This chapter should be cited as follows:
Ata B, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421123

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 15

Reproductive medicine for the obstetrician and gynecologist

Volume Editors: Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS

Published in association with the
International Federation of
Fertility Societies

Chapter

Therapies for the Female

First published: November 2024

Study Assessment Option

By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
See end of chapter for details

INTRODUCTION

Spontaneous pregnancy occurs by fertilization of a competent oocyte by a competent sperm in the ampullary portion of the Fallopian tube. The embryo develops in the Fallopian tube to the blastocyst stage during the first 5–6 days of fertilization and eventually reaches the endometrial cavity. There, the hatched blastocyst implants in a receptive endometrium, a status, which the endometrium only attains for a limited period that coincides with the time when the embryo arrives in the endometrial cavity, i.e., 5th–7th days postovulation. Disruptions in any of these steps decrease the probability of a pregnancy and lead to infertility.

Certain causes of infertility are relatively easy to diagnose, such as oligo-anovulation, tubal blockage, uterine anomalies or abnormalities in semen analysis, such as low progressive motile sperm count. However, in a substantial proportion of couples presenting with infertility none of these are present and this is called “unexplained infertility”.¹ Clearly, there are other factors contributing to infertility, and the current assessment technologies are short of diagnosing many problems at the molecular level. Yet, since we cannot diagnose and treat them, the term “unexplained infertility” is still used, and, in practice, it helps the couple to explain that “unexplained infertility” does not mean “everything is normal” but the reason for infertility is not oligo-anovulation, tubal blockage, uterine anomalies or low motile sperm count. It is important to also note that each and every gamete does not have the potential for live birth, and the leading cause is meiotic errors. Oocyte meiotic errors increase with female age, which is a strong marker of female fertility. Fecundity declines with increasing age. The term unexplained infertility may be appropriate until the age of 40 years, and perhaps “age-related fertility decline” would be more appropriate after then.²

In the presence of an obvious etiology for infertility, the treatment aims to rectify or bypass it. Examples are ovulation induction for the anovulatory patient, i.e., rectifying anovulation, or employing in vitro fertilization (IVF) for tubal blockage, i.e., bypassing the blocked tubes. These may be called rational therapies. Whereas the management of unexplained infertility mainly depends on increasing the numbers of gametes to increase the probability of pregnancy, such as in an ovarian stimulation & intrauterine insemination (IUI) cycle or in vitro fertilization cycle.¹ Importantly, the latter does not only increase the number of gametes available for fertilization but also bypasses multiple steps in the fertilization process.

Since the definition of infertility, assessment of an infertile patient or couple, surgical management of tubal or uterine pathology, therapies for male factor, IUI and IVF are covered in other chapters, this chapter focuses on the management of ovulatory disorders.

Oligo-anovulation is invariably characterized by oligo-amenorrhea. The World Health Organization categorization of ovulatory disorders depends on the serum concentrations of endogenous follicle stimulating hormone (FSH), estradiol (E2) and prolactin (PRL).³ There are three categories numbered as WHO1, WHO2, and WHO3. WHO1 is hypogonadotropic hypoestrogenic anovulation, where the underlying pathology is at the hypothalamo-pituitary level. The follicles cannot grow to ovulation due to the absence of adequate follicle stimulating hormone (FSH). WHO2 is named normogonadotropic normoestrogenic and almost always includes women with polycystic ovarian syndrome (PCOS). WHO3 is hypergonadotropic hypoestrogenic anovulation, where the primary pathology is of ovarian origin, i.e., premature ovarian insufficiency in reproductive aged women. Women who are oligo-anovulatory due to hyperprolactinemia do not fall into any of these categories. While the International Federation of Gynecology and Obstetrics (FIGO) has recently proposed a new and more detailed classification system for ovulatory disorders, the WHO system will be followed in the current chapter since the former is not in widespread use yet and most other resources on the management of anovulation follow the latter.⁴

