92 |
O. Davis |
References
1.\ Munster K, Schmidt L, Helm P. Length and variation in the menstrual cycle- a cross-sectional study from a Danish county. Br J Obstet Gynaecol. 1992;99:422.
2.\ Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. Br Med J (Clin Res Ed). 1984;88:7–9.
3.\ Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L, ESHRE Working Group on Poor Ovarian Response De nition. ESHRE Consensus on the de nition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):616–24.
4.\ WHO. Laboratory manual for the examination and processing of human semen. 5th ed. Geneva: WHO; 2010.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Chapter 14
Hypothalamic Hypogonadism
David Reichman
Case
A 28-year-old G1P1 presents to her gynecologist with no menses over the last 4 months. She was previously trying to conceive for about 15 months and is distraught about the impact her lack of menses may have on her fertility. A home urine pregnancy test has been repeatedly negative. Her gynecologic history is notable for previously cyclic menses every 31–33 days. She conceived easily and had a normal vaginal delivery of her healthy daughter 4 years ago. She breastfed for 1 year and had resumption of menses when her child was 6 months of age. Her past medical history is notable only for mild gastroesophageal re ux and a 2-year history of anorexia in college, which resolved through psychological therapy and working with a nutritionist. Her only surgery was wisdom teeth removal as a teenager. She has recently suffered the death of her mother who had a long battle with small-cell lung cancer.
On exam, the patient is well appearing and in no distress. She is 5′8″ tall and weighs 120 lb (BMI 18.24 kg/m2). Pelvic exam is unremarkable, and transvaginal ultrasound reveals normal uterine anatomy, a 4 mm homogenous endometrial stripe, and no adnexal masses. Several follicles were noted in each ovary in various phases of early follicular development. Serologic examination reveals an FSH of 1.6 mIU/ mL, LH of 2.1 mIU/mL, E2 of 25 pg/mL, and P4 of 0.2 ng/mL. Serum bhCG level is negative. Anti-Mullerian hormone level is 3.5 ng/mL. Thyroid function, prolactin level and serum androgens are within normal limits.
On further discussion with the patient, she reports that she has been exercising daily to help cope with her grief from her mother’s death. She has been taking four vigorous cycling classes, three Pilates sessions, and jogging 20 miles/week. About
D. Reichman (*)
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: der2005@med.cornell.edu
© Springer Nature Switzerland AG 2023 |
93 |
P. H. Chung, Z. Rosenwaks (eds.), Problem-Focused Reproductive Endocrinology and Infertility, Contemporary Endocrinology, https://doi.org/10.1007/978-3-031-19443-6_14
94 |
D. Reichman |
8 months ago she initiated a new diet that involves eating only an avocado for breakfast, a vegetarian salad for lunch, and a protein with steamed vegetables for dinner. We discussed with her a diagnosis of functional hypothalamic amenorrhea and various ways to address the causes of the dysfunction. After several months of increased caloric intake and reduced exercise regimen, the patient resumed menses which were occurring every 30–40 days. To ensure regular ovulation, she was started on monthly low-dose clomiphene citrate (50 mg day 3–7) and was monitored by blood work and ultrasound each cycle. Human chorionic gonadotropin (hCG) trigger was given when follicles were mature. Timed intercourse instructions were reviewed. She conceived after 3 months of such treatment.
Discussion
Functional hypothalamic hypogonadism is one of the most common causes of secondary amenorrhea, and most frequently originates from low energy availability due to a combination of inadequate caloric intake and excessive energy expenditure. The so-called female athlete triad refers to excessive exercise/disordered eating, irregular or absent menses, and bone mineral density loss. Such individuals may have lower circulating levels of leptin, which acts as a signal from peripheral adipocytes to the CNS to reduce gonadotropin pulsatility [1].
Organic, nonfunctional causes of hypothalamic hypogonadism (rarer than functional cases) include central mass lesions, pituitary infarction, prior pituitary surgery, or prior infection or radiation. Such causes frequently present with panhypopituitarism rather than the isolated hypogonadism like our patient illustrated above. Regardless of etiology, hypothalamic hypogonadism is characterized by decreased GnRH pulsatility, abnormal or absent follicular development, and insuffcient mid-cycle luteinizing hormone levels, leading to anovulation and associated low estradiol levels.
Diagnosis of hypothalamic hypogonadism is triggered by the presence of amenorrhea or oligomenorrhea with associated low serum levels of FSH, LH, and estradiol. History should focus on precipitating factors such as increased stress, physical exercise, decline in nutritional status, or a combination of such factors. Pertinent questions include history of eating disorders, recent weight loss, amount of exercise, psycho-social stressors, and dietary intake. The patient’s previous BMI at which she exhibited cyclic menses should be established. For a diagnosis of functional hypothalamic amenorrhea, other organic causes should frst be excluded based on history, exam, and pituitary imaging if indicated.
Biochemical testing should include human chorionic gonadotropin (hCG) to exclude pregnancy, prolactin to detect hyperprolactinemia, thyroid-stimulating hormone, and free T4 levels to exclude thyroid disease, in addition to FSH, LH, and E2. Thin women with polycystic ovary syndrome (PCOS) can present a diagnostic chal- lenge—serum androgens should be sent in the setting of clinic evidence of hyperandrogenism to help differentiate between thin-PCOS and mild hypothalamic
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
14 Hypothalamic Hypogonadism |
95 |
hypogonadism. AMH may also be useful here as it is frequently elevated in individuals with PCOS, but a high AMH is by no means diagnostic. If medical disorders triggering a hypothalamic state are suspected, complete blood counts, in ammatory markers (ESR, CRP), and basic metabolic panel should also be done.
