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in women of child-bearing age interested in subsequent fertility due to potential long-term teratogenicity.
In summary, hypothalamic hypogonadism is one of the most common causes of secondary amenorrhea and most frequently results from an energy imbalance involving either caloric restriction or over energy expenditure. After the diagnosis has been established and other organic causes ruled out, frst-line therapy involves lifestyle modifcation to address the underlying pathophysiology. If endogenous GnRH pulsatility cannot be restored, fertility issues can be achieved with either oral ovulation induction agents or injectable gonadotropins. Last but not least, potential bone loss can be addressed via hormone replacement therapy.
References
1.\ Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. 2005;366(9479):74–85.
2.\ Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, et al. Functional hypothalamic amenorrhea: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1413–39.
3.\ Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170(1):3–11.
4.\ Perkins RB, Hall JE, Martin KA. Aetiology, previous menstrual function and patterns of neuro- endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea. Hum Reprod. 2001;16(10):2198–205.
5.\ Golden NH, Jacobson MS, Schebendach J, Solanto MV, Hertz SM, Shenken IR, et al. Resumption of menses in anorexia nervosa. Arch Pediatr Adolesc Med. 1997;151(1):16–21.
6.\ Michopoulos V, Mancini F, Loucks TL, Berga SL. Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial. Fertil Steril. 2013;99(7):2084–91.
7.\ Blais MA, Becker AG, Burwell RA, Flores AT, Nussbaum KM, Greenwood DN, et al. Pregnancy: outcome and impact on symptomatology in a cohort of eating-disordered women. Int J Eat Disord. 2000;27(2):140–9.
8.\ Misra M, Katzman DK, Estella NM, Eddy KT, Weigel T, Goldstein MA, et al. Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial. J Clin Psychiatry. 2013;74(8):765–71.
9.\ Ackerman KE, Singhal V, Baskaran C, Slattery M, Campoverde Reyes KJ, Toth A, et al. Oestrogen replacement improves bone mineral density in oligo-amenorrhoeic athletes: a randomised clinical trial. Br J Sports Med. 2019;53(4):229–36.
Chapter 15
Endometriosis and Infertility
Glenn Schattman
Case
A 29-year-old G0 female presents for a second opinion regarding her infertility. She states that she and her husband have been trying to conceive for the last year and ideally would like two children. Her gynecologist gave her clomiphene citrate for three cycles, and she failed to become pregnant. She was then referred to a local reproductive endocrinologist for further evaluation and treatment. Her work-up revealed an anti-Mullerian hormone (AMH) level of 4.3 ng/mL. A hysterosalpingogram (HSG) showed normal uterine cavity, right distal tubal obstruction without hydrosalpinx, and a patent left fallopian tube with possible peri-tubal adhesions. Her husband had a normal semen analysis. Pelvic ultrasound revealed a 4 cm right ovarian complex cyst that was most compatible with an endometrioma. Additionally, the report revealed some limited mobility of the pelvic organs consistent with pelvic endometriosis and adhesions. Her antral follicle count was approximately 25 on the left ovary, and but there were just a few scattered follicles surrounding the complex cyst on the right. On being further questioned, she remembered that at age 19 she suffered from severe dysmenorrhea and deep dyspareunia for which she was placed on birth control pills. Some relief was observed.
She was advised to proceed directly to in vitro fertilization (IVF) by her local infertility specialist to bypass the tubal factor, which was likely related to adhesive disease from endometriosis. On her rst cycle, she had 14 oocytes retrieved. She was told that there was some dif culty getting access to the left ovary, and there was no oocyte retrieved from the right ovary due to the cyst. She was given a dose of IV antibiotics as there was some dark-colored fuid aspirated during the retrieval from
G. Schattman (*)
Reproductive Medicine and Ob/Gyn, The Ronald Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Medical College of Cornell University, New York, NY, USA e-mail: glschatt@med.cornell.edu
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P. H. Chung, Z. Rosenwaks (eds.), Problem-Focused Reproductive Endocrinology and Infertility, Contemporary Endocrinology, https://doi.org/10.1007/978-3-031-19443-6_15
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the left ovary. Of the 14 oocytes retrieved, all were mature and ten fertilized normally with standard insemination. Only two embryos developed to the blastocyst stage, and both were biopsied and cryopreserved for preimplantation genetic testing for aneuploidy (PGT-A). PGT-A results later revealed that only one embryo was euploid; it was transferred but did not result in any pregnancy.
The patient presented to our of ce for a second opinion and to discuss her options. Given the size of the cyst and possibly a more severe form of endometriosis, she was advised to undergo laparoscopy to remove the cyst and evaluate/treat any pelvic disease before IVF. At surgery, she was noted to have stage 4 endometriosis with pelvic adhesions and diffuse endometriotic lesions. After lysing adhesions and removing visible disease as well as resecting the right ovarian cyst, bilateral tubal patency was also restored and con rmed on chromotubation. After surgery, she was encouraged to become pregnant naturally. After timed intercourse for 4 months, she successfully conceived and subsequently delivered a healthy full-term infant.