THE PURPOSE OF OVULATION INDUCTION

The term ovulation induction refers to interventions for restoration of monofollicular development and monoovulation in oligo-anovulatory women. The distinction between monofollicular and multifollicular development is crucial and cannot be overstated. This is due to the fact that the two complications of ovulation induction, namely multiple pregnancies and ovarian hyperstimulation syndrome (OHSS), both of which result from multifollicular development. Multiple pregnancy and associated preterm delivery are among the leading reasons of neonatal death and disability. Clearly the risk of multiple pregnancy, including high order multiples, rise in parallel to the number of growing follicles in an ovulation induction cycle. Currently, reckless ovulation induction is the leading cause of multiple pregnancy since the number of embryos transferred in an IVF cycle is controlled and single embryo transfer is becoming the norm.⁵ On the other hand, OHSS is a potentially lethal iatrogenic complication characterized by increased vascular permeability leading to hemoconcentration and possible thromboembolic complications. OHSS occurs due to increased production of vasoactive substances from multiple luteinized follicles and when pregnancy occurs, endogenous human chorionic gonadotropin (hCG) from the trophoblasts continues to stimulate multiple corpora lutea to increase the duration and severity of OHSS.⁶ Both risks are unjustifiable for an otherwise healthy infertile woman, since they can almost always be prevented with careful medical practice.

Follicular growth during ovulation induction is monitored by transvaginal ultrasound examinations and, when necessary, with serum E2 levels, and it is always possible to recognize multifollicular growth and take necessary actions to prevent it, including cancelation of the cycle. The latter sounds hard to swallow but is always better and safer than facing multiple pregnancy or OHSS.

OVULATION INDUCTION FOR HYPOGONADOTROPIC HYPOESTROGENIC ANOVULATION

Once the diagnosis of hypogonadotropic hypoestrogenic anovulation is made, the underlying reason needs to be identified to plan management. The new FIGO acronym GAIN–FIT, which stands for Genetic, Autoimmune, Iatrogenic, Neoplasm and Functional, Infectious/inflammatory, Trauma & Vascular can help to plan the differential diagnosis.⁴ Accompanying symptoms and findings also help for diagnosis. For instance, a lower than normal body mass index, history of excessive weight loss or exercise can suggest functional hypothalamic amenorrhea, whereas galactorrhea points towards a prolactinoma. The use of antidopaminergic antipsychotics may be the underlying reason for hypogonadotropic hypoestrogenic anovulation. Clearly a detailed history and focused physical examination are essential before starting ovulation induction. The differential diagnosis must exclude a central nervous system neoplasm with cranial magnetic resonance imaging when necessary.

In the presence of an underlying reason its treatment often restores ovulation, and no further treatment may be warranted. It is also important to ensure maternal well-being prior to fertility promoting treatment. In case of functional hypothalamic amenorrhea, behavioral treatment can resolve anovulation as well as restore maternal body weight prior to a pregnancy. Ovulation induction should be done after restoring normal body mass index.⁷

Hyperprolactinemia is simply managed by dopamine agonists and cabergoline is usually the first choice due to its favorable side-effect profile. A weekly single dose of 0.5 mg orally, or 0.25 mg twice a week rapidly normalizes prolactin levels in about 90% of patients.

In other cases, ovulation can be restored by pulsatile gonadotropin releasing hormone agonist treatment; however, it is a cumbersome method which is rarely used in common practice. It should be noted that the GnRH pump will almost invariably provide monofollicular development even without monitoring and can be regarded the safest approach where available and affordable. Ovulation induction with either exogenous FSH and luteinizing hormone (LH) administration or human menopausal gonadotropins (hMG), which includes hCG to provide LH-like activity is the mainstay of treatment for patients with hypogonadotropic hypoestrogenic anovulation without another treatable underlying pathology. Hormonal stimulation can start right away since these patients are hypoestrogenic and have a thin endometrium. However, after longstanding hypogonadism and amenorrhea, priming the endometrium with two cycles of sequential estrogen and progesterone may be considered. Induction should start with a low dose of gonadotropins, typically 75 IU/day to avoid multifollicular growth.⁷ Response to stimulation is monitored with serial ultrasound examinations and serum estradiol levels as necessary. In the absence of follicular growth after a week on stimulation the dosage is cautiously increased stepwise, traditionally by increments of 37.5 or 75 IU/day. When a dominant follicle >10 mm emerges, the same dosage is continued until the follicle reaches preovulatory diameter of 18–20 mm, when ovulation is triggered with hCG. There is no agreement regarding the dosage of hCG for trigger but 5000 IU suffices. The couple can be advised to have intercourse on the day of the trigger and 36–48 hours later.

If no dominant follicle emerges despite stimulation with a daily gonadotropin dosage of 225 IU, the cycle is canceled and the next cycle can be commenced with a higher initial dosage, i.e., if the starting dosage was 75 IU/day, the new cycle can be commenced with 112.5 or 150 IU/day.

