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Bachmann A et al.  
The Gonadotropins FSH and LH and their use in Adult Women – an Overview
(Joint Statement by the German Society for Gynecological Endocrinology and Reproductive Medicine [DGGEF] and the German Professional Association of Gynecologists [BVF])

Journal für Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2015; 12 (4): 360-376

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Keywords: biosimilarsgonadotropinshCGmodified natural cyclenatural cylenew FSH-moleculesOHSSovarian hyperstimulation

The glycoprotein hormones LH and FSH are essential for reproduction. They consist of two polypeptide units. The alpha unit has 92 amino acids and is virtually identical for FSH, LH, thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG). The secretion in the anterior pituitary gland underlies neuroendocrine control of the hypothalamic-pituitary-gonadal axis. Depending on the level of maturity of the follicle and on the phase of the menstrual cycle LH and FSH regulate the steroidogenesis in theka- and granulosacells of the ovary. The pregnancy hormone hCG is produced by Langerhans cells in the syncytiotrophoblast of the placenta. It is very similar to LH in structure and binds to the LH receptor, but with a half-life of 36 h has a longer effect in duration. hCG administration can replace the LH peak in the middle of the ovarian cycle and helps to improve luteal function. However, it cannot prevent regression of the corpus luteum. For more than 30 years gonadotropins have been crucial elements of pharmacological ovarian stimulation in assisted reproductive techniques (ART) in primary and secondary infertility and the treatment of hypogonadotropic hypogonadism. First menotropins have been extracted from the urine of postmenopausal women. The application of recombinant DNA technology has resulted in the development of recombinant FSH. Further aims have been to avoid daily injections by modifying the FSH molecule.
Compounds available at present:
– Highly purified human-derived follicle-stimulating hormone: Bravelle® (Ferring)
– Recombinant-DNA products:
-- Follitropin alpha: Gonal-F® (Merck-Serono)
-- rec. FSH: Follitropin beta: Puregon® (MSD)
-- long acting rec. FSH: Corifollitropin alpha: Elonva® (MSD)
-- rec. hLH: Lutropin alpha: Luveris® (Merck Serono)
– Compounds with more than one active agent:
-- human urinary-derived preparations: hMG HP: FSH,LH,hCG = 75 IU LH: Menogon HP® (Ferring)
-- recombinant fixed-dose combinations: 150 IE rec-hFSH / 75 IU rec-hLH Pergoveris® (Merck Serono)
Dosing: FSH and hMG preparations can be dosed equally and are applicable for single use or may be combined with each other. This also applies to recombinant fixed-dose combinations and long-acting FSH preparations. The dosage always must be adapted to the age, AFC (antral follicle count) and AMH (Anti muellerian hormone) of the individual patient. From day 3 to 9 of the menstrual cycle up to 100 IU of FSH might be injected daily for timed intercourse or intrauterine inseminations and up to 300 IU for IVF/ICSI.
In order to achieve a successful outcome of ART it is also important to choose a suitable stimulation regimen. There are protocols for controlled ovarian hyperstimulation using GnRH agonists (long protocol, short protocol, ultra-short protocol, ultra-long protocol) or GnRH antagonists as adjuvant therapy.
Step-up-protocols: In a step-up regimen patients start with a lower dosage in order to avoid hyperresponse of the ovaries. The dosage as well as the intervals can be adjusted individually during stimulation.
Step-down-protocols: In order to achieve a maximum amount of recruited follicles in a step-down protocol patients start with a higher dosage and then decrease the dosage step by step in order to avoid hyperstimulation.
In the long GnRH agonist protocol (long protocol, GnRHa long) GnRHa treatment is initiated in the mid-luteal phase of the preceding cycle at least 10–14 days before stimulation with gonadotropins starts. The protocol allows both physicians and patients to schedule the start of stimulation according to their needs. However, for potential high-responder patients there are limited possibilities to avoid ovarian hyperstimulation syndrome. According to the annual report of the German IVF Register (D.I.R) the long-protocol was the second most used regimen in Germany in 2013. It has been used in 27.2% (2402 of 8824) IVF cycles and 28.6 % (8784 of 30710) ICSI cycles.
In the short protocol the agonist is initiated in the early follicular phase (day 1 to 3 of the cycle). In the ultra-short protocol, a shorter period of GnRH-a administration for 3 days is chosen. The short GnRH protocols have been used in 6.5% of all ICSI cycles and 7.6% of all IVF cycles in Germany in 2013. The ultra-long-protocol uses ovarian suppression for up to 6 months as a recognized treatment of endometriosis prior to the administration of gonadotropins. Stimulation starts 14 days after the last monthly injection of GnRHa and is similar to the long protocol.
GnRH-antagonist protocols are frequently used in women who are low-responders to ovarian stimulation or potential high-responders. The GnRH antagonist is usually initiated on the 6th day of FSH administration or when the dominant follicle has a diameter of at least 12 mm. Triggering ovulation using GnRH agonists instead of hCG can prevent severe ovarian hyperstimulation syndrome (OHSS). Because of impaired luteal function and in high-risk patients it seems prudent to freeze all embryos for future transfer. In 2013 the GnRH-antagonist protocol was the most commonly used protocol according to the DIR annual report. It has been used in 55.7% (4914 of 8824) IVF cycles and 55.6% (17,080 of 30,710) ICSI cycles.
New IVF protocols using less gonadotropins and an GnRH antagonist starting at the stage of a dominant follicle (modified natural cycle) or no gonadotropins at all (natural cycle IVF) have also been established. To date there is no reported benefit as far as life-birth-rates are concerned compared to conventional protocols.
Ovarian hyperstimulation: Iatrogenic hyperstimulation and induction of ovulation with hCG can result in activation of the ovarian renin angiotensin system leading to symptoms of ovarian hyperstimulation syndrom (OHSS). To date there are no consistent standards of treatment. Consensus over an interdisciplinary approach yet has to be achieved.
Future aspects: At present biosimilars are also available. New FSH molecules are subject of current research. Pharmacokintetics and Pharmacodynamics of different substances vary to a great extent, oral effective GnRH antagonists, oral effective gonadotropins.
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