Discussion
Endometriosis is a common disease found in as many as 25–50% of women with infertility and up to 80% of patients with pelvic pain [1]. Whether endometriosis reduces fecundability remains controversial, although the patient described above clearly has both symptomatic endometriosis and infertility. Mechanisms for endometriosis-associated infertility include altered tubal function, altered peritoneal environment affecting ef cient ovum pick up and tubal transport, impaired fertilization, ovulatory disorders with altered luteal hormone production, impaired implantation, and poor oocyte/embryo quality [2]. It is important to note that the actual mechanisms of these hypothetical etiologies for infertility remain unproven. This couple’s infertility appears to be related to her tubal obstruction and adhesions, likely a result of the infammatory condition secondary to the endometriosis. In infertile patients with no evidence of tubal disease and an otherwise normal evaluation, diagnostic laparoscopy to look for endometriosis is not warranted. Even if endometriosis is found, the improvement in monthly fecundability is not clinically signi cant. Two randomized controlled trials [3, 4] attempted to address if asymptomatic infertile patients with minimal or mild endometriosis (the stage of disease most commonly found at diagnostic laparoscopy in this population) would bene t from surgical ablation or excision. However, since only about 30% of asymptomatic infertile patients were noted to have endometriosis, and fewer yet will have stage 1–2 (minimal-mild) disease, the actual number of laparoscopies needed to be performed for each additional pregnancy is approximately 40! [2] Thus, diagnostic laparoscopy for unexplained infertility is not indicated.
More advanced disease, as described in our patient who had a 4 cm endometrioma, pelvic pain, and less mobile pelvic organs, is an entirely different clinical condition which should require surgery, not only for symptom relief and fertility improvement but also for pathology of the cyst to be established [5]. Laparoscopy
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not only restored pelvic anatomy by removing the endometrioma, it also relieved tubal obstruction, allowing for normal conception to occur. It should be emphasized, however, surgical removal of endometriomas should be performed carefully so that normal ovarian cortical tissues will not be damaged.
Medical therapy, such as hormone suppression using a GnRH agonist, GnRH antagonist or androgen therapy will only serve to delay conception and has not been shown to improve fecundability. Therefore, it has no role in treating endometriosis- related infertility.
Since de nitive or pathological diagnosis of endometriosis in asymptomatic patients requires a diagnostic laparoscopy with biopsy, one should be cognizant of the fact that some patients with unexplained infertility may in fact have endometriosis. If the infertility evaluation is otherwise normal, conventional treatments with ovulation induction and intrauterine insemination (IUI) are rst indicated. The number of treatment cycles will depend on the age of the patient. Patients with diminished ovarian reserve or are older than age 35 should not procrastinate or delay treatment and should consider undergoing IVF right away or if IUI is not successful after 3 cycles.
In the patient described above, with the 4 cm adnexal mass and tubal disease, surgery rather than IVF should have been the rst treatment route. Because tubal disease associated with her endometriosis is the most likely cause for her infertility, surgical intervention would restore her ability to conceive spontaneously. Her pelvic pain was also alleviated although pain relief in these patients is often only temporarily relieved by surgery. Success with IVF rst without surgery would be limited in our patient due to her distorted anatomy which reduced access to her ovaries, resulting in fewer oocytes retrieved and fewer embryos available for selection for transfer. Her chances were further impacted upon by mandatory PGT-A which is not advantageous in women younger than 35 (see Chap. 32).
Even if the anatomy cannot be fully restored at the time of laparoscopy, surgery often improves symptoms and ovarian access when IVF is performed. There is no role for aspiration of endometriomas either before stimulation or at the time of oocyte retrieval, as these are very likely to recur in a short period of time. Aspiration can increase the risk of infection and will not improve ovarian response to stimulation or overall pregnancy rates [6]. Medical treatment following surgery has not been shown to improve IVF outcomes either and, as mentioned previously, will only serve to delay attempts at pregnancy. This is especially critical for older patients with an already compromised ovarian reserve.
There has been some interest in pretreating endometriosis patients who have failed to conceive in a prior IVF cycle with a GnRH agonist for 3–6 months. This treatment is based on the theory that endometriosis negatively affects oocyte quality and endometrial receptivity. Therefore it is thought that creating a hypo-estrogenic state to debulk disease may reverse this effect. Although a meta-analysis showed improved clinical pregnancy rates in the treatment arm, the extremely high rates of live births in the treatment and control groups in two of the studies make the results of this meta-analysis more dif cult to interpret [7]. Further studies are needed before GnRH-a treatment prior to IVF can be routinely recommended for women with endometriosis, even in those who have had a prior failed IVF cycle.
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