Coadministration of growth hormone (GH) is reserved for women with hypopituitarism. GH can increase follicles' sensitivity to gonadotropins. Recommended dosage is 24 IU every other day or 12 IU daily.⁷

In case of multifollicular growth, it is best to cancel the cycle by stopping further stimulation and withhold the hCG trigger. The patient must be advised to avoid intercourse or employ strict contraception until after the demise of the growing follicles. A subsequent cycle should be started with a lower daily gonadotropin dose to achieve monofollicular growth.

While the hCG used to trigger ovulation would be expected to sustain the corpus luteum, which is essential for continuation of an ensuing pregnancy, many practitioners employ luteal phase support with vaginal progesterone administration in varying dosages and durations to cover for the period between the weaning of hCG effect and placental takeover of progesterone production around the 7th gestational week. The author prefers 300 mg/day vaginal micronized progesterone until the completion of the 8th gestational week. While 1500–2500 IU hCG twice a week can be used to sustain corpus luteum, it would be difficult to assess pregnancy afterwards as it would affect serum hCG levels.

High cumulative live birth rates over 6–12 ovulation induction cycles have been reported; however, with wide variation, e.g., 65–89%, with relatively high pregnancy loss rates between 23 and 32% and multiple pregnancy rates around 30%.^8,9,10,11

While the principles are simple, ovarian stimulation for hypogonadotropic hypoestrogenic anovulation can be complex and is best undertaken by fertility specialists with experience in gonadotropin use.

OVULATION INDUCTION FOR NORMOGONADOTROPIC NORMOESTROGENIC ANOVULATION

The vast majority of patients in this category are women with PCOS. The first-line management of PCOS associated oligo-anovulation is lifestyle modifications for obese patients.¹² Oral glucose tolerance test should be recommended to women with PCOS regardless of the body mass index (BMI) as part of the preconceptional assessment.¹² Weight loss alone can address metabolic problems as well as oligo-anovulation in these patients. Achieving a BMI by preferentially a multimodal approach including healthy eating and increased physical activity also decreases the risks of obstetric complications such as gestational diabetes.

Oral antiestrogens, i.e., letrozole or clomiphene citrate are the first-line agents for medical ovulation induction if an obese patient remains oligo-anovulatory despite weight loss, and for nonobese PCOS patients.^12,13 They both increase endogenous FSH levels through different mechanisms. Letrozole is suggested to be the first-line pharmacological treatment for ovulation induction in PCOS, as it has been unequivocally shown to provide higher rates of live birth regardless of BMI.^12,14 The choice depends on availability and affordability of letrozole for ovulation induction, which is used off label for this indication. It should be noted that clomiphene is also off label for ovulation induction in some countries. Both letrozole and clomiphene citrate are more effective than metformin for ovulation induction.¹²

Ovulation induction with letrozole or clomiphene are similar in the method of administration. Either agent is given for 5 days, and follicle growth is monitored 3–4 days after the last dose to see if there is a growing follicle. The starting dose for letrozole is often 2.5–5 mg/day, for clomiphene it is 50–100 mg/day. Multifollicular growth is rare with letrozole but may occur more often with clomiphene. Moreover, clomiphene has a less favorable side-effect profile which may even include temporary loss of vision, so starting with the lower dose is better. Since PCOS patients are almost constantly in the follicular phase, induction can start at any time without inducing a withdrawal bleeding.^15,16 However, if the patient presents in the luteal phase, e.g., presence of a corpus luteum, hyperechogenic endometrium, which can be confirmed with serum progesterone levels upon suspicion, the period should be awaited to start induction to avoid embryonic exposure to stimulation agents in the case of a pregnancy.

Once a dominant follicle is confirmed, ovulation trigger with hCG is not mandatory and ensuring adequate coital exposure around the expected time of ovulation will suffice. However, if an IUI is planned, trigger would enable proper timing. If the patient ovulates but does not achieve a pregnancy she would have a period about 3 weeks after the last pill. If she does not, a pregnancy test is required. Having a period essentially confirms ovulation.

In the absence of follicular response to the starting dose, manifested as the lack of follicular growth during monitoring or a negative pregnancy test despite missing a period, the dosage can be increased to the next step, either for the new cycle or in the same cycle. The latter is defined as the stairstep protocol, the next dosage is given for another 5 days without inducing a withdrawal bleeding.¹⁷ The increments are 2.5 mg/day for letrozole and 50 mg/day for clomiphene. Doses of 10 mg/day letrozole and 250 mg/day clomiphene are considered maximal, and if a patient remains anovulatory despite these dosages second-line methods, such as gonadotropins or ovarian drilling can be considered.¹² However, both second-line interventions require expertise since they are significantly more costly and complication prone than first-line oral antiestrogens.

