OVULATION DISORDERS: HOW TO REMEDY THEM

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Ovulation disorders, according to the World Health Organisation, affect approximately 25% of infertility diagnoses, and 70% of women with chronic anovulation are affected by polycystic ovary syndrome (PCOS). Chronic anovulation is a situation characterised by the constant presence of anovulatory cycles, a physiological condition in the post-pubertal and peri-menopausal period but not during a woman's fertile life. A history of regular, cyclic menstrual cycles with premenstrual symptoms (e.g. breast tension, fluid retention) is sufficient to establish the existence of ovulation. Anovulation should be suspected when menstrual cycles occur irregularly, with cycles shorter than 21 days or longer than 35 days, or if the patient reports abnormal uterine bleeding or amenorrhoea. Ovulation generally occurs 14 days before the start of menstruation. When the menstrual history is unclear or inadequate, ovulation can be documented by means of the post-ovulatory serum progesterone level obtained in the expected mid-menstrual phase, approximately 1 week before the expected menstruation. It is also important to assay oestradiol and LH at the presumed ovulation to verify the peak of these hormones. A useful diagnostic tool remains transvaginal pelvic ultrasound, which makes it possible to recognise the presence of growing periovulatory follicles or the presence of the corpus luteum. The most common cause of anovulation is polycystic ovary syndrome (PCOS), which affects 70% of women with anovulation. Obesity itself is associated with anovulation independently of PCOS; women with a body mass index (BMI) greater than 27 have a higher risk of anovulatory infertility than women with a normal BMI both because of disruptions to the hypothalamic-pituitary axis and because adipocytes act as a true endocrine organ leading to alterations in the woman's hormonal balance. Other causes include thyroid diseases (2%-3%), diseases of the pituitary gland (e.g. prolactinoma, 13%), elevated androgen levels from adrenal hyperplasia or adrenal tumour (2%), idiopathic chronic anovulation (7%-8%) and functional hypothalamic amenorrhoea (e.g. due to underweight, eating disorders and excessive exercise). Patients with eating disorders present anovulatory infertility more often than women without eating disorders. Chronic anovulation can lead not only to menstrual irregularities in duration and quantity but also to amenorrhoea. There are two types of amenorrhoea, primary amenorrhoea, defined as the lifelong absence of menstruation, requires evaluation if menarche has not occurred by the age of 16-18 years or three years after telarche; and secondary amenorrhoea, that which involves the anovulatory cause, which is characterised by the cessation of previously regular menses for three months or previously irregular menses for six months and requires evaluation. Aetiologies of amenorrhoea may include abnormalities of the efflux tract, primary ovarian insufficiency, hypothalamic or pituitary disorders, other disorders of the endocrine glands, and sequelae of chronic, physiological or induced diseases. The anamnesis should include the onset and course of menstruation, eating and exercise habits, the presence of psychosocial stressors, changes in body weight, drug use, galactorrhoea and chronic diseases. Further questions may concern neurological, vasomotor, hyperandrogenic or thyroid-related symptoms. Besides pregnancy, functional amenorrhoea and PCOS are the most common causes of secondary amenorrhoea.

Understanding the clinical signs and symptoms of each diagnosis in the differential and laboratory examinations (in the evaluation of the hormonal picture: LH, FSH, oestradiol, androgens, progesterone, prolactin, cortisol, thyroid hormones) to confirm or exclude a diagnosis allows the patient to be advised and treated appropriately. Once the cause has been identified, treatment is proposed, which for obvious reasons is very variable as it can be based on pharmacological therapy, behavioural measures such as an adjustment of the diet or the proposal of psychological support. In some cases it is necessary to increase the caloric intake, such as amenorrhoea due to excessive exercise or underweight with BMI < 19, in the diametrically opposite cases such as single obesity or obesity associated with PCOS, it is necessary to reduce the caloric intake by fine-tuning the distribution of fat and carbohydrate intake. As for the pharmacological approach, two oral drugs are used for ovulation induction. Clomiphene citrate is a selective oestrogen receptor modifier that blocks the negative feedback effect of circulating oestradiol and causes an increase in the frequency and pulsatility of hypothalamic gonadotropin-releasing hormone (GnRH) release and the subsequent production of pituitary FSH and luteinising hormone (LH), promoting ovarian follicular growth. Letrozole blocks aromatase, reducing serum oestradiol concentrations and stimulating pituitary gonadotropins. Both clomiphene citrate and aromatase inhibitors have lower multiple pregnancy rates than 10%, most of which are twin pregnancies. Alternatively, in cases where there is no desire for pregnancy, the therapeutic proposal is based on the use of oral contraceptive pills for the sole purpose of restoring menstruation or improving bone mineral density.

These oral ovulation-inducing agents are less useful in women with hypogonadotropic hypogonadism, who may show limited or no response to endogenous pituitary gonadotropins. In these patients, the use of pulsatile administration of GnRH restores physiological stimulation of endogenous FSH and LH with the aim of inducing follicular maturation and ovulation. The pulse frequency is adjusted to mimic the physiological variation in GnRH pulses. Treatment with pulsatile GnRH results in pregnancy rates from 93% to 100% after a maximum of 6 months and is well tolerated with no reported cases of severe ovarian hyperstimulation syndrome. Alternatively, exogenous gonadotropins can be used to directly stimulate ovarian follicles. In women with hypogonadotropic hypogonadism, intrinsic ovulatory dysfunction requires the use of an exogenous ovulatory trigger.

As for hypothalamic amenorrhoea, on the other hand, which is sustained by a defence mechanism and not a pathology, in patients who tend to hypoalnourish themselves and engage in intense physical activity, the focus is placed as a therapeutic proposal on the dietary regimen and encouraging a reduction if not suspension of physical activity, while also proposing psychological support. Stress in fact, both physical and psychological, is a determining factor in hypothalamic amenorrhoea, which sooner or later induces an alteration in the neuroendocrine modulation of the hypothalamic-pituitary-ovarian axis. In addition to these behavioural measures, Naltrexone can be proposed, since opioidergic hypertone is the main pathogenic mechanism, for a period of 3-6 months: in many cases a return of regular menstrual activity is achieved. One can also use L-acetyl-carnitine, which can modulate the activity of the various neurotransmitters involved in central stress. If the requirement is only the restoration of menstrual cyclicity and a contraceptive desire is associated in the patient, oral contraceptive therapy can also be proposed, which protects against the risks of hypoestrogenism.

 

References

Catherine M Gordon, et al. Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017 May 1;102(5):1413-1439. doi: 10.1210/jc.2017-00131.

Christou F, Pitteloud N, Gomez F. The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea. Gynecol Endocrinol. 2017;33(8):598–601. doi:10.1080/09513590.2017.1296948

David A. Klein, et al. Amenorrhea: A Systematic Approach to Diagnosis and Management. Am Fam Physician. 2019;100(1):39-48

Erica Silvestris, et al. Obesity as disruptor of female fertility. Reprod Biol Endocrinol. 2018 Mar 9;16(1):22. doi: 10.1186/s12958-018-0336-z

Sandra Ann Carson, et al. Diagnosis and Management of Infertility: A Review. JAMA. 2021 Jul 6;326(1):65-76. doi: 10.1001/jama.2021.4788