Dynamic testing is not required to make the diagnosis but can be a low-cost modality for determining whether PCOS or functional hypothalamic hypogonadism is a more likely diagnosis. Failure to exhibit a withdrawal bleed to a progestin challenge or a thin endometrial stripe on pelvic ultrasound suggests estrogen defciency as seen in hypogonadism. Measurement of serum estradiol in conjunction with serum gonadotropins, however, often provides enough data. MRI of the pituitary is indicated in women with hyperprolactinemia, unexplained hypogonadotropic hypogonadism, or localizing CNS symptoms, such as new onset headaches or visual changes. Bone mineral density assessment should be conducted in patients with >6 months amenorrhea or those in whom severe malnutrition is suspected.
Treatment in patients with functional hypothalamic hypogonadism should focus on anovulatory infertility (if patients desire conception), and consequences of hypoestrogenemia such as sexual dysfunction and low bone mineral density [2]. Once a diagnosis is confrmed, primary management should involve counseling the patient regarding the underlying condition’s pathophysiology and how it can be addressed through lifestyle modifcations. Often this means educating patients regarding target body weight goals and adequate caloric intake for the amount of energy being expended on a daily basis. Reduction in exercise intensity, duration, and frequency, along with dietary changes to increase caloric intake, is often suffcient to bring about resumption of menses [3]. Individuals who have a BMI <18.5 kg/ m2 and exhibit secondary amenorrhea should be instructed to increase caloric intake and decrease exercise so as to re-attain normal BMI and the weight at which they previously exhibited cyclic menses [4]. It is important to convey to signifcantly underweight patients that it can take several months even after achieving a normal BMI for menses to resume [5]. Return to menses sometimes requires patients to attain a weight greater than what they previously had when cyclic menses occurred.
In cases where functional hypothalamic hypogonadism is due, at least in part, to disordered eating, a multidisciplinary approach involving a psychiatrist or psychologist, a dietitian with expertise in eating disorders, and the patient’s primary physician should be employed. Cognitive behavioral therapy or family-based therapy have both shown effcacy in addressing psychological issues underpinning disordered eating such as distorted body image and prior trauma [6]. Where necessary, adjuvant treatment with pharmacologic therapy such as SSRIs can help in high- stress individuals where therapy alone is insuffcient.
Fertility is impaired in individuals with hypothalamic hypogonadism due to anovulation. Where possible, treatment should begin with the same lifestyle modifcation to increase BMI, reduce physical activity, and improve nutritional intake to allow for restoration of normal GnRH pulsatility. Overly thin patients should be apprised of the risks of conceiving and carrying a pregnancy with an extremely low BMI, which has been associated with higher miscarriage rates and low birth weight [7]. When lifestyle modifcation is inadequate or falls short of resuming normal
96 |
D. Reichman |
cyclic menstruation, as in our patient, ovulation induction agents can be used. Whereas oral agents such as letrozole or clomiphene citrate are the mainstays of ovulation induction in amenorrheic individuals with PCOS, such agents are frequently insuffcient to either induce ovulation or sustain follicular development in patients with functional hypogonadism. A trial of clomiphene citrate is reasonable in patients who do not exhibit profound gonadotropin suppression. A reasonable starting dose is 50 mg for 5 days, with careful monitoring thereafter with transvaginal ultrasonography to assess follicular development and measure serum estradiol. Frequently, such patients will mount an initial brief response that is enough to initiate follicular development but insuffcient to sustain growth or potentiate an LH surge. A human chorionic gonadotropin injection can be used to evoke follicle rupture and increase luteal production of estradiol and progesterone. However some patients will be highly sensitive to these ovulation induction agents and pose a risk of developing multiple follicles. Therefore ovarian hyperstimulation syndrome and multiple pregnancies have to be avoided by careful monitoring with ultrasound examination and blood work.
In individuals who do not mount a suffcient response to oral ovulation induction agents, or who are too profoundly suppressed to attempt a trial of oral therapy, injectable gonadotropins can be employed for follicular recruitment. Use of gonadotropins is usually combined with intrauterine insemination (IUI) or IVF. The latter has the beneft of reducing the risk of multiple gestation by allowing for single embryo transfer, with the downside, however, of being more expensive and invasive to the patient. Injectable ovulation induction (IUI) requires patience on the part of both physician and patient, with careful serologic and ultrasound monitoring so that much less robust follicular recruitment can be achieved (no more than 2–3 dominant follicles). Injectable gonadotropins carry a high risk of twins or higher-order multiple gestations, and the patient must be prepared for either cycle cancellation or conversion to IVF if too high a response is encountered. To prevent such a scenario, a “low and slow” approach to dosing should be pursued. Dosing should commence at between 50 and 75 units of FSH or combined FSH/LH per day (dependent on patient BMI and antral follicle count) and not increased until at least 5–7 days of treatment has not shown an increase in estradiol or follicular growth. As an alternative to injectable gonadotropins, a GnRH pump can be employed, but unfortunately these pumps are not commercially available in the United States.
For those patients not in pursuit of fertility, and in whom lifestyle modifcation is not curative, therapy should focus on maintenance of bone density. Patients should be encouraged to supplement with both calcium and vitamin D. This supplementation should occur in conjunction with hormone replacement therapy using transdermal estrogen and cyclic progestin. Such therapy may also enhance overall well-being indices [8]. One patch of estradiol (0.1 mg) can be changed every 96 h, with oral medroxyprogesterone 10 mg or norethindrone 5 mg taken for 10–14 days each month to induce withdrawal and protect against the hyperplasia risk of unopposed estrogen [9]. Combined oral contraceptive pills are not recommended for hormone replacement, as they are inferior in improving bone density as compared to physiologic replacement. It is important to note that bisphosphonates are contra-indicated
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/