and eating disorders, poor controlled diabetes and thyroid disorders, stress habits, pituitary tumors (e.g. prolactinomas) or pituitary infarct (Sheehan’s syndrome) are well described, however deficiency of LH and FSH action has received much less attention, even though it is now recognised that both production and action are relevant for human fertility and are of clinical interest for medically assisted reproduction. The action of LH and FSH is determined by a variety of factors such as the frequency and amplitude of GnRH peaks, the different isoforms of LH and FSH, polymorphism of LH and FSH and their receptors and intracellular signaling. Furthermore in medically assisted reproduction individual demographic, clinical and treatment factors, such as ageing, comorbidities and the effect of oral contraceptives and GnRH analogue protocols can influence gonadotropin action and the response to exogenous gonadotropins. Moreover, increasing evidence indicates that anti-Mullerian hormone (AMH) plays a role in the neuroendocrine control of reproduction and in LH/FSH action. It seems that AMH increases LH pulsatility and secretion, inhibits follicle growth by decreasing the sensitivity of ovarian follicles to FSH and decrease aromatase activity and LH receptors in granulosa cells.
GnRH agonists and antagonists and are used during ovarian stimulation to prevent premature ovulation, thus enabling retrieval of more oocytes, cause transient LH and FSH deficiency. Usually, the residual circulating levels of LH are sufficient to support steroidogenesis in theca cells. However, LH levels much lower than baseline can negatively affect IVF outcomes in some women.
In medically assisted reproduction, a combination of factors such as advanced maternal age (ΑΜΑ) – where there is an age-related impairment of GnRH pulses – and genetic variants of gonadotropins or their receptors that impair gonadotropin action, may further exacerbate the transient reduced LH and FSH production caused by GnRH analogues, and result in a low or sub-optimal response to ovarian stimulation.
Several studies have shown that r-hFSH and r-hLH co-treatment can improve ovarian stimulation in women with transient LH and FSH deficiency after GnRH agonist or antagonist treatment especially in subgroups of patients who are more prone to develop LH and FSH deficiency after GnRH analogues, such as women of advanced maternal age and hypo-responders. The impaired functioning of the LH and FSH systems in AMA women, could be exacerbated by the transient gonadotropin deficiency induced by GnRH analogue regimens during ovarian stimulation. Recent data supports that co-treatment with r-hLH and r-hFSH in women between the ages of 35 and 39 years improve both live birth and implantation rates. Regarding hypo response to ovarian stimulation LH and FSH action may be reduced by receptor and post-receptor defects that cause a reduced response to ovarian stimulation. Studies on hypo-response found that ovarian stimulation with r-hFSH/r-hLH resulted in significantly higher clinical pregnancy
Finally, the benefit of r-hFSH/r-hLH treatment for women of advanced age may also be related to the effect of LH on embryo implantation.
Suggested bibliography
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
LH and FSH deficiency is a spectrum conditions with various aetiologies