Overall, letrozole provides significantly higher cumulative live birth rates than clomiphene across all categories of BMI (relative risk of 1.49, 95% confidence interval between 1.27 and 1.74).¹⁴ Per cycle live birth rates are about 4% and 6%, with clomiphene and letrozole, respectively.¹⁸ Pregnancy loss rates per pregnancy are similar at around 20% with both drugs.¹⁴ Likewise, multiple pregnancy rates are similar with both drugs.¹⁴

Gonadotropins must be used in a strict low-dose step up protocol, even a chronic low-dose step up protocol.¹² Low-dose step up protocol involves starting a daily gonadotropin dosage of 75 IU/day or less, depending on clinical judgement. Response should be assessed no later than the 7th day of stimulation and dose increments should not be undertaken earlier than 7-day intervals. In the chronic low-dose step up protocol the first increment is done after the 14th day of stimulation in the absence of a dominant follicle. The major risk is multifollicular growth and multiple pregnancy. The cycle should be canceled if more than two follicles >14 mm emerge and the patient should be advised to strictly avoid unprotected intercourse until after ovulation. The maximal dosage is traditionally defined as 225 IU/day which contributes significant cost to the treatment. The decision to use gonadotropins should be only undertaken following a detailed discussion of anticipated pregnancy rates and cost of treatment per cycle including medication and monitoring. Currently, gonadotropin ovulation induction for PCOS is best undertaken only in fertility units with sufficient expertise.

Laparoscopic ovarian drilling induces ovulation by decreasing intraovarian androgen production through destruction of ovarian tissue. The surgical procedure is not without risks, notably periovarian adhesion formation which may interfere with fertility. Rendering the patient ovulatory for a prolonged period of time rather than for just one cycle as with medical ovulation induction can be regarded as an advantage; however, the invasive nature of the intervention, loss of ovarian tissue, surgical risks and costs have led ovarian drilling to lose its popularity and it is very rarely applied if at all.¹²

The maximum number of ovulatory cycles without achieving a live birth depends on the resilience of the patient and the treating physician. At least for letrozole, the first five ovulatory cycles provide similar chances of live birth.¹⁸ The latest guidelines suggest after 6–9 cycles the patient can proceed to assisted reproductive technology, since intrauterine insemination does not improve the chances of conception as long as the semen parameters are within normal limits.¹²

Ovulation induction for hypergonadotropic hypoestrogenic anovulation

The primary pathology is the lack of ovarian follicles and these patients are characterized by elevated endogenous FSH levels. Obviously, there is no room for ovulation induction for hypergonadotropic hypoestrogenic anovulation. Depending on their menopausal status, these patients can be best served by assisted reproductive technology if they are relatively young and still have occasional ovulations, i.e., patients with premature ovarian insufficiency. Patients with premature ovarian insufficiency should undergo genetic assessment including a karyotype and fragile X premutation screening.¹⁹ Karyotype abnormalities and fragile X premutation have different implications, which need to be discussed in advance with the patient. Detection of Y chromosome would require gonadectomy, whereas the presence of fragile X premutation would require screening of other family members and possibly embryos to prevent affected children/grandchildren.¹⁹ Primary ovarian insufficiency (POI) can manifest as part of autoimmune polyglandular syndromes (APGS), which are characterized by failure of multiple endocrine organs due to autoimmune damage. Women with otherwise unexplained POI should be tested for anti-thyroid peroxidase antibodies and anti-21 hydroxylase antibodies (or alternatively adrenocortical antibodies) as they are likely to have autoimmune hypothyroidism and adrenal failure can follow POI in a few years in women with APGS. Positivity of anti-thyroid peroxidase would require measurement of serum thyroid stimulating hormone levels, and presence of anti-21 hydroxylase (or adrenocortical) antibodies would require referral to an endocrinologist to check for adrenal insufficiency.¹⁹

Oocyte donation, wherever it is allowed and accessible, is often the only realistic treatment option as of now.

PRACTICE RECOMMENDATIONS

Online Study Assessment Option
All readers who are qualified doctors or allied medical professionals can now automatically receive 2 Continuing Professional Development credits from FIGO plus a Study Completion Certificate from GLOWM for successfully answering 4 multiple choice questions (randomly selected) based on the study of this chapter.
Medical students can receive the Study Completion Certificate only.

 

(To find out more about FIGO’s Continuing Professional Development awards programme CLICK HERE)

 

I wish to proceed with Study Assessment for this